A compound, its preparation and use

Abstract

The application provides a compound, a preparation method and use thereof, and belongs to the technical field of medicines.The structure of the compound is shown in formula I.The compound has high sedative, hypnotic and / or anesthetic effects, can control status epilepticus, and has analgesic effects, so that when the compound is used in clinical application, the use of opioid analgesic drugs such as fentanyl, alfentanil, sufentanil or remifentanil can be reduced or eliminated, thereby reducing the occurrence of adverse reactions such as circulatory depression, respiratory depression, urinary retention and skin itching of the opioid analgesic drugs.

Description

A compound, a preparation method and use thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a compound, a preparation method and use thereof. BACKGROUND

[0002] Clinically, anesthetic drugs play an important role in the induction of general anesthesia, the maintenance of general anesthesia and the sedation of ICU critical patients. Propofol is a fast and short-acting intravenous general anesthetic used in clinical practice, which has the advantages of rapid onset of anesthetic induction, rapid recovery and perfect functional recovery, and low incidence of postoperative nausea and vomiting. However, the intravenous general anesthetic drugs used in clinical practice, including propofol, etomidate, fospropofol disodium and cyclopropofol, do not have analgesic effect. If a compound has sedative, hypnotic and / or anesthetic effect, can control status epilepticus and has analgesic effect, it can achieve more perfect analgesia, significantly reduce the use amount of opioid analgesic drugs, reduce the adverse reactions of opioid analgesic drugs, and make the sedation, hypnotic and / or anesthesia process more stable. At the same time, it can also reduce the use amount of other drugs in combined anesthesia, accelerate the recovery of the patient from the sedation, hypnotic and / or anesthesia state, and increase the safety of the patient. Therefore, it is urgent to develop a drug which not only has sedative, hypnotic and / or anesthetic effect, can control status epilepticus, but also has analgesic effect. SUMMARY

[0003] The purpose of the present application is to provide a compound, a preparation method and use thereof.

[0004] The present application provides a compound, a tautomer thereof, an endo-racemate thereof, an exo-racemate thereof, an enantiomer thereof, a diastereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof or a deuterated derivative thereof, the structure of the compound is shown as formula I:

[0005] L0 is selected from none, C 1-5 alkylene, C 2-5 alkenylene;

[0006] R0 is selected from cyano, COOR 01 , OCOR 01 , CONR 02 R 03 , OCONR 02 R 03 , NR 02 R 03 , OL9OR 01 , OL9R 01 , COR 01 , L9R 01 ; R01 selected from C 1-8 alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated oxacyclyl, R 02 selected from hydrogen, C 1-8 alkyl, R 03 selected from hydrogen, C 1-8 alkyl, unsubstituted or substituted with one or more R 04 substituted L8R L , or R 02 , R 03 together form a 5-6 membered saturated nitrogen heterocycle; L8is selected from null, C 10 alkylene, R 1-5 selected from 5-6 membered heteroaryl, R L each independently selected from CONR 04 R 05 , C 06 alkyl, C 1-8 alkoxy, R 1-8 , R 05 each independently selected from hydrogen, C 06 alkyl, R 1-8 each independently selected from C 10 alkyl, L9is selected from null, C 1-8 alkylene;

[0007] R1is selected from hydrogen, LR 1-5 ;

[0008] L is selected from null, C a alkylene;

[0009] R 1-5 is selected from unsubstituted or substituted with one or more R a C a1 alkyl, unsubstituted or substituted with one or more R 1-8 C a1 alkyl, unsubstituted or substituted with one or more R 1-8 C a1 alkoxy, unsubstituted or substituted with one or more R 2-8 alkenyl, hydroxyl, N3, CN, NO2, halogen, 3-8 membered saturated cycloalkyl, NR b R c , COOR a24 ; R b is selected from hydrogen, C 1-8 alkyl, R c is selected from hydrogen, C 1-8 alkyl, or R b , R c together form a 3-8 membered saturated nitrogen heterocycle; R a1 each independently selected from halogen; R a2 is selected from C1-8 alkyl;

[0010] Alternatively, R1 connected to L0R0 forms a structure that is not replaced or is occupied by one or more R... q3 The substituted 3-5 member heterocycle; the R q3 Each independently selected from =O, C 1-5 Alkyl, COOR q4 R q4 Selected from C 1-8 alkyl;

[0011] Y1 is selected from N and CR3; Y2 is selected from N and CR4; Y3 is selected from N and CR5; Y4 is selected from N and CR2; and 0 or 1 of Y1, Y2, Y3 and Y4 are N;

[0012] R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, unsubstituted or surrounded by one or more R groups. 3a Replacement C 1-8 Alkyl; R 3a Each is independently selected from halogens;

[0013] Z is selected from C=O, C=S, C=CH2, CR r R s ;R r Selected from hydrogen, C 1-8 Alkyl, R s Selected from hydrogen, C 1-8 alkyl;

[0014] L1 is selected from None, O, S, NR a3 , N = CH, C 1-5 Alkylene; R a3 Selected from hydrogen, C 1-8 alkyl;

[0015] L2 is selected from none, unreplaced, or replaced by one or more R values. x Replacement C 1-5 Alkylene, unsubstituted or with one or more R x Replacement C 2-5 Ideonyl; R x Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, hydroxyl groups;

[0016] A is selected from none, COL3, COO, OCO, CONH, O, S, SO, SO2;

[0017] L3 is selected from none, C 1-5 Alkylene;

[0018] R6 is selected from hydrogen, unsubstituted or surrounded by one or more R6 groups. 6asubstituted C 1-8 alkyl, unsubstituted or substituted by one or more R 6a substituted C 1-8 alkoxy, unsubstituted or substituted by one or more R 6a substituted C 2-8 alkenyl, unsubstituted or substituted by one or more R 6a substituted C 2-8 alkynyl, NR7R8, unsubstituted or substituted by one or more R 6a substituted 3-8 membered saturated cycloalkyl, unsubstituted or substituted by one or more R 6a substituted 3-8 membered saturated heterocyclyl, OCOR 6b , unsubstituted or substituted by one or more R v substituted phenyl, unsubstituted or substituted by one or more R v substituted 5-6 membered heteroaryl, OL4R y ; R 6a each independently selected from C 1-8 alkyl, C 1-8 alkoxy, halogen, hydroxyl; R 6b selected from C 1-8 alkyl;

[0019] R7is selected from hydrogen, C 1-8 alkyl, L5R z1 ;

[0020] R8is selected from C 1-8 alkyl, C 1-8 alkoxy, 3-8 membered saturated cycloalkyl, unsubstituted or substituted by one or more R v substituted 5-6 membered heteroaryl, L7R z3 ;

[0021] or, R7, R8are linked to form a 3-8 membered saturated nitrogen heterocycle, unsubstituted or substituted by one or more R 7a substituted 3-8 membered saturated nitrogen heterocycle;

[0022] R 7a each independently selected from C 1-8 alkyl;

[0023] R v each independently selected from C 1-8 alkyl, halogen substituted C 1-8 alkyl, C 1-8 alkoxy, halogen substituted C 1-8 alkoxy, halogen, CN, CONR v1 R v2 ; R v1 selected from hydrogen, C 1-8 alkyl, R v2 selected from hydrogen, C 1-8 alkyl;

[0024] L5is selected from C 1-5 alkylene; R z1 is selected from the group consisting of 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, which is unsubstituted or substituted by one or more R w1 is selected from the group consisting of 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, which is unsubstituted or substituted by one or more R w1 are each independently selected from the group consisting of OR w2 , R w2 is selected from the group consisting of C 1-5 alkyl, 3-8 membered saturated cycloalkyl;

[0025] L7is selected from C 1-5 alkylene; R z3 is selected from the group consisting of 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, which is unsubstituted or substituted by one or more R w5 is selected from the group consisting of 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, which is unsubstituted or substituted by one or more R w5 are each independently selected from the group consisting of OR w6 , R w6 is selected from the group consisting of C 1-8 alkyl, 3-8 membered saturated cycloalkyl;

[0026] L4is selected from the group consisting of none, C 1-5 alkylene; R y is selected from the group consisting of hydrogen, C 1-8 alkyl, phenyl.

[0027] Further, the structure of the compound is as shown in Formula II-1, Formula II-2, Formula II-3, Formula II-4, or Formula II-5:

[0028] L0is selected from the group consisting of none, C 1-4 alkylene, C 2-4 alkenylene;

[0029] R0is selected from the group consisting of cyano, COOR 01 , OCOR 01 , CONR 02 R 03 , OCONR 02 R 03 , NR 02 R 03 , OL9OR 01 , OL9R 01 , COR 01 , L9R 01 ; R 01 is selected from the group consisting of C 1-6 alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated oxacyclyl, R 02 is selected from the group consisting of hydrogen, C 1-6 alkyl, R 03 is selected from the group consisting of hydrogen, C 1-6 alkyl, which is unsubstituted or substituted by one or two or more R04 Replaced L8R L , or R 02 R 03 The connection is formed without being replaced or by more than one R 10 Substituted 6-membered saturated nitrogen heterocycle; L8 is selected from none, C 1-3 Alkylene, R L Selected from 5-6 quinone heteroaryl groups, R 04 Each independently selected from CONR 05 R 06 C 1-6 Alkyl, C 1-6 Alkoxy, R 05 R 06 Each is independently selected from hydrogen, C 1-6 Alkyl, R 10 Each independently selected from C 1-5 Alkyl group, L9 is selected from none, C 1-3 Alkylene;

[0030] R1 is selected from hydrogen, LR a ;

[0031] L is selected from none, C 1-5 Alkylene;

[0032] R a Selected from those that have not been replaced or have been replaced by one or more R a1 Replacement C 1-5 Alkyl, 3-6 saturated cycloalkyl, COOR a2 ;R a1 Each is independently selected from halogens; R a2 Selected from C 1-5 alkyl;

[0033] Alternatively, R1 connected to L0R0 forms a structure that is not replaced or is occupied by one or more R... q3 The substituted 3-5 membered oxygen-containing heterocycle, wherein the oxygen-containing heterocycle contains 0 or 1 nitrogen atom; the R q3 Each independently selected from =O, C 1-5 Alkyl, COOR q4 R q4 Selected from C 1-5 alkyl;

[0034] R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, unsubstituted or surrounded by one or more R groups. 3a Replacement C 1-5 Alkyl; R 3a Each is independently selected from halogens;

[0035] L1 is selected from None, O, S, NR a3 , N = CH, C1-5 Alkylene; R a3 Selected from hydrogen, C 1-5 alkyl;

[0036] L2 is selected from none, unreplaced, or replaced by one or more R values. x Replacement C 1-5 Alkylene, unsubstituted or with one or more R x Replacement C 2-5 Ideonyl; R x Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, hydroxyl groups;

[0037] A is selected from none, COL3, COO, OCO, CONH, O, S, SO, SO2;

[0038] L3 is selected from none, C 1-5 Alkylene;

[0039] R6 is selected from hydrogen, unsubstituted or surrounded by one or more R6 groups. 6a Replacement C 1-5 Alkyl, unsubstituted or with one or more R 6a Replacement C 1-5 Alkyl group, unsubstituted or with one or more R groups 6a Replacement C 2-5 Alkenyl, unsubstituted or with one or more R 6a Replacement C 2-5 Alkyne group, NR7R8, unsubstituted or with one or more R groups 6a Substituted 3-6 saturated cycloalkyl groups, unsubstituted or with one or more R groups 6a Substituted 3-6 saturated heterocyclic groups, OCOR 6b Not replaced or replaced by more than one R v Substituted phenyl, unsubstituted or with one or more R v Substituted 5-6 aryl heteroaryl, OL4R y ;R 6a Each independently selected from C 1-5 Alkyl, C 1-5 Alkoxy, halogen, hydroxyl; R 6b Selected from C 1-5 alkyl;

[0040] R7 is selected from hydrogen, C 1-5 Alkyl, L5R z1 ;

[0041] R8 is selected from C 1-5 Alkyl, C 1-5 Alkoxy, 3-6 membered saturated cycloalkyl, unsubstituted or with one or more R vsubstituted 5-6 membered heteroaryl, L7R z3 ;

[0042] Alternatively, R7, R8are linked to form a 3-6 membered saturated nitrogen heterocycle, which is unsubstituted or substituted by one or more R 7a substituted 3-6 membered saturated nitrogen heterocycle;

[0043] R 7a each independently selected from C 1-5 alkyl;

[0044] R v each independently selected from C 1-5 alkyl, halogen substituted C 1-5 alkyl, C 1-5 alkoxy, halogen substituted C 1-5 alkoxy, halogen, CN, CONR v1 R v2 ; R v1 selected from hydrogen, C 1-5 alkyl, R v2 selected from hydrogen, C 1-5 alkyl;

[0045] L5is selected from C 1-5 alkylene; R z1 selected from unsubstituted or substituted by one or more R w1 substituted 5-6 membered heteroaryl; R w1 each independently selected from OR w2 , R w2 selected from C 1-5 alkyl, 3-6 membered saturated cycloalkyl;

[0046] L7is selected from C 1-5 alkylene; R z3 selected from unsubstituted or substituted by one or more R w5 substituted 5-6 membered heteroaryl, 3-6 membered saturated cycloalkyl; R w5 each independently selected from OR w6 , R w6 selected from C 1-5 alkyl, 3-6 membered saturated cycloalkyl;

[0047] L4is selected from none, C 1-5 alkylene; R y selected from hydrogen, C 1-5 alkyl, phenyl.

[0048] Further, the structure of the compound is shown in Formula III-1, Formula III-2, Formula III-3, Formula III-4, or Formula III-5:

[0049] b is selected from 0, 1 or 2;

[0050] R 01 selected from C 1-4 alkyl;

[0051] L1, L2, A, R6, R1, R2, R3, R4, R5 are as described above.

[0052] Further, the structure of the compound is shown in formula IV:

[0053] b is selected from 0, 1 or 2;

[0054] R 02 selected from hydrogen, C 1-4 alkyl, R 03 selected from hydrogen, C 1-4 alkyl, unsubstituted or substituted by one or more R 04 L8R L , or R 02 , R 03 are linked to form a 6-membered saturated nitrogen heterocycle unsubstituted or substituted by one or more R 10 L8 is selected from none, C 1-2 alkylene, R L selected from R 04 each independently selected from CONR 05 R 06 , C 1-4 alkyl, C 1-4 alkoxy, R 05 , R 06 each independently selected from hydrogen, C 1-4 alkyl, R 10 each independently selected from C 1- 4alkyl;

[0055] L1, L2, A, R6, R1, R2, R3, R4, R5 are as described above.

[0056] Further, the structure of the compound is shown in formula V:

[0057] b is selected from 0, 1 or 2;

[0058] R 01 selected from C 1-4 alkyl, NR 02 R 03 ;

[0059] R 02 selected from hydrogen, C 1-4 alkyl, R 03 selected from hydrogen, C 1-4 alkyl, unsubstituted or substituted by one or more R04 substituted L8R L , or R 02 , R 03 to form a 6-membered saturated nitrogen heterocycle, which is unsubstituted or substituted by one or more R 10 substituted L8is selected from the group consisting of nothing, C 1-2 alkylene, R L is selected from the group consisting of R 04 are each independently selected from the group consisting of CONR 05 R 06 , C 1-4 alkyl, C 1-4 alkoxy, R 05 , R 06 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, R 10 are each independently selected from the group consisting of C 1- 4alkyl;

[0060] L1, L2, A, R6, R1, R2, R3, R4, R5 are as described above.

[0061] Further, the structure of the compound is as shown in formula VI:

[0062] b is selected from 0, 1, 2, or 3;

[0063] a is selected from 0 or 1;

[0064] R 01 is selected from the group consisting of hydrogen, unsubstituted or substituted by one or two or more R 04 substituted L8R L ; L8is selected from the group consisting of nothing, C 1-5 alkylene, R L is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, 3-8 membered saturated cycloalkyl, 3-8 membered saturated oxacyclyl, 5-6 membered heteroaryl, R 04 are each independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy;

[0065] L1, L2, A, R6, R1, R2, R3, R4, R5 are as described above.

[0066] Further, the structure of the compound is as shown in formula VII-1, VII-2, VII-3, VII-4, VII-5:

[0067] X1is selected from N, CR A ; X2is selected from N, CR B ; X1, X2are not simultaneously N;

[0068] R A R B Each element is independently selected from hydrogen, halogen, unsubstituted or composed of one or more R atoms. 3a Replacement C 1-8 Alkyl; R 3a Each is independently selected from halogens;

[0069] L1, L2, A, R6, R1, R2, R3, R4, and R5 are as described above.

[0070] Furthermore, the aforementioned The structure is

[0071] L1 is selected from None, O, S, NR a3 , N = CH, C 1-3 Alkylene; R a3 Selected from hydrogen, C 1-3 alkyl;

[0072] L2 is selected from none, unreplaced, or replaced by one or more R values. x Replacement C 1-3 Alkylene, unsubstituted or with one or more R x Replacement C 2-3 Ideonyl; R x Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, hydroxyl groups;

[0073] L3 is selected from none, C 1-3 Alkylene;

[0074] R6 is selected from hydrogen, unsubstituted or surrounded by one or more R6 groups. 6a Replacement C 1-5 Alkyl, unsubstituted or with one or more R 6a Replacement C 1-5 Alkyl group, unsubstituted or with one or more R groups 6a Replacement C 2-3 Alkenyl, unsubstituted or with one or more R 6a Replacement C 2-3 acetylenic, NR t R u Not replaced or replaced by more than one R 6a Substituted 3-6 saturated cycloalkyl groups, unsubstituted or with one or more R groups 6a Substituted 3-6 saturated heterocyclic groups, OCOR 6b phenyl, one or more R v Substituted phenyl, 5-6 aziridine, or one or more R vsubstituted 5-6 membered nitrogen heteroaryl; R 6a each independently selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, halogen, hydroxy; R 6b selected from the group consisting of C 1-3 alkyl;

[0075] R v each independently selected from the group consisting of C 1-3 alkyl, halogen substituted C 1-3 alkyl, C 1-3 alkoxy, halogen substituted C 1-3 alkoxy, halogen, CONR v1 R v2 ; R v1 selected from the group consisting of hydrogen, C 1-5 alkyl, R v2 selected from the group consisting of hydrogen, C 1-5 alkyl;

[0076] R t selected from the group consisting of hydrogen, C 1-3 alkyl, R u selected from the group consisting of hydrogen, C 1-3 alkyl.

[0077] Further, the group consisting of:

[0078] L1is selected from the group consisting of nothing, O, S, NR a3 , N=CH, C 1-3 alkylene; R a3 selected from the group consisting of hydrogen, C 1-3 alkyl; L2is selected from the group consisting of nothing, unsubstituted or substituted C x alkylene, unsubstituted or substituted C 1-3 alkylene, unsubstituted or substituted C x alkylene, unsubstituted or substituted C 2-3 alkylene; R x each independently selected from the group consisting of C 1-3 alkyl, C 1-3 alkoxy, hydroxy;

[0079] A is selected from the group consisting of nothing, OCO, CONH, O, S, SO, SO2;

[0080] R6is selected from the group consisting of hydrogen, unsubstituted or substituted C 6a alkyl, unsubstituted or substituted C 1-5 alkyl, unsubstituted or substituted C 6a alkyl, unsubstituted or substituted C 1-5 alkyl, unsubstituted or substituted C 6a alkyl, unsubstituted or substituted C 2-3 alkyl, unsubstituted or substituted C6a substituted C 2-3 alkynyl, NR t R u , unsubstituted or substituted by one or more R 6a substituted 3-5 membered saturated cycloalkyl, unsubstituted or substituted by one or more R 6a substituted 3-5 membered saturated heterocyclyl, OCOR 6b , phenyl, one or more R v substituted phenyl, 5-6 membered nitrogen heteroaryl, one or more R v substituted 5-6 membered nitrogen heteroaryl, OL4R y ; R 6a each independently selected from C 1-3 alkyl, C 1-3 alkoxy, halogen, hydroxyl; R 6b selected from C 1-3 alkyl;

[0081] R t selected from hydrogen, C 1-3 alkyl, L5R z1 , R u selected from hydrogen, C 1-3 alkyl, L6R z2 ;

[0082] L5 is selected from C 1-3 alkylene; R z1 selected from unsubstituted or substituted by one or more R w1 substituted 5-6 membered heteroaryl; R w1 each independently selected from OR w2 , R w2 selected from C 1-3 alkyl, 3-5 membered saturated cycloalkyl;

[0083] L6 is selected from C 1-3 alkylene; R z2 selected from unsubstituted or substituted by one or more R w3 substituted 5-6 membered heteroaryl; R w3 each independently selected from OR w4 , R w4 selected from C 1-3 alkyl, 3-5 membered saturated cycloalkyl;

[0084] L4 is selected from none, C 1-3 alkylene; R y selected from hydrogen, C 1-3 alkyl, phenyl;

[0085] R v each independently selected from C 1-3 alkyl, halogen substituted C 1-3 alkyl, C1-3 alkoxy- or halogen-substituted C 1-3 Alkoxy, halogen, CN, CONR v1 R v2 ;R v1 Selected from hydrogen, C 1-3 Alkyl, R v2 Selected from hydrogen, C 1-3 alkyl.

[0086] Furthermore, the aforementioned The structure is as follows: c is selected from 0, 1, 2 or 3, and R6 is as described above.

[0087] Furthermore, the aforementioned The structure is

[0088] L1 is selected from None, O, S, NR a3 , N = CH, C 1-3 Alkylene; R a3 Selected from hydrogen, C 1-3 alkyl;

[0089] L2 is selected from none, C 1-3 Alkylene;

[0090] R7 is selected from hydrogen, C 1-3 alkyl;

[0091] R8 is selected from C 1-4 Alkyl, C 1-4 Alkoxy, 3-4 membered saturated cycloalkyl, one or more R v Substituted 5-6 nitrile aryl groups, L7R z3 ;

[0092] Alternatively, the connection of R7 and R8 forms a structure that is not replaced or is formed by one or more R... 7a Substituted 4-6 membered saturated nitrogen heterocycles;

[0093] R 7a Each independently selected from C 1-3 alkyl;

[0094] R v Each independently selected from C 1-3 Alkyl, halogen-substituted C 1-3 Alkyl, C 1-3 alkoxy- or halogen-substituted C 1-3 Alkoxy, halogen, CN, CONR v1 R v2 ;R v1 Selected from hydrogen, C 1-3 Alkyl, R v2 Selected from hydrogen, C1-3 alkyl;

[0095] L7is selected from C 1-3 alkylene; R z3 is selected from the following groups, which are unsubstituted or substituted with one or more R w5 5-6 membered heteroaryl, 3-4 membered saturated cycloalkyl; R w5 each independently selected from OR w6 , R w6 is selected from C 1-3 alkyl, 3-5 membered saturated cycloalkyl.

[0096] Further, the structure of the compound is

[0097] L1is selected from the absence, O, S, NR a3 , N=CH, C 1-3 alkylene; R a3 is selected from hydrogen, C 1-3 alkyl;

[0098] L2is selected from the absence, C 1-3 alkylene;

[0099] R6is selected from hydrogen, C 6a alkyl, C 1-4 alkyl, which is unsubstituted or substituted with one or more R 6a C 1-4 alkoxy, NR7R8; R 6a each independently selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, hydroxyl;

[0100] R7is selected from hydrogen, C 1-4 alkyl;

[0101] R8is selected from C 1-4 alkyl;

[0102] or R7, R8are linked to form a 3-6 membered saturated nitrogen heterocycle, which is unsubstituted or substituted with one or more R 7a substituents;

[0103] R 7a each independently selected from C 1-4 alkyl.

[0104] Further, the compound is selected from one of the following compounds:

[0105] Further, the pharmaceutically acceptable salt is selected from the group consisting of citrate, hydrofluoride, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene-2-carboxylate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, xinafoate, or p-toluenesulfonate.

[0106] The present application also provides a pharmaceutical composition which is a preparation obtained by adding a pharmaceutically acceptable adjuvant to the above-mentioned compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative as an active ingredient.

[0107] The present application also provides the use of the above-mentioned compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative in the manufacture of a medicament having analgesic action, and / or, having anesthetic, sedative, hypnotic action and / or being able to control status epilepticus.

[0108] "Having analgesic action, and / or, having anesthetic, sedative, hypnotic action and / or being able to control status epilepticus" includes the following three cases: (1) having analgesic action; (2) having anesthetic, sedative, hypnotic action and / or being able to control status epilepticus; (3) having both anesthetic, sedative, hypnotic action and / or being able to control status epilepticus, and also having analgesic action.

[0109] The "having anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus, while also having analgesic effect" according to the present application means that there is no response to noxious stimuli or the response threshold to noxious stimuli is increased when the compound according to the present application produces sedative, hypnotic and / or anesthetic effect.

[0110] The "drug having a sedative effect" according to the present application means a drug that effectively helps sleep and effectively improves sleep. That is, it can avoid the serious harm of insomnia to the human body, treat insomnia, and improve sleep quality.

[0111] The "drug having a hypnotic effect" according to the present application means a drug that can induce sleepiness and promote sleep. That is, it has an inhibitory effect on the central nervous system, a small dose causes sedation, and an overdose causes general anesthesia.

[0112] The "drug having an anesthetic effect" according to the present application means a reversible inhibition of the central nervous system and / or peripheral nervous system produced by the drug. The main feature of this inhibition is the loss of sensation, especially pain. Preferably, the anesthetic is general anesthesia.

[0113] The "general anesthesia" according to the present application, referred to as general anesthesia, means a temporary inhibition of the central nervous system produced after the anesthetic enters the body, and the clinical manifestations are loss of consciousness, loss of general pain, amnesia, reflex inhibition and skeletal muscle relaxation.

[0114] The "status epilepticus" according to the present application means that the consciousness is not completely recovered between the continuous seizures of epilepsy, or the seizures frequently recur or last for more than 30 minutes without stopping on their own. Long-term seizures of epilepsy, if not treated in time, can cause irreversible brain damage due to high fever, circulatory failure or neuronal excitotoxicity, resulting in a high rate of disability and mortality. Therefore, status epilepticus is a common emergency in internal medicine.

[0115] Definitions of terms used in the present application: unless otherwise specified, the initial definition of a group or term provided herein applies throughout the specification for that group or term; for terms not specifically defined herein, the meaning given to them by those skilled in the art should be given in the light of the disclosure and the context.

[0116] The minimum and maximum values of the carbon content in the hydrocarbon group are indicated by the prefix, for example, the prefix C a～b Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C 1-5 Alkyl means a straight-chain or branched alkyl group containing 1, 2, 3, 4 or 5 carbon atoms, C 1-5 Alkoxy means a straight-chain or branched alkoxy group containing 1, 2, 3, 4 or 5 carbon atoms, C 1-5 Alkylene means a straight-chain or branched alkylene group containing 1, 2, 3, 4 or 5 carbon atoms, C 2-3Alkenyl refers to a straight-chain or branched alkenyl group containing 2 or 3 carbon atoms, and the like.

[0117] Halogen is fluorine, chlorine, bromine or iodine.

[0118] More than one means one or more than one, and the like.

[0119] In the chemical structure of the compound of the present application, the bond represents unspecified configuration, i.e. if there are chiral isomers in the chemical structure, the bond may be or simultaneously contain both configurations.

[0120] In the chemical structure of the compound of the present application, the bond represents unspecified cis-trans isomerism, the bond may be "cis, i.e. Z type" or "trans, i.e. E type", or simultaneously contain "cis, i.e. Z type" and "trans, i.e. E type".

[0121] Compared with the prior art, the compound provided by the present application has the following beneficial effects:

[0122] The present application first found that the compound of the present application not only has high sedative, hypnotic and / or anesthetic effect, but also has analgesic effect, and can reduce or not use opioid analgesic drugs such as fentanyl, alfentanil, sufentanil or remifentanil in clinical application, thereby reducing the occurrence of adverse reactions such as circulatory depression, respiratory depression, urinary retention and skin itching of opioid analgesic drugs.

[0123] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and conventional means in the art, other various forms of modifications, substitutions or changes can be made without departing from the above basic technical idea of the present application.

[0124] The above content of the present application will be further described in detail through the specific embodiments in the form of examples. However, this should not be understood as the scope of the above subject matter of the present application is limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. DETAILED DESCRIPTION

[0125] The raw materials and equipment used in the present application are known products, which are obtained by purchasing commercially available products.

[0126] The following are the preparation method of the compound and the structure characterization data.

[0127] Example 1. Synthesis of compounds 1.1-1.15

[0128] Potassium tert-butoxide (28 g, 0.25 mmol, 2.5 eq) was dissolved in 500 mL dry DMF under nitrogen protection, the temperature was reduced to -40 °C. 100 mL of p-bromonitrobenzene (20.2 g, 0.1 mmol, 1 eq) and methyl chloroacetate (12.0 g, 0.11 mmol, 1.1 eq) dry DMF mixed solution was added dropwise, after the end of dropwise addition, -20 °C for 30 min, then bromoethyl acetate (18.4 g, 0.11 mmol, 1.1 eq) was added dropwise. The reaction was slowly warmed to room temperature, extracted with ethyl acetate and water three times, combined organic layers, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 5:1) to obtain compound 1-1 (19.8 g, 55.0%, colorless transparent syrup).

[0129] Sodium hydride (2.2 g, 55 mol, 1.1 eq, 40% mineral oil wrapped) was suspended in 200 mL dry DMF under nitrogen protection, cooled to -10 °C, iodomethane (8.4 g, 60 mmol, 1.2 eq) was added, then 1-2 (18 g, 50 mmol, 1 eq) dry DMF solution was added dropwise, slowly warmed to room temperature after stirring for 1 hour, saturated aqueous ammonium chloride solution was added to quench the reaction. Extracted with ethyl acetate and water three times, combined organic layers, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 4:1) to obtain compound 1-3 (17.1 g, colorless transparent syrup, 91.4%)

[0130] 30 mL of compound 1-3 (3.73 g, 10 mmol, 1 eq) and 4,4'-dipyridine (78 mg, 0.5 mmol, 0.05 eq) DMF solution was cooled to -10 °C, and tetrahydroxyboron (1.79 g, 20 mol, 2 eq) solid was added slowly in batches. Continue to stir for 2 hours, slowly warm to room temperature, continue to stir for 4 hours. Extracted with ethyl acetate and water three times, combined organic layers, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 2:1~1:1) to obtain compound 1.1 (NS-366) (770 mg, white solid, 23.5%).

[0131] Compound 1.1 (NS-366): white solid, 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.65 (d, J = 1.9 Hz, 1H), 7.46 (dd, J = 8.2, 1.9 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 3.86 (m, 2H), 3.15 (d, J = 16.7 Hz, 1H), 2.89 (d, J = 16.7 Hz, 1H), 1.29 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 328.01, 330.01, Found 328.0, 330.0.

[0132] Compound 1.1 (98.4 g, 3 mmol) was dissolved in 1 mL dry DMF, potassium bicarbonate (60 mg, 0.6 mmol, 2 eq) and bromomethylcyclopropyl ketone (59 mg, 0.36 mmol, 1.2 eq) were added, stirred at room temperature for 1 hour, extracted with ethyl acetate and water three times, combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 3:1) to obtain compound 1.2 (i.e. NS-394) (83.0 mg, 67.5%).

[0133] Compound 1.2 (i.e. NS-394): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 8.3, 1.9 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 5.09 (s, 2H), 3.86 (m, 2H), 3.20 (d, J = 16.9 Hz, 1H), 2.94 (d, J = 16.9 Hz, 1H), 2.22 (ddd, J = 12.2, 7.7, 4.7 Hz, 1H), 1.31 (s, 3H), 0.98 (m, 7H). LC-MS: [M+H] + Calcd 410.05, 412.05, Found 410.0, 412.0.

[0134] Referring to the above synthesis, compound 1.1 was reacted with 2-bromoacetophenone, iodomethane, iodoethane, 2-iodopropane, 2-iodobutane, bromomethyl methyl ether, bromoacetic dimethylamine, iodopropane, iodoisobutane, iodomethylcyclopropane, bromomethyl ethyl ether, 2-bromoethyl isopropyl ether and chloroformic dimethylamine in the presence of potassium bicarbonate to synthesize compounds 1.3~1.15, respectively.

[0135] Compound 1.3 (i.e. NS-395): white solid, 1H NMR (400 MHz, DMSO-d6) δ 7.96 (m, 2H), 7.72 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 6.5 Hz, 1H), 7.57 (t, J = 7.7 Hz, 2H), 7.53 (dd, J = 8.3, 1.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 5.65 (s, 2H), 3.84 (m, 2H), 3.20 (d, J = 16.9 Hz, 1H), 2.95 (d, J = 16.9 Hz, 1H), 1.32 (s, 3H), 0.96 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 446.05, 448.05, Found 446.0, 448.0.

[0136] Compound 1.4 (i.e. NS-374): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 3.93 (s, 3H), 3.87 (m, 2H), 3.21 (d, J = 17.0 Hz, 1H), 2.94 (d, J = 16.9 Hz, 1H), 1.31 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 342.03, 344.03, Found 342.0, 344.0.

[0137] Compound 1.5 (i.e. NS-601): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.2, 2.0 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 4.19 (qd, J = 7.0, 0.8 Hz, 2H), 3.86 (m, 2H), 3.20 (d, J = 16.9 Hz, 1H), 2.94 (d, J = 16.9 Hz, 1H), 1.33 (m, 6H), 0.98 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 356.04, 358.04, Found 356.0, 358.0.

[0138] Compound 1.6 (i.e. NS-602): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 4.52 (hept, J = 6.2 Hz, 1H), 3.86 (m, 2H), 3.20 (d, J = 16.9 Hz, 1H), 2.92 (d, J = 16.9 Hz, 1H), 1.31 (s, 3H), 1.30 (d, J = 4.6 Hz, 6H), 0.98 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 370.06, 372.06, Found 370.0, 372.0.

[0139] Compound 1.7 (i.e. NS-603): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.3 Hz, 1H), 7.48 (dd, J = 8.3, 1.9 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 4.34 (hept, J = 6.4 Hz, 1H), 3.87 (m, 2H), 3.20 (d, J = 16.9 Hz, 1H), 2.93 (d, J = 16.9 Hz, 1H), 1.68 (m, 2H), 1.31 (s, 3H), 1.27 (d, J = 6.2 Hz, 3H), 0.99 (td, J = 7.5, 3.9 Hz, 6H). LC-MS: [M+H] + Calcd 384.07, 386.07, Found 384.0, 386.0.

[0140] Compound 1.8 (i.e. NS-615): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 1.9 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 5.16 (d, J = 7.2 Hz, 1H), 5.13 (d, J = 7.1 Hz, 1H), 3.86 (m, 2H), 3.59 (s, 3H), 3.20 (d, J = 16.9 Hz, 1H), 2.94 (d, J = 16.9 Hz, 1H), 1.32 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 372.04, 374.04, Found 372.0, 374.0.

[0141] Compound 1.9 (i.e. NS-367): pale yellow syrup,1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 4.91 (s, 1H), 4.89 (s, 1H), 3.86 (m, 2H), 3.20 (d, J = 16.9 Hz, 1H), 2.98 (s, 3H), 2.94 (d, J = 16.9 Hz, 1H), 2.85 (s, 3H), 1.31 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 413.06, 415.06, Found 413.0, 415.0.

[0142] Compound 1.10 (i.e. NS-904): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 4.09 (m, 2H), 3.87 (m, 2H), 3.20 (d, J = 16.9 Hz, 1H), 2.93 (d, J = 16.9 Hz, 1H), 1.74 (m, 2H), 1.31 (s, 3H), 1.00 (m, 6H). LC-MS: [M+H] + Calcd 370.06, 372.06, Found 370.0, 372.0.

[0143] Compound 1.11 (i.e. NS-905): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 3.88 (m, 4H), 3.20 (d, J = 16.9 Hz, 1H), 2.93 (d, J = 16.9 Hz, 1H), 2.04 (dp, J = 13.5, 6.8 Hz, 1H), 1.30 (s, 3H), 1.03 (dd, J = 6.7, 1.7 Hz, 6H), 0.99 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 384.07, 386.06, Found 384.0, 386.0.

[0144] Compound 1.12 (i.e. NS-906): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.2, 2.0 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 3.97 (d, J = 7.4 Hz, 2H), 3.86 (m, 2H), 3.19 (d, J = 16.9 Hz, 1H), 2.93 (d, J = 16.9 Hz, 1H), 1.31 (s, 3H), 1.21 (M, 1H), 0.98 (t, J = 7.1 Hz, 3H), 0.58 (m, 2H), 0.35 (m, 2H). LC-MS: [M+H] + Calcd 382.06, 384.06, Found 382.0, 384.0.

[0145] Compound 1.13 (i.e. NS-907): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 2.0 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 5.18 (d, J = 7.3 Hz, 1H), 5.16 (d, J = 7.3 Hz, 1H), 3.87 (m, 4H), 3.19 (d, J = 16.8 Hz, 1H), 2.94 (d, J = 16.8 Hz, 1H), 1.32 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 386.05, 388.05, Found 386.0, 388.0.

[0146] Compound 1.14 (i.e. NS-908): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.25 (m, 2H), 3.87 (m, 2H), 3.66 (td, J = 4.7, 1.7 Hz, 2H), 3.59 (dt, J = 12.2, 6.1 Hz, 1H), 3.20 (d, J = 16.9 Hz, 1H), 2.93 (d, J = 16.9 Hz, 1H), 1.31 (s, 3H), 1.11 (dd, J = 10.2, 6.1 Hz, 6H), 0.98 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 414.08, 416.08, Found 414.0, 416.0.

[0147] Compound 1.15 (i.e. NS-369): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 1.9 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 3.89 (m, 2H), 3.22 (d, J = 16.8 Hz, 1H), 3.11 (s, 3H), 2.96 (s, 3H), 2.95 (d, J = 16.8 Hz, 1H), 1.35 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 399.05, 401.05, Found 399.0, 401.0.

[0148] Example 2. Synthesis of compounds 2.1-2.9

[0149] Methyl isopropylamine (146 mg, 2 mmol, 1 eq) was dissolved in 3 mL of dry tetrahydrofuran under nitrogen protection, 1 mL of triphosgene (237 mg, 0.8 mmol, 0.4 eq) in tetrahydrofuran was added dropwise under ice bath condition, after slowly rising to room temperature, methyl tert-butyl ether and water were added and extracted three times, the organic layer was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude chloroformyl methyl isopropylamine.

[0150] Referring to Example 1, the above-mentioned crude chloroformyl methyl isopropylamine and 1.1 (64 mg, 0.2 mmol, 1 eq), potassium bicarbonate (100 mg, 1 mmol, 5 eq) were used to synthesize compound 2.1 (i.e. NS-609).

[0151] Compound 2.1 (i.e. NS-609): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 1.9 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 3.89 (m, 2H), 3.22 (d, J = 16.8 Hz, 1H), 3.11 (s, 3H), 2.96 (s, 3H), 2.95 (d, J = 16.8 Hz, 1H), 1.35 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] +Calcd 427.08, 429.08, Found 427.1, 429.1.

[0152] Referring to the synthesis of compound 2.2, the corresponding chloroformamide was synthesized using methylpropylamine (146 mg, 2 mmol), N-methylisobutylamine (174 mg, 2 mmol), diethylamine (146 mg, 2 mmol), 3,3-dimethylcyclobutylamine hydrochloride (232 mg, 2 mmol), tetrahydropyrrole (142 mg, 2 mmol), methylethylamine (118 mg, 2 mmol), methylcyclopropylamine (142 mg, 2 mmol) and cyclobutylamine hydrochloride (186 mg, 2 mmol) as starting materials, respectively, and reacted with compound 1.1 in the presence of potassium bicarbonate to give compounds 2.2-2.9, respectively.

[0153] Compound 2.2 (i.e. NS-610): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 8.2, 1.9 Hz, 1H), 6.91 (d, J = 8.1 Hz, 0.5H), 6.85 (d, J = 8.1 Hz, 0.5H), 3.89 (m, 2H), 3.41 (t, J = 8.0 Hz, 1H), 3.27 (t, J = 8.0 Hz, 1H), 3.22 (d, J = 16.7 Hz, 1H), 3.10 (s, 1.5H), 2.96 (s, 1.5H), 2.95 (d, J = 16.7 Hz, 1H), 1.71 (m, 1H), 1.59 (m, 1H), 1.36 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.3 Hz, 1.5H), 0.88 (t, J = 7.3 Hz, 1.5H). LC-MS: [M+H] + Calcd 427.08, 429.08, Found 427.1, 429.1.

[0154] Compound 2.3 (i.e. NS-611): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 8.3, 1.7 Hz, 1H), 6.91 (d, J = 8.3 Hz, 0.5H), 6.82 (d, J = 8.3 Hz, 0.5H), 3.88 (q, J = 7.0 Hz, 2H), 3.28 (dd, J = 7.1, 4.0 Hz, 1H), 3.22 (d, J = 16.8 Hz, 1H), 3.14 (dd, J = 7.3, 2.1 Hz, 1H), 3.10 (s, 1.5H), 2.96 (s, 1.5H), 2.96 (d, J = 16.8 Hz, 1H), 2.03 (m, 1H), 1.35 (s, 3H), 0.96 (t, J = 7.3 Hz, 3H), 0.99 (dd, J = 6.1, 2.6 Hz, 3H), 0.89 (dd, J = 6.1, 2.6 Hz, 3H). LC-MS: [M+H] + Calcd 441.09, 443.09, Found 441.1, 443.1.

[0155] Compound 2.4 (i.e. NS-661): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.3, 1.9 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 3.89 (m, 2H), 3.47 (br s, 2H), 3.35 (br s, 2H), 3.22 (d, J = 16.7 Hz, 1H), 2.95 (d, J = 16.7 Hz, 1H), 1.36 (s, 3H), 1.28 (s, 3H), 1.15 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 427.08, 429.08, Found 427.1, 429.1.

[0156] Compound 2.5 (i.e. NS-662): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.3, 1.9 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 3.87 (m, 6H), 3.22 (d, J = 16.8 Hz, 1H), 2.95 (d, J = 16.9 Hz, 1H), 1.34 (s, 3H), 1.32 (s, 6H), 0.98 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] +Calcd 439.08, 441.08, Found 439.1, 441.1.

[0157] Compound 2.6 (i.e. NS-663): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.3, 1.9 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.89 (m, 2H), 3.62 (m, 1H), 3.53 (m, 1H), 3.40 (t, J = 6.7 Hz, 2H), 3.23 (d, J = 16.8 Hz, 1H), 2.96 (d, J = 16.8 Hz, 1H), 1.98 (m, 2H), 1.90 (m, 2H), 1.00 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 425.06, 427.06, Found 425.1, 427.1.

[0158] Compound 2.7 (i.e. NS-664): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 6.91 (dd, J = 13.1, 8.5 Hz, 1H), 3.89 (m, 2H), 3.48 (m, 1H), 3.35 (m, 1H), 3.22 (d, J = 16.7 Hz, 1H), 3.09 (s, 1.5H), 2.96 (s, 1.5H), 2.96 (d, J = 16.8 Hz, 1H), 1.36 (s, 3H), 1.27 (t, J = 7.0 Hz, 1.5H), 1.14 (t, J = 6.9 Hz, 1.5H), 1.00 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 413.06, 415.06, Found 413.0, 415.0.

[0159] Compound 2.8 (i.e. NS-665): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 8.3, 1.7 Hz, 1H), 6.89 (dd, J = 15.2, 8.3 Hz, 1H), 3.89 (m, 2H), 3.34 (m, 1H), 3.22 (m, 2H), 3.16 (s, 1.5H), 3.02 (s, 1.5H), 2.96 (d, J = 16.8 Hz, 1H), 1.36 (s, 3H), 1.20 (br s, 0.5H), 1.06 (br s, 0.5H), 1.00 (t, J = 7.1 Hz, 3H), 0.54 (m, 2H), 0.38 (m, 1H), 0.28 (m, 1H). LC-MS: [M+H] + Calcd 439.08, 441.08, Found 439.1, 441.1.

[0160] Compound 2.9 (i.e. NS-666): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.3, 1.8 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 4.33 (s, 1H), 4.25 (s, 1H), 4.09 (s, 2H), 3.88 (m, 2H), 3.22 (d, J = 16.8 Hz, 1H), 2.95 (d, J = 16.8 Hz, 1H), 2.37 (m, 2H), 1.34 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 411.05, 413.05, Found 411.0, 413.0.

[0161] Example 3. Synthesis of compounds 3.1 and 3.2

[0162] Allylbenzene (118 mg, 1 mmol) was dissolved in dry dichloromethane under nitrogen protection, m-chloroperoxybenzoic acid (85%, 244 mg, 1.2 mmol) was added portionwise at 0 °C, stirred at room temperature overnight, after the reaction was terminated by sodium thiosulfate, dichloromethane was removed, methyl tert-butyl ether and water were added, the organic phase was extracted by water three times, the organic phase was washed by saturated potassium carbonate solution, 1 N dilute hydrochloric acid, saturated brine solution in turn. After drying over anhydrous sodium sulfate, concentration, compound 3-1 was obtained by silica gel column purification (P:E = 2:1). Compound 3-1 was dissolved in dry DMF, compound 1.1 (98 mg, 0.3 mmol, 1 eq) and potassium carbonate (50 mg, 0.36 mmol, 1.2 eq) were added under nitrogen protection, stirred at 70 °C for 16 hours, extracted by ethyl acetate and water three times, the organic phase was washed by saturated brine solution, dried over anhydrous sodium sulfate, concentrated, compound 3-2 (116 mg, 84.3%) was obtained by silica gel column purification (P:E = 2:1).

[0163] Compound 3-2 was dissolved in dichloromethane, dess-martin reagent (108 mg, 0.26 mmol) was added portionwise, and oxidation was carried out overnight. After ethyl acetate was added, the mixture was filtered through celite, and the filtrate was stirred with sodium thiosulfate solution for 1 hour, then separated into organic and aqueous layers. The organic layer was dried over sodium sulfate, concentrated, and compound 3.1 (101 mg, 87.0%) was obtained by silica gel column purification (P:E = 3:1).

[0164] Compound 3.1 (i.e. NS-396): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 2.0 Hz, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.25 (m, 3H), 7.15 (d, J = 8.3 Hz, 1H), 5.05 (s, 2H), 3.87 (m, 4H), 3.20 (d, J = 17.0 Hz, 1H), 2.94 (d, J = 16.9 Hz, 1H), 1.29 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 460.07, 462.07, Found 460.0, 462.0.

[0165] Referring to the above synthesis, compound 3.2 (101 mg, 87.0%) was generated by using vinylpyridine as raw material, through epoxidation, epoxide ring opening with compound 1.1 under alkaline conditions, and Dess-Martin oxidation.

[0166] Compound 3.2 (i.e. NS-427): light yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J = 4.5, 1.5 Hz, 2H), 7.97 (dd, J = 4.5, 1.5 Hz, 2H), 7.69 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.45 (d, J = 18.5 Hz, 1H), 5.35 (d, J = 18.5 Hz, 1H), 3.88 (m, 2H), 3.16 (d, J = 16.5 Hz, 1H), 2.92 (d, J = 16.5 Hz, 1H), 1.35 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 431.05, 433.05, Found 431.0, 433.0.

[0167] Example 4. Synthesis of compounds 4.1-4.4

[0168] Referring to the synthesis of Example 1, compound 4-1 was obtained by reacting with tert-butyl bromoacetate, compound 4-2 was obtained after methylation, and compound 4-3 was obtained after reduction and ring closure, and compound 4.1 was obtained after methylation.

[0169] Compound 4.1 (i.e. NS-388): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.2, 2.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 3.93 (s, 3H), 3.00 (d, J = 16.0 Hz, 1H), 2.84 (d, J = 15.9 Hz, 1H), 1.30 (s, 3H), 1.11 (s, 9H). LC-MS: [M+H] + Calcd 370.06, 372.06, Found 370.0, 372.0.

[0170] Compound 4.1 (74 mg, 0.2 mmol) was dissolved in 1.5 mL of dry isopropanol, 0.3 mL of acetyl chloride was added dropwise under ice bath, the reaction was raised to room temperature, and stirred at room temperature for 18 hours, TLC detection showed that the reaction was complete, the organic solvent was removed. Saturated sodium bicarbonate solution and ethyl acetate were added and separated, the organic phase was combined, washed with brine, concentrated, and purified on a silica gel column (P:E = 3:1) to obtain the target compound 4.2 (i.e. NS-386) (61 mg, 85.7%, colorless transparent syrup).

[0171] Compound 4.2 (i.e. NS-386): light yellow syrup,1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 8.2, 2.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 4.64 (hept, J = 6.3 Hz, 1H), 3.94 (s, 3H), 3.13 (d, J = 16.5 Hz, 1H), 2.91 (d, J = 16.5 Hz, 1H), 1.31 (s, 3H), 0.95 (dd, J = 6.2, 4.7 Hz, 6H). LC-MS: [M+H] + Calcd 356.04, 358.04, Found 356.0, 358.0.

[0172] Referring to the above synthesis, ester exchange under acidic condition was carried out with methanol and isobutanol as solvent to give compounds 4.3 and 4.4, respectively.

[0173] Compound 4.3 (i.e. NS-387): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 8.2, 2.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 4.64 (hept, J = 6.3 Hz, 1H), 3.94 (s, 3H), 3.13 (d, J = 16.5 Hz, 1H), 2.91 (d, J = 16.5 Hz, 1H), 1.31 (s, 3H), 0.95 (dd, J = 6.2, 4.7 Hz, 6H). LC-MS: [M+H] + Calcd 356.04, 358.04, Found 356.0, 358.0.

[0174] Compound 4.4 (i.e. NS-389): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 3.92 (s, 3H), 3.63 (d, J = 6.5 Hz, 2H), 3.25 (d, J = 16.9 Hz, 1H), 2.97 (d, J = 16.9 Hz, 1H), 1.66 (dp, J = 13.5, 6.8 Hz, 1H), 1.31 (s, 3H), 0.75 (d, J = 4.8 Hz, 3H), 0.74 (d, J = 4.8 Hz, 3H). LC-MS: [M+H] + Calcd 356.04, 358.04, Found 356.0, 358.0.

[0175] Example 5. Synthesis of compounds 5.1-5.9

[0176] Reference Example 4. Synthesis of compound 5-1 from compound 4-3 by acid catalyzed transesterification in isopropanol.

[0177] Reference Example 1. Synthesis of compounds 5.1-5.6 from compound 5-1 (102 mg, 0.3 mmol) with iodoisobutane (66 mg, 036 mmol, 1.2 eq), iodoisopentane (71 mg, 0.36 mmol, 1.2 eq), 3-(iodomethyl)oxetane (71 mg, 0.36 mmol, 1.2 eq), bromobutyronitrile (54 mg, 0.36 mmol, 1.2 eq), bromomethylcyclopropyl ketone (59 mg, 0.36 mmol, 1.2 eq), 2-bromoacetophenone (72 mg, 0.36 mmol, 1.2 eq), respectively.

[0178] Compound 5.1 (i.e. NS-671): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 8.2, 1.9 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 4.64 (dd, J = 12.5, 6.2 Hz, 1H), 3.93 (d, J = 6.6 Hz, 2H), 3.13 (d, J = 16.5 Hz, 1H), 2.89 (d, J = 16.5 Hz, 1H), 2.04 (hept, J = 6.7 Hz, 1H), 1.31 (s, 3H), 1.04 (d, J = 3.2 Hz, 3H), 1.02 (d, J = 3.2 Hz, 3H), 0.96 (s, 3H), 0.95 (s, 3H). LC-MS: [M+H] + Calcd 398.09, 400.09, Found 398.1, 400.1.

[0179] Compound 5.2 (i.e. NS-672): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 4.64 (hept, J = 6.2 Hz, 1H), 4.17 (t, J = 6.6 Hz, 2H), 3.13 (d, J = 16.5 Hz, 1H), 2.89 (d, J = 16.5 Hz, 1H), 1.82 (hept, J = 6.5 Hz, 1H), 1.63 (q, J = 6.8 Hz, 2H), 1.31 (s, 3H), 0.95 (d, J = 6.5 Hz, 12H). LC-MS: [M+H] + Calcd 412.10, 414.10, Found 412.1, 414.1.

[0180] Compound 5.3 (i.e. NS-673): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.8 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 4.70 (m, 2H), 4.64 (dt, J = 12.4, 6.3 Hz, 1H), 4.46 (td, J = 6.0, 1.7 Hz, 2H), 4.41 (d, J = 7.0 Hz, 2H), 3.40 (dt, J = 13.7, 6.8 Hz, 1H), 3.13 (d, J = 16.6 Hz, 1H), 2.90 (d, J = 16.6 Hz, 1H), 1.31 (s, 3H), 0.95 (d, J = 6.2 Hz, 6H). LC-MS: [M+H] + Calcd 412.07, 414.07, Found 412.1, 414.1.

[0181] Compound 5.4 (i.e. NS-667): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 4.93 (s, 2H), 4.63 (hept, J = 6.5 Hz, 1H), 3.12 (d, J = 16.5 Hz, 1H), 2.89 (d, J = 16.5 Hz, 1H), 2.55 (q, J = 7.3 Hz, 2H), 1.29 (d, J = 14.2 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H), 0.95 (s, 3H), 0.93 (s, 3H). LC-MS: [M+H] +Calcd 412.07, 414.07, Found 412.1, 414.1.

[0182] Compound 5.5 (i.e. NS-668): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H), 7.51 (dd, J = 8.3, 2.0 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.11 (s, 2H), 4.64 (hept, J = 6.1 Hz, 1H), 3.13 (d, J = 16.5 Hz, 1H), 2.91 (d, J = 16.5 Hz, 1H), 2.22 (ddd, J = 12.3, 7.8, 4.7 Hz, 1H), 1.31 (s, 3H), 0.97 (m, 10H). LC-MS: [M+H] + Calcd 424.07, 426.07, Found 424.1, 426.1.

[0183] Compound 5.6 (i.e. NS-669): white solid, 1 H NMR (400 MHz, DMSO-d6). δ 7.96 (m, 2H), 7.70 (m, 2H), 7.57 (m, 2H), 7.53 (dd, J = 8.3, 2.0 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5.67 (s, 2H), 4.60 ((hept, J = 6.5 Hz, 1H), 3.13 (d, J = 16.5 Hz, 1H), 2.91 (d, J = 16.5 Hz, 1H), 1.32 (s, 3H), 0.94 (d, J = 6.2 Hz, 3H), 0.91 (d, J = 6.2 Hz, 3H). LC-MS: [M+H] + Calcd 460.07, 462.07, Found 460.1, 462.1.

[0184] Reference Example 3, using compound p-methoxyallylbenzene and allylbenzene as starting material respectively to generate compounds 5.7 and 5.8 through epoxidation, epoxide ring opening with compound 5-1 and Dess-Martin oxidation.

[0185] Compound 5.7 (i.e. NS-675): white solid, 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 8.9 Hz, 2H), 7.70 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 5.58 (s, 2H), 4.61 (hept, J = 6.2 Hz, 1H), 3.13 (d, J = 16.5 Hz, 1H), 2.91 (d, J = 16.6 Hz, 1H), 1.32 (s, 3H), 0.93 (dd, J = 9.6, 6.2 Hz, 6H). LC-MS: [M+H] + Calcd 490.08, 492.08, Found 490.1, 492.1.

[0186] Compound 5.8 (i.e. NS-670): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 1.9 Hz, 1H), 7.33 (m, 2H), 7.24 (m, 3H), 7.16 (d, J = 8.3 Hz, 1H), 5.06 (s, 2H), 4.63 (hept, J = 6.2 Hz, 1H), 3.93 (d, J = 16.6 Hz, 1H), 3.88 (d, J = 16.8 Hz, 1H), 3.13 (d, J = 16.6 Hz, 1H), 2.90 (d, J = 16.5 Hz, 1H), 1.29 (s, 3H), 0.95 (d, J = 2.8 Hz, 3H), 0.93 (d, J = 2.8 Hz, 3H). LC-MS: [M+H] + Calcd 474.08, 476.08, Found 474.1, 476.1.

[0187] Reference Example 4, compound 5.9 was prepared from compound 4-3 by ester exchange under acidic condition in methanol, followed by reaction with iodomethylcyclopropane according to Reference Example 1.

[0188] Compound 5.9 (i.e. NS-1259): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.2, 1.9 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 3.97 (d, J = 7.4 Hz, 2H), 3.44 (s, 3H), 3.24 (d, J = 17.2 Hz, 1H), 2.95 (d, J = 17.2 Hz, 1H), 1.31 (s, 3H), 1.23 (m, 1H), 0.58 (m, 2H), 0.36 (m, 2H). LC-MS: [M+H] + Calcd 368.04, 370.04, Found 367.8, 369.8.

[0189] Example 6. Synthesis of compounds 6.1-6.3

[0190] Referring to Example 1, the starting material 5-1 (342 mg, 1 mmol) and 1-BOC-(3-iodomethyl)azetidine (327 mg, 1.1 mmol) were reacted to obtain compound 6-1 (480 mg, 93.9%).

[0191] Compound 6-1 was dissolved in 10 mL of ethanol, 1 mL of HCl was added, and the reaction was carried out at room temperature for 16 hours. The solvent was removed under reduced pressure, and purification was carried out on a reverse-phase C18 column (ACN / H2O = 1 / 5-1 / 1) to obtain compound 6.1 (355 mg, 92.0%).

[0192] Compound 6.1 (247 mg, 0.6 mmol), potassium carbonate (166 mg, 1.2 mmol), and iodomethane (213 mg, 1.5) were stirred in dry 1 mL of DMF for 6 hours. Purification was carried out directly on a reverse-phase C18 column (ACN / H2O = 1 / 9-6 / 4) to obtain compound 6.2 (61 mg, 24.0%) and compound 6.3 (73 mg, 21.5%)

[0193] Compound 6.1 (i.e., NS-703): white solid, 1H NMR (400 MHz, DMSO-d6) δ 9.03 (br s, 2 H), 7.75 (d, J = 1.9 Hz, 1 H), 7.52 (dd, J = 8.2, 1.9 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H), 4.65 (hept, J = 6.2 Hz, 1 H), 4.37 (d, J = 6.6 Hz, 2 H), 4.07 (m, 2 H), 3.92 (m, 2 H), 3.23 (dd, J = 14.8, 8.0 Hz, 1 H), 3.17 (d, J = 16.6 Hz, 1 H), 2.91 (d, J = 16.6 Hz, 1 H), 1.32 (s, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.7 Hz, 3 H). LC-MS: [M+H] + Calcd 411.08, 413.08, Found 411.1, 413.1.

[0194] Compound 6.2 (i.e. NS-674): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1 H), 7.76 (d, J = 1.9 Hz, 1 H), 7.54 (dd, J = 8.3, 1.9 Hz, 1 H), 7.08 (d, J = 8.2 Hz, 1 H), 4.65 (hept, J = 6.2 Hz, 1 H), 4.38 (d, J = 6.5 Hz, 2 H), 4.17 (br s, 2 H), 4.06 (br s, 2 H), 3.22 (m, 2 H), 2.93 (d, J = 16.6 Hz, 1 H), 2.86 (s, 3 H), 1.34 (s, 3 H), 0.97 (t, J = 6.4 Hz, 6 H). LC-MS: [M+H] + Calcd 425.10, 427.10, Found 425.1, 427.1.

[0195] Compound 6.3 (i.e. NS-704): yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.2, 1.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.64 (hept, J = 6.2 Hz, 1H), 4.41 (d, J = 6.3 Hz, 2H), 4.36 (m, 2H), 4.28 (dd, J = 11.1, 9.3 Hz, 2H), 3.51 (m, 1H), 3.24 (s, 3H), 3.17 (d, J = 16.6 Hz, 1H), 3.16 (s, 3H), 2.92 (d, J = 16.6 Hz, 1H), 1.33 (s, 3H), 0.96 (dd, J = 6.2, 2.1 Hz, 6H). LC-MS: [M] + Calcd 439.12, 441.12, Found 439.1, 441.1.

[0196] Example 7. Synthesis of compounds 7.1-7.3

[0197] Each compound 4.1 (74 mg, 0.2 mmol) was dissolved in 2 mL of dry dichloromethane, 0.4 mL of trifluoroacetic acid was added dropwise, and the reaction was stirred at room temperature for 18 hours. After TLC detection of the complete reaction, the organic solvent was removed under reduced pressure to obtain 7-1

[0198] Under nitrogen protection, dichlorosulfoxide and a catalytic amount of DMF were added, and after refluxing for 2 hours, the organic solvent was removed under reduced pressure. Under nitrogen protection, the crude product was redissolved in dry tetrahydrofuran, cooled to -30°C, and methylpropylamine (73 mg, 1 mmol), N-methylisobutylamine (87 mg, 1 mmol), and methylisopropylamine (73 mg, 1 mmol) were added, respectively. After 30 minutes, the organic solvent was removed under reduced pressure, and the target compounds 7.1-7.3 were obtained after silica gel column purification (P:E = 2:1).

[0199] Compound 7.1 (i.e. NS-390): light yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 7.60 (dd, J = 4.8, 1.9 Hz, 1H), 7.43 (m, 1H), 6.94 (dd, J = 8.2, 2.0 Hz, 1H), 3.90 (d, J = 2.1 Hz, 3H), 3.39 (d, J = 17.1 Hz, 0.5H), 3.36 (d, J = 17.1 Hz, 0.5H), 3.24 (t, J = 7.6 Hz, 1H), 3.04 (t, J = 7.3 Hz, 1H), 2.95 (s, 1.5H), 2.93 (d, J = 15.1 Hz, 0.5H), 2.92 (d, J = 17.1 Hz, 0.5H), 2.91 (m, 1H), 2.62 (s, 1.5H), 1.55 (m, 1H), 1.31 (m, 1H), 1.27 (s, 3H), 0.90 (t, J = 7.4 Hz, 1.5H), 0.66 (t, J = 7.4 Hz, 1.5H). LC-MS: [M+H] + Calcd 369.07, 371.07, Found 369.1, 371.1.

[0200] Compound 7.2 (i.e. NS-391): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 1.9 Hz, 0.6H), 7.55 (d, J = 1.9 Hz, 0.4H), 7.44 (dd, J = 4.9, 1.9 Hz, 0.4H), 7.41 (dd, J = 4.9, 2.0 Hz, 0.6H), 6.94 (d, J = 6.8 Hz, 0.4H), 6.92 (d, J = 7.0 Hz, 0.6H), 3.91 (s, 1.2H), 3.89 (s, 1.8H), 3.39 (m, 1H), 3.12 (d, J = 7.7 Hz, 0.8H), 2.96 (s, 1.8H), 2.92 (m, 4H), 2.61 (s, 1.2H), 1.92 (m, 0.4H), 1.71 (m, 0.6H), 1.28 (s, 1.8H), 1.27 (s, 1.2H), 0.90 (d, J = 6.6 Hz, 2.4H), 0.70 (d, J = 6.7 Hz, 1.8H), 0.61 (d, J = 6.6 Hz, 1.8H). LC-MS: [M+H] + Calcd 383.09, 385.09, Found 383.1, 385.1.

[0201] Compound 7.3 (i.e. NS-392): light yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 1.9 Hz, 0.45H), 7.60 (d, J = 1.9 Hz, 0.55H), 7.44 (t, J = 2.1 Hz, 0.45H), 7.42 (t, J = 2.1 Hz, 0.55H), 6.95 (d, J = 1.4 Hz, 0.55H), 6.93 (d, J = 1.4 Hz, 0.45H), 4.38 (m, 0.55H), 4.12 (m, 0.45H), 3.45 (d, J = 17.0 Hz, 0.45H), 3.33 (d, J = 17.0 Hz, 0.55H), 2.96 (d, J = 17.0 Hz, 0.45H), 2.90 (d, J = 17.1 Hz, 0.55H), 2.79 (s, 1.65H), 2.48 (s, 1.35H), 1.26 (s, 3H), 1.13 (d, J = 6.6 Hz, 2.7H), 0.93 (d, J = 6.8 Hz, 1.65H), 0.86 (d, J = 6.8 Hz, 1.65H). LC-MS: [M+H] + Calcd 369.07, 371.07, Found 369.1, 371.1.

[0202] Example 8. Synthesis of compounds 8.1-8.4

[0203] Compound 4-2 (201 mg, 0.5 mmol) was dissolved in 5 mL of dry dichloromethane, 1 mL of trifluoroacetic acid was added dropwise, and stirred at room temperature for 18 hours. After TLC detection of the complete reaction, the organic solvent was removed under reduced pressure. Under nitrogen protection, dichlorosulfoxide and a catalytic amount of DMF were added, and refluxed for 2 hours. After removing the organic solvent under reduced pressure, the crude product was dissolved in dry tetrahydrofuran under nitrogen protection, cooled to -30°C, and methyl isopropylamine (146 mg, 2 mmol) was added. After 30 minutes, the organic solvent was removed under reduced pressure, and the target compound 8-1 (173 mg, 86.0%, colorless transparent syrup) was obtained after silica gel column purification (P:E = 2:1).

[0204] Compound 8-1 (173 mg, 0.43 mmol, 1 eq) was dissolved in 50 mL of tetrahydrofuran, ammonium chloride (184 mg, 3.44 mmol, 8 eq) was added, and zinc powder (112 mg, 1.72 mmol, 4 eq) was added in batches under ice bath conditions. The reaction was slowly warmed to room temperature and stirred at room temperature overnight. The reaction was removed from the Buchner funnel to remove the insoluble matter, and the filtrate was removed from the organic solvent. Ethyl acetate and water were added to the liquid-liquid extraction three times, and the organic layer was combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 2:1) to obtain compound 8-2 (131 mg, white solid, 85.8%).

[0205] Referring to Example 1, compound 8-2 and bromobutyronitrile were reacted in the presence of potassium bicarbonate to obtain compound 8.1 (i.e., NS-693) (68 mg, 85.0%).

[0206] Compound 8.1 (i.e., NS-693): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 1.9 Hz, 0.45H), 7.59 (d, J = 1.9 Hz, 0.55H), 7.45 ((t, J = 2.1 Hz, 0.45H), 7.43 ((t, J = 2.1 Hz, 0.55H), 7.11 (d, J = 2.3 Hz, 0.55H), 7.09 (d, J = 2.3 Hz, 0.45H), 4.89 (s, 2H), 4.37 (m, 0.55H), 4.11 (s, 0.45H), 3.46 (d, J = 17.1 Hz, 0.45H), 3.35 (d, J = 17.1 Hz, 0.55H), 2.95 (d, J = 17.0 Hz, 0.45H), 2.90 (d, J = 17.0 Hz, 0.55H), 2.79 (s, 1.65H), 2.57 (q, J = 7.2 Hz, 2H), 2.48 (s, 1.35H), 1.27 (s, 3H), 1.12 (dd, J = 6.5, 2.7 Hz, 2.7H), 0.98 (t, J = 7.3 Hz, 3H), 0.93 (d, J = 6.8 Hz, 1.65H), 0.85 (d, J = 6.8 Hz, 1.65H). LC-MS: [M+H] + Calcd 425.10, 427.10, Found 425.1, 427.1.

[0207] Referring to the above synthesis, 4-aminopyridine carboxamide was reacted with a carboxylic acid after hydrolysis of the tert-butyl ester to synthesize intermediate 8-3, which was further reduced by zinc powder to synthesize compound 8-4.

[0208] Referring to Example 1, compound 8-4 was reacted with iodomethane, 2-bromoacetyldimethylamine, chloroformyldimethylamine to give compounds 8.2-8.4.

[0209] Compound 8.2 (i.e. NS-781): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.59 (dd, J = 5.5, 2.2 Hz, 2H), 7.48 (dd, J = 8.2, 2.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 3.95 (s, 3H), 3.30 (d, J = 16.9 Hz, 1H), 3.07 (d, J = 16.9 Hz, 1H), 1.34 (s, 3H). LC-MS: [M+H] + Calcd 433.04, 435.04, Found 433.0, 435.0.

[0210] Compound 8.3 (i.e. NS-783): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 5.5, 2.2 Hz, 1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 4.92 (s, 2H), 3.29 (d, J = 16.9 Hz, 1H), 3.07 (d, J = 16.9 Hz, 1H), 2.99 (s, 3H), 2.86 (s, 3H), 1.34 (s, 3H). LC-MS: [M+H] + Calcd 504.08, 506.08, Found 504.1, 506.1.

[0211] Compound 8.4 (i.e. NS-784): white solid, 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.58 (m, 2H), 7.46 (dd, J = 8.3, 1.9 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 3.33 (d, J = 16.4 Hz, 1H), 3.13 (s, 3H), 3.08 (d, J = 16.9 Hz, 2H), 2.97 (s, 3H), 1.39 (s, 3H). LC-MS: [M+H] + Calcd 490.06, 492.06, Found 490.1, 492.1.

[0212] Example 9. Synthesis of compound 9.1

[0213] Sodium hydride (220 g, 5.5 mol, 1.1 eq, 40% mineral oil package) was suspended in 20 mL of dry DMF under nitrogen protection, cooled to -10 °C, then 9-1 (1.8 g, 50 mmol, 1 eq) of dry DMF solution was added dropwise, 30 min later, ethyl bromoacetate (1.0 g, 6 mmol, 1.2 eq) was added dropwise, after slowly rising to room temperature, stirring for 1 h, saturated aqueous ammonium chloride was added to quench the reaction. Extracted with ethyl acetate and water three times, combined the organic layer, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified on silica gel column (P:E = 4:1) to give compound 9-1 (1.98 g, colorless transparent syrup, 88.8%).

[0214] Referring to Example 1, compound 9-1 was reduced by nitro and ring closure, then methylated to give compound 9.1.

[0215] Compound 9.1 (i.e. NS-368): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 3.85 (m, 5H), 3.10 (d, J = 16.1 Hz, 2H), 2.92 (d, J = 16.1 Hz, 2H), 0.96 (t, J = 7.1 Hz, 6H). LC-MS: [M+H] + Calcd 414.05, 416.05, Found 414.0, 416.0.

[0216] Example 10. Synthesis of compounds 10.1-10.14

[0217] 50 mL of compound 1-3 (3.74 g, 10 mol, 1 eq) and 4,4'-dipyridine (78 mg, 0.5 mol, 0.05 eq) in DMF was cooled to -40 °C, and tetrahydroxyboron (2.69 g, 30 mol, 3 eq) solid was added in batches. After stirring for 2 hours, it was slowly raised to room temperature, heated to 70 °C and stirred overnight, extracted with ethyl acetate and water three times, the organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 3:1-2:1) to obtain compound 10-1 (2.83 g, 93.7%).

[0218] Compound 10-1 (63 mg, 0.2 mmol, 1 eq) was dissolved in 1 mL of dry DMF, potassium carbonate (56 mg, 0.4 mmol, 2 eq) and chloroformic dimethylamine (32 mg, 0.3 mmol, 1.5 eq) were added, stirred at room temperature for 2 hours, extracted with ethyl acetate and water three times, the organic layer was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 3:1) to obtain compound 10.1 (i.e. NS-430) (71 mg, 83.0%).

[0219] Compound 10.1 (i.e. NS-430): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.47 (dd, J = 8.4, 1.9 Hz, 1H), 6.96 (m, 1H), 3.88 (m, 2H), 3.33 (br s, 1H), 3.24 (d, J = 16.6 Hz, 1H), 3.02 (m, 5H), 2.05 (m, 0.5H), 1.91 (br s, 0.5H), 1.35 (s, 1.5H), 1.32 (s, 1.5H), 0.97 (m, 6.5H), 0.76 (m, 2.5H). LC-MS: [M+H] + Calcd 425.10, 427.10, Found 425.1, 427.1.

[0220] Referring to the above synthesis, compound 10-1 was reacted with bromomethylcyclopropyl ketone, 2-bromoacetophenone, and bromobutyronitrile respectively to obtain compounds 10.2-10.4.

[0221] Compound 10.2 (i.e. NS-424): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.84 (d, J = 18.2 Hz, 1H), 4.76 (d, J = 18.2 Hz, 1H), 3.86 (m, 2H), 3.13 (d, J = 16.5 Hz, 1H), 2.89 (d, J = 16.5 Hz, 1H), 2.21 (m, 1H), 1.31 (s, 3H), 0.96 (m, 7H). LC-MS: [M+H] + Calcd 394.06, 396.06, Found 394.0, 396.0.

[0222] Compound 10.3 (i.e. NS-425): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.4 Hz, 2H), 7.75 (t, J = 7.3 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.62 (t, J = 7.7 Hz, 2H), 7.41 (dd, J = 8.3, 1.9 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 5.41 (d, J = 18.3 Hz, 1H), 5.31 (d, J = 18.2 Hz, 1H), 3.89 (m, 2H), 3.16 (d, J = 16.4 Hz, 1H), 2.92 (d, J = 16.4 Hz, 1H), 1.36 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 430.06, 432.06, Found 430.0, 432.0.

[0223] Compound 10.4 (i.e. NS-429): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.71 (d, J = 18.1 Hz, 1H), 4.58 (d, J = 18.1 Hz, 1H), 3.86 (m, 2H), 3.12 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.5 Hz, 1H), 2.60 (q, J = 7.3 Hz, 2H), 1.31 (s, 3H), 0.98 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] +Calcd 382.06, 384.06, Found 382.0, 384.0.

[0224] Compound 10-1 (90 mg, 0.3 mmol) was dissolved in dry tetrahydrofuran under nitrogen protection, sodium hydride (14 mg, 0.36 mmol, 1.2 eq, 40% mineral oil wrapped) was added under ice water bath, after stirring at room temperature for 1 hour, 2-bromoethyl methyl ether (63 mg, 0.45 mmol), 1-iodobutane (84 mg, 0.45 mmol), 2-bromoethyl isopropyl ether (75 mg, 0.45 mmol), bromomethyl ethyl ether (63 mg, 0.45 mmol), bromomethyl methyl ether (57 mg, 0.45 mmol), 1-iodopentane (90 mg, 0.45 mmol), 1-iodoisopentane (90 mg, 0.45 mmol), 2-bromoethyl ethyl ether (69 mg, 0.45 mmol), 1-iodoisobutane (84 mg, 0.45 mmol) and iodomethyl cyclopropane (82 mg, 0.45 mmol) were added under ice water bath, and stirred at room temperature for 2 hours, and then quenched by saturated aqueous ammonium chloride solution. Extracted with ethyl acetate and water, and the organic layers were combined. Dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 4:1~3:1) to obtain compounds 10.5~10.14 (68.0~87.0%).

[0225] Compound 10.5 (i.e. NS-901): white waxy, 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 3.83 (m, 4H), 3.53 (m, 2H), 3.25 (s, 3H), 3.10 (d, J = 16.5 Hz, 1H), 2.87 (d, J = 16.5 Hz, 1H), 1.25 (s, 3H), 0.94 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 370.06, 372.06, Found 370.0, 372.0.

[0226] Compound 10.6 (i.e. NS-902): white waxy, 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 3.84 (m, 2H), 3.67 (m, 2H), 3.11 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.5 Hz, 1H), 1.57 (m, 2H), 1.33 (dq, J = 14.7, 7.4 Hz, 2H), 1.26 (s, 3H), 0.93 (m, 6H). LC-MS: [M+H] + Calcd 368.08, 370.08, Found 368.1, 370.1.

[0227] Compound 10.7 (i.e. NS-903): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.3, 2.1 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.86 (m, 3H), 3.75 (ddd, J = 14.2, 11.1, 6.3 Hz, 1H), 3.56 (m, 3H), 3.11 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.5 Hz, 1H), 1.27 (s, 3H), 1.03 (d, J = 6.1 Hz, 6H), 0.95 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 398.09, 400.09, Found 398.1, 400.1.

[0228] Compound 10.8 (i.e. NS-993): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 8.3, 2.1 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 5.14 (d, J = 11.1 Hz, 1H), 5.11 (d, J = 11.1 Hz, 1H), 3.85 (m, 2H), 3.52 (m, 2H), 3.18 (d, J = 16.7 Hz, 1H), 2.94 (d, J = 16.7 Hz, 1H), 1.30 (s, 3H), 1.11 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 370.06, 372.06, Found 369.8, 371.8.

[0229] Compound 10.9 (i.e. NS-994): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.3, 2.1 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 5.11 (d, J = 11.0 Hz, 1H), 5.07 (d, J = 11.0 Hz, 1H), 3.86 (m, 2H), 3.27 (s, 3H), 3.19 (d, J = 16.8 Hz, 1H), 2.95 (d, J = 16.8 Hz, 1H), 1.31 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 356.04, 358.04, Found 355.8, 357.8.

[0230] Compound 10.10 (i.e. NS-990): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 3.83 (m, 2H), 3.66 (m, 2H), 3.12 (d, J = 16.6 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 1.59 (m, 2H), 1.31 (m, 4H), 1.25 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 6.8 Hz, 3H). LC-MS: [M+H] + Calcd 382.09, 384.09, Found 355.8, 357.8.

[0231] Compound 10.11 (i.e. NS-991): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 3.83 (m, 2H), 3.68 (m, 2H), 3.12 (d, J = 16.6 Hz, 1H), 2.88 (d, J = 16.6 Hz, 1H), 1.61 (dp, J = 13.1, 6.5 Hz, 1H), 1.46 (dt, J = 8.6, 4.4 Hz, 2H), 1.25 (s, 3H), 0.95 (m, 9H). LC-MS: [M+H] + Calcd 382.09, 384.09, Found 355.8, 357.8.

[0232] Compound 10.12 (i.e. NS-992): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 1.9 Hz, 1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 3.83 (m, 4H), 3.56 (m, 2H), 3.43 (m, 2H), 3.10 (d, J = 16.5 Hz, 1H), 2.87 (d, J = 16.5 Hz, 1H), 1.25 (s, 3H), 1.05 (t, J = 7.0 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 384.07, 386.07, Found 383.8, 385.8.

[0233] Compound 10.13 (i.e. NS-995): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 3.84 (m, 2H), 3.48 (qd, J = 13.8, 7.4 Hz, 2H), 3.13 (d, J = 16.6 Hz, 1H), 2.89 (d, J = 16.6 Hz, 1H), 2.05 (dp, J = 13.8, 6.9 Hz, 1H), 1.27 (s, 3H), 0.93 (m, 9H). LC-MS: [M+H] + Calcd 368.08, 370.08, Found 367.8, 369.8.

[0234] Compound 10.14 (i.e. NS-1203): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 3.83 (m, 2H), 3.59 (dd, J = 6.6, 4.5 Hz, 2H), 3.11 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.5 Hz, 1H), 1.26 (s, 3H), 1.12 (m, 1H), 0.93 (t, J = 7.1 Hz, 3H), 0.45 (m, 2H), 0.34 (m, 2H). LC-MS: [M+H] +Calcd 366.06, 368.06, Found 365.8, 367.8.

[0235] Example 11. Synthesis of compound 11.1

[0236] To compound 10-1 (94 mg, 0.3 mmol) and sodium carbonate (4 mg, 0.03 mmol), 3 mL water and 1-octenone (63 mg, 0.5 mmol) were added. The tube was sealed and heated at 100 °C for 16 h. Ethyl acetate was added and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification on silica gel column (P:E = 4:1 to 3:1) gave compound 11.1.

[0237] Compound 11.1 (i.e. NS-432): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 3.84 (m, 4H), 3.10 (d, J = 16.6 Hz, 1H), 2.86 (d, J = 16.6 Hz, 1H), 2.75 (dd, J = 11.7, 7.1 Hz, 2H), 2.44 (t, J = 7.3 Hz, 3H), 1.45 (m, 2H), 1.21 (m, 7H), 0.95 (t, J = 7.1 Hz, 3H), 0.84 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 438.12, 440.12, Found 438.1, 440.1.

[0238] Example 12. Synthesis of compounds 12.1 and 12.2

[0239] A solution of compound 10-1 (312 mg, 1 mmol), 4-chloro-2-pyridinecarbonitrile (276 mg, 2 mmol), L-proline (46 mg, 0.4 mmol), and cesium carbonate (752 mg, 2 mmol) in DMSO was stirred at room temperature for 30 min under nitrogen. Copper(I) iodide (190 mg, 1 mmol) was added and the reaction was stirred at 100 °C for 6 h. Ethyl acetate and water were added and the organic layer was combined. The organic layer was dried over anhydrous sodium sulfate and concentrated. Purification on silica gel column (P:E = 1:1 to 100% EA to 10% DCM / MeOH) gave compound 12.1 (61 mg, 14.1%).

[0240] Compound 12.1 (i.e. NS-506): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J = 5.3 Hz, 1H), 8.24 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.74 (dd, J = 5.3, 2.1 Hz, 1H), 7.47 (dd, J = 8.4, 2.1 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 3.89 (m, 2H), 3.27 (d, J = 16.9 Hz, 1H), 3.07 (d, J = 16.9 Hz, 1H), 1.43 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 432.05, 434.05, Found 432.0, 434.0.

[0241] Compound 10-1 was coupled with 2-chloro-5-iodopyridine according to the procedure described above to give compound 12.2.

[0242] Compound 12.2 (i.e. NS-1267): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.5 Hz, 1H), 7.98 (dd, J = 8.5, 2.7 Hz, 1H), 7.80 (dd, J = 7.7, 5.3 Hz, 2H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.91 (m, 2H), 3.29 (d, J = 16.9 Hz, 1H), 3.05 (d, J = 16.9 Hz, 1H), 1.43 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 423.00, 425.00, Found 422.8, 424.8.

[0243] Example 13. Synthesis of compounds 13.1-13.3

[0244] Compound 4-2 was reduced from nitro to amino with tetrahydroxydiboron and simultaneously ring-closed according to the procedure of Example 10 to give compound 13-1, which was reacted with 1-bromoethyl methyl ether, 1-iodobutane, 1-bromoethyl ethyl ether respectively to give alkyl products;

[0245] The above alkylated products were subjected to ester exchange under acidic condition in methanol solution to give compounds 13.1-13.3 according to the transesterification reaction of Example 4.

[0246] Compound 13.1 (i.e. NS-1257): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 3.89 (dt, J = 14.3, 6.1 Hz, 1H), 3.80 (dt, J = 14.4, 5.6 Hz, 1H), 3.54 (m, 2H), 3.41 (s, 3H), 3.26 (s, 3H), 3.17 (d, J = 16.9 Hz, 1H), 2.91 (d, J = 16.9 Hz, 1H), 1.26 (s, 3H). LC-MS: [M+H] + Calcd 356.04, 358.04, Found 355.8, 357.8.

[0247] Compound 13.2 (i.e. NS-1258): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 3.67 (m, 2H), 3.41 (s, 3H), 3.17 (d, J = 16.9 Hz, 1H), 2.91 (d, J = 16.9 Hz, 1H), 1.57 (m, 2H), 1.34 (m, 2H), 1.25 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 354.06, 356.06, Found 353.8, 355.8.

[0248] Compound 13.3 (i.e. NS-1260): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.89 (m, 1H), 3.79 (m, 1H), 3.57 (m, 2H), 3.46 (ddd, J = 12.1, 8.2, 6.0 Hz, 2H), 3.42 (d, J = 4.9 Hz, 3H), 3.17 (d, J = 16.9 Hz, 1H), 2.91 (d, J = 16.9 Hz, 1H), 1.26 (s, 3H), 1.07 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 370.06, 372.06, Found 369.8, 371.8.

[0249] Example 14. Synthesis of compounds 14.1-14.10

[0250] Referring to Example 1, compounds 1-2 were reacted with iodoethane, iodoisopropane and (iodomethyl)cyclopropane respectively to give compounds 14-1-14-3;

[0251] Referring to Example 10, compounds 14-1-14-3 were reduced to amino by tetrahydroxydiboron and simultaneously ring-closing to give compounds 14-4-14-6, which were reacted with bromobutyronitrile, 2-bromoacetophenone and bromomethylcyclopropanone respectively in the presence of potassium carbonate to give compounds 14.1-14.8.

[0252] Compound 14.1 (i.e. NS-431): pale yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.74 (d, J = 18.1 Hz, 1H), 4.55 (d, J = 18.1 Hz, 1H), 3.84 (m, 2H), 3.09 (d, J = 16.2 Hz, 1H), 2.86 (d, J = 16.2 Hz, 1H), 2.62 (q, J = 7.3 Hz, 2H), 1.85 (dq, J = 14.9, 7.5 Hz, 1H), 1.74 (dq, J = 14.4, 7.2 Hz, 1H), 0.97 (m, 6H), 0.59 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 396.07, 398.07, Found 396.1, 398.1.

[0253] Compound 14.2 (i.e. NS-433): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.2 Hz, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.62 (dd, J = 11.1, 4.6 Hz, 3H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.42 (d, J = 18.2 Hz, 1H), 5.27 (d, J = 18.1 Hz, 1H), 3.87 (pd, J = 7.9, 3.7 Hz, 2H), 3.11 (d, J = 16.2 Hz, 1H), 2.89 (d, J = 16.2 Hz, 1H), 1.89 (dq, J = 15.0, 7.5 Hz, 1H), 1.78 (dq, J = 14.8, 7.3 Hz, 1H), 0.97 (t, J = 7.1 Hz, 3H), 0.64 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 444.07, 446.07, Found 444.1, 446.1.

[0254] Compound 14.3 (i.e. NS-440): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.76 (d, J = 18.1 Hz, 1H), 4.53 (d, J = 18.1 Hz, 1H), 3.83 (m, 2H), 3.02 (d, J = 15.9 Hz, 1H), 2.83 (s, 1H), 2.63 (q, J = 7.3 Hz, 2H), 1.85 (dd, J = 13.8, 6.4 Hz, 1H), 1.72 (dd, J = 13.7, 5.6 Hz, 1H), 1.36 (m, 1H), 0.99 (t, J = 7.3 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H), 0.52 (d, J = 6.6 Hz, 3H). LC-MS: [M+H] + Calcd 424.10, 426.10, Found 424.1, 426.1.

[0255] Compound 14.4 (i.e. NS-439): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 7.2 Hz, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.61 (t, J = 7.7 Hz, 2H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 5.44 (d, J = 18.2 Hz, 1H), 5.23 (d, J = 18.2 Hz, 1H), 3.86 (m, 2H), 3.04 (d, J = 15.8 Hz, 1H), 2.83 (d, J = 15.8 Hz, 1H), 1.88 (dd, J = 13.7, 6.5 Hz, 1H), 1.76 (dd, J = 13.7, 5.4 Hz, 1H), 1.44 (hept, J = 6.4 Hz, 1H), 0.96 (t, J = 7.1 Hz, 3H), 0.74 (d, J = 6.7 Hz, 3H), 0.54 (d, J = 6.6 Hz, 3H). LC-MS: [M+H] + Calcd 472.10, 474.10, Found 472.1, 474.1.

[0256] Compound 14.5 (i.e. NS-441): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 7.2 Hz, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.61 (t, J = 7.7 Hz, 2H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 5.44 (d, J = 18.2 Hz, 1H), 5.23 (d, J = 18.2 Hz, 1H), 3.86 (m, 2H), 3.04 (d, J = 15.8 Hz, 1H), 2.83 (d, J = 15.8 Hz, 1H), 1.88 (dd, J = 13.7, 6.5 Hz, 1H), 1.76 (dd, J = 13.7, 5.4 Hz, 1H), 1.44 (hept, J = 6.4 Hz, 1H), 0.96 (t, J = 7.1 Hz, 3H), 0.74 (d, J = 6.7 Hz, 3H), 0.54 (d, J = 6.6 Hz, 3H). LC-MS: [M+H] + Calcd 436.10, 438.10, Found 436.1, 438.1.

[0257] Compound 14.6 (i.e. NS-444): white solid, 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 4.73 (d, J = 18.1 Hz, 1H), 4.54 (d, J = 18.0 Hz, 1H), 3.84 (m, 2H), 3.11 (d, J = 16.3 Hz, 1H), 2.90 (d, J = 16.3 Hz, 1H), 2.62 (q, J = 7.3 Hz, 2H), 1.83 (dd, J = 13.7, 6.4 Hz, 1H), 1.58 (dd, J = 13.7, 7.2 Hz, 1H), 0.98 (m, 3H), 0.95 (t, J = 7.1 Hz, 3H), 0.43 (m, 1H), 0.28 (m, 1H), 0.18 (ddd, J = 13.0, 9.0, 4.1 Hz, 1H), -0.05 (dt, J = 9.2, 4.7 Hz, 1H), -0.19 (td, J = 9.3, 5.1 Hz, 1H). LC-MS: [M+H] + Calcd 422.09, 424.09, Found 422.1, 424.1.

[0258] Compound 14.7 (i.e. NS-445): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.3, 2.0 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.86 (d, J = 18.1 Hz, 1H), 4.71 (d, J = 18.1 Hz, 1H), 3.84 (m, 2H), 3.12 (d, J = 16.4 Hz, 1H), 2.90 (d, J = 16.3 Hz, 1H), 2.23 (m, 1H), 1.82 (dd, J = 13.6, 6.4 Hz, 1H), 1.58 (dd, J = 13.7, 7.2 Hz, 1H), 0.97 (m, 7H), 0.42 (m, 1H), 0.26 (m, 1H), 0.16 (m, 1H), -0.06 (td, J = 9.3, 5.0 Hz, 1H), -0.20 (td, J = 9.3, 4.9 Hz, 1H). LC-MS: [M+H] + Calcd 434.09, 436.09, Found 434.1, 436.1.

[0259] Compound 14.8 (i.e. NS-443): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.12 (m, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.61 (t, J = 7.7 Hz, 2H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.43 (d, J = 18.1 Hz, 1H), 5.26 (d, J = 18.1 Hz, 1H), 3.87 (m, 2H), 3.14 (d, J = 16.3 Hz, 1H), 2.93 (d, J = 16.3 Hz, 1H), 1.83 (dd, J = 13.7, 6.6 Hz, 1H), 1.64 (dd, J = 13.6, 7.0 Hz, 1H), 0.97 (t, J = 7.1 Hz, 3H), 0.52 (m, 1H), 0.32 (m, 1H), 0.20 (m, 1H), -0.03 (td, J = 9.3, 4.8 Hz, 1H), -0.17 (td, J = 9.3, 5.0 Hz, 1H). LC-MS: [M+H] + Calcd 470.09, 472.09, Found 470.1, 472.1.

[0260] Reference Example 11, compounds 14-5 and 14-6 were reacted with 1-octen-3-one to give compounds 14.9 and 14.10, respectively.

[0261] Compound 14.9 (i.e. NS-438): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.3, 2.0 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 3.83 (m, 4H), 3.02 (d, J = 16.1 Hz, 1H), 2.81 (d, J = 15.9 Hz, 1H), 2.78 (t, 2H), 2.45 (t, J = 7.3 Hz, 2H), 1.81 (dd, J = 13.7, 5.8 Hz, 1H), 1.67 (dd, J = 13.7, 6.4 Hz, 1H), 1.46 (m, 2H), 1.24 (m, 4H), 1.11 (hept, J = 6.4 Hz, 1H), 0.93 (t, J = 7.1 Hz, 3H), 0.85 (t, J = 7.1 Hz, 3H), 0.66 (d, J = 6.6 Hz, 3H), 0.51 (d, J = 6.6 Hz, 3H). LC-MS: [M+H] + Calcd 480.17, 482.17, Found 480.2, 482.2.

[0262] Compound 14.10 (i.e. NS-442): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 2.0 Hz, 1H), 7.45 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.86 (m, 4H), 3.09 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.5 Hz, 1H), 2.78 (t, J = 7.2 Hz, 2H), 2.46 (t, J = 7.3 Hz, 2H), 1.91 (dd, J = 14.0, 4.5 Hz, 1H), 1.45 (m, 3H), 1.24 (m, 5H), 0.95 (t, J = 7.1 Hz, 3H), 0.86 (t, J = 7.0 Hz, 3H), 0.15 (m, 3H), -0.04 (m, 1H), -0.20 (td, J = 8.5, 4.2 Hz, 1H). LC-MS: [M+H] + Calcd 478.15, 480.15, Found 478.1, 480.1.

[0263] Example 15. Synthesis of compounds 15.1-15.5

[0264] According to Reference Example 8, compound 4-2 was subjected to ester hydrolysis of tert-butyl ester and condensation with dibutylamine to give compound 15-1.

[0265] According to the procedure of Example 10, compound 4-2 was subjected to reduction of nitro group to amino group with tetrahydroxydiboron and simultaneous ring closure to give compound 15-2.

[0266] According to Reference Example 10, compound 15-2 was reacted with bromobutyronitrile, bromoethyl methyl ether, bromoethyl isopropyl ether and 1-iodobutane respectively to give compounds 15.1-15.5.

[0267] Compound 15.1 (i.e. NS-1627): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.3, 1.9 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.66 (d, J = 18.0 Hz, 1H), 4.49 (d, J = 18.0 Hz, 1H), 3.30 (d, J = 16.6 Hz, 2H), 3.19 (m, 2H), 2.99 (t, J = 7.4 Hz, 2H), 2.88 (d, J = 16.6 Hz, 1H), 2.60 (q, J = 7.2 Hz, 2H), 1.54 (m, 2H), 1.25 (m, 5H), 0.97 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H), 0.66 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 437.14, 439.14, Found 436.9, 438.9.

[0268] Compound 15.2 (i.e. NS-1629): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.3, 2.0 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 3.90 (dt, J = 14.2, 6.1 Hz, 1H), 3.71 (dt, J = 14.3, 5.7 Hz, 1H), 3.52 (m, 2H), 3.27 (m, 5H), 3.16 (m, 1H), 2.98 (m, 2H), 2.85 (d, J = 16.5 Hz, 1H), 1.53 (m, 2H), 1.24 (m, 5H), 0.90 (t, J = 7.3 Hz, 3H), 0.65 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 425.14, 427.14, Found 424.9, 426.9.

[0269] Compound 15.3 (i.e. NS-1631): white solid, 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.3, 2.0 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 3.86 (dt, J = 13.7, 6.2 Hz, 1H), 3.68 (dt, J = 14.0, 5.7 Hz, 1H), 3.55 (m, 3H), 3.26 (m, 2H), 3.16 (m, 1H), 2.98 (m, 2H), 2.84 (d, J = 16.5 Hz, 1H), 1.53 (m, 2H), 1.24 (m, 5H), 1.03 (d, J = 6.1 Hz, 6H), 0.90 (t, J = 7.3 Hz, 3H), 0.65 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 453.19, 455.19, Found 452.9, 454.9.

[0270] Compound 15.4 (i.e. NS-1633): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.3, 2.0 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.63 (m, 2H), 3.21 (m, 3H), 2.98 (m, 2H), 2.85 (d, J = 16.6 Hz, 1H), 1.55 (dq, J = 9.7, 7.1 Hz, 4H), 1.34 (dt, J = 14.9, 7.4 Hz, 2H), 1.24 (m, 5H), 0.90 (t, J = 7.3 Hz, 6H), 0.65 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 423.16, 425.16, Found 422.9, 424.9.

[0271] Following the procedures described above, compound 4-2 was hydrolyzed from the tert-butyl ester and reacted with N-methylpiperazine to give compound 15-3, which was reduced to close the ring and reacted with iodobutane to give compound 15.5.

[0272] Compound 15.5 (i.e. NS-1630): light pink solid, 1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.3, 2.0 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 3.63 (m, 2H), 3.44 (m, 2H), 3.32 (d, J = 16.8 Hz, 1H), 3.22 (t, J = 4.8 Hz, 2H), 2.86 (d, J = 16.8 Hz, 1H), 2.29 (br s, 2H), 2.15 (m, 4H), 2.07 (m, 1H), 1.56 (m, 2H), 1.33 (m, 2H), 1.21 (s, 3H), 0.90 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 422.14, 424.14, Found 421.9, 423.9.

[0273] Example 16. Synthesis of compounds 16.1-16.2

[0274] Compound 8-4 (420 mg, 1 mmol, 1 eq) was dissolved in 1 mL dry DMF, potassium bicarbonate (150 mg, 1.5 mmol, 1.5 eq) and ethyl 2-bromoacetate (175 mg, 1.05 mmol, 1.05 eq) were added, after stirring at room temperature for 2 hours, TLC detection showed that the reaction was complete. Potassium carbonate (276 mg, 2 mmol, 2 eq) was added and stirring was continued for 16 hours. The organic layer was extracted with ethyl acetate and water three times, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 2:1) to obtain compound 16-1.

[0275] Referring to Example 10, compound 16-1 was reacted with bromobutanone and iodomethane respectively to obtain compounds 16.1 and 16.2.

[0276] Compound 16.1 (i.e. NS-508): white solid, 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.42 (d, J = 5.5 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 8.03 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 5.5, 2.1 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 4.73 (d, J = 18.0 Hz, 1H), 4.61 (d, J = 18.1 Hz, 1H), 3.26 (d, J = 16.5 Hz, 1H), 3.01 (d, J = 16.5 Hz, 1H), 2.61 (q, J = 7.3 Hz, 2H), 1.36 (s, 3H), 0.98 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 473.07, 475.07, Found 473.1, 475.1.

[0277] Compound 16.2 (i.e. NS-509): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.03 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 7.54 (dd, J = 5.5, 2.2 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 3.23 (d, J = 16.6 Hz, 1H), 3.17 (s, 3H), 3.01 (d, J = 16.6 Hz, 1H), 1.30 (s, 3H). LC-MS: [M+H] + Calcd 417.05, 419.05, Found 417.0, 419.0.

[0278] Example 17. Synthesis of compounds 17.1-17.12

[0279] Compound 10-1 (3.12 g, 10 mmol) was dissolved in dry DMF under nitrogen protection, sodium hydride (88 mg, 2.2 mmol) was added portionwise under ice water bath, after stirring at room temperature for 30 minutes, diphenyl phosphine hydroxylamine (2.57 g, 11 mmol) was added, and stirred at 80°C for 16 hours. Ethyl acetate and water were added, and the organic phase was separated and washed with saturated brine. After drying over anhydrous sodium sulfate, concentration and purification on silica gel column (P:E = 3:1~1:1), compound 17.1 (3.08 mg, 94.2%) was obtained.

[0280] Compound 17.1 (i.e. NS-1636): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.2, 1.9 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 5.12 (s, 2H), 3.84 (m, 2H), 3.09 (d, J = 16.5 Hz, 1H), 2.87 (d, J = 16.5 Hz, 1H), 1.27 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 327.03, 329.03, Found 326.8, 328.8.

[0281] Compound 17.1 (169 mg, 0.5 mmol), triethyl orthoformate (318 mg, 3 mmol) and acetic acid (180 mg, 3 mmol) were dissolved in 2.5 ml of 1,2-dichloroethane, N-methyl n-propylamine (110 mg, 1.5 mmol) was added, and heated to 70°C for 16 hours. The reaction was terminated with triethylamine, concentrated under reduced pressure, and purified on silica gel column (P:E = 3:1~2:1) to obtain compound 17.2.

[0282] Compound 17.2 (i.e. NS-1220): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (brs, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 3.85 (m, 2H), 3.26 (s, 2H), 3.09 (d, J = 16.4 Hz, 1H), 2.95 (s, 3H), 2.87 (d, J = 16.4 Hz, 1H), 1.60 (brs, 2H), 1.31 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H), 0.89 (brs, 3H). LC-MS: [M+H] +Calcd 410.10, 412.10, Found 409.9, 411.9.

[0283] Referring to the above synthesis, compound 17.1 was reacted with N-methylisopropylamine, N-methylisobutylamine, N-methyl ethylamine, tetrahydropyrrole, morpholine, N-methylisobutylamine, N-methylpiperazine, 2-methylpyrrolidine, indoline, 2-methylaminothiazole, respectively, to give compounds 17.3-17.12.

[0284] Compound 17.3 (i.e. NS-1216): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (br s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 3.85 (m, 2H), 3.71 (br s, 1H), 3.09 (d, J = 16.4 Hz, 1H), 2.87 (d, J = 16.3 Hz, 1H), 2.86 (s, 3H), 1.31 (s, 3H), 1.20 (d, J = 6.6 Hz, 6H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 410.10, 412.10, Found 409.9, 411.9.

[0285] Compound 17.4 (i.e. NS-1219): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 3.85 (m, 2H), 3.33 (br s, 1H), 3.09 (d, J = 16.4 Hz, 1H), 2.87 (d, J = 16.4 Hz, 1H), 2.83 (s, 3H), 1.53 (m, 2H), 1.31 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H), 0.97 (td, J = 7.1, 2.3 Hz, 3H), 0.85 (t, J = 6.4 Hz, 3H). LC-MS: [M+H] + Calcd 424.12, 426.12, Found 423.9, 425.9.

[0286] Compound 17.5 (i.e. NS-1215): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.61 (d, J = 1.9 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 3.85 (m, 2H), 3.35 (br s, 2H), 3.10 (d, J = 16.4 Hz, 1H), 2.95 (s, 3H), 2.87 (d, J = 16.4 Hz, 1H), 1.31 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 396.08, 398.08, Found 395.8, 397.8.

[0287] Compound 17.6 (i.e. NS-1214): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.40 (dd, J = 8.2, 2.0 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 3.85 (m, 2H), 3.42 (br s, 4H), 3.10 (d, J = 16.4 Hz, 1H), 2.87 (d, J = 16.4 Hz, 1H), 1.92 (br s, 4H), 1.30 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 408.08, 410.08, Found 407.8, 409.8.

[0288] Compound 17.7 (i.e. NS-1256): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 6.2 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.85 (m, 2H), 3.67 (m, 4H), 3.45 (br s, 4H), 3.11 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.5 Hz, 1H), 1.31 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 424.08, 426.08, Found 423.8, 425.8.

[0289] Compound 17.8 (i.e. NS-1217): pale yellow syrup,1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.81 (m, 1H), 3.85 (qd, J = 7.1, 1.4 Hz, 2H), 3.09 (d, J = 16.4 Hz, 1H), 3.07 (brs, 2H), 2.96 (s, 3H), 2.87 (d, J = 16.4 Hz, 1H), 1.97 (brs, 1H), 1.31 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H), 0.90 (brs, 6H). LC-MS: [M+H] + Calcd 424.12, 426.12, Found 423.9, 425.9.

[0290] Compound 17.9 (i.e. NS-1218): yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 3.85 (m, 2H), 3.45 (brs, 4H), 3.11 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.5 Hz, 1H), 2.42 (m, 4H), 2.27 (s, 3H), 1.31 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 437.11, 439.11, Found 436.9, 438.9.

[0291] Compound 17.10 (i.e. NS-1293): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.61 (d, J = 1.5 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 3.85 (m, 3H), 3.43 (m, 2H), 3.10 (dd, J = 16.4, 0.5 Hz, 1H), 2.87 (dd, J = 16.4, 1.6 Hz, 1H), 2.08 (dt, J = 13.6, 6.9 Hz, 1H), 1.99 (m, 1H), 1.88 (dt, J = 12.0, 6.0 Hz, 1H), 1.59 (m, 1H), 1.31 (d, J = 1.3 Hz, 3H), 1.23 (d, J = 6.0 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 422.10, 424.10, Found 421.9, 423.9.

[0292] Compound 17.11 (i.e. NS-1294): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 8.2, 1.9 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.21 (m, 2H), 6.98 (t, J = 7.8 Hz, 2H), 4.08 (t, J = 8.6 Hz, 2H), 3.86 (m, 2H), 3.24 (t, J = 8.6 Hz, 2H), 3.17 (d, J = 16.6 Hz, 1H), 2.94 (d, J = 16.5 Hz, 1H), 1.38 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 456.08, 458.08, Found 455.8, 457.8.

[0293] Compound 17.12 (i.e. NS-1295): white solid, 1H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 3.5 Hz, 1H), 7.51 (dd, J = 8.3, 2.0 Hz, 1H), 7.35 (d, J = 3.5 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 3.83 (m, 2H), 3.20 (d, J = 16.7 Hz, 1H), 2.97 (d, J = 16.7 Hz, 1H), 1.37 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 451.04, 453.04, Found 450.8, 452.8.

[0294] Example 18. Synthesis of compound 18.1

[0295] Compound 17.1 (98 mg, 0.3 mmol) was dissolved in acetonitrile, N,N- dimethylformamide dimethyl acetal (119 mg, 1 mmol) was added, heated to 50 °C overnight. Compound 18.1 (i.e. NS-1213) (83 mg, 72.4%) was obtained after concentration under reduced pressure and purification by silica gel column (P:E = 3:1 ~ 2:1).

[0296] Compound 18.1 (i.e. NS-1213): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 3.85 (m, 2H), 3.10 (d, J = 16.4 Hz, 1H), 2.87 (d, J = 16.4 Hz, 1H), 1.31 (s, 3H), 0.97 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 382.07, 384.07, Found 381.8, 383.8.

[0297] Example 19. Synthesis of compounds 19.1-19.6

[0298] Compound 17.1 (327 mg, 1 mmol) and cyclopropylcarboxaldehyde (105 mg, 1.5 mmol) were dissolved in dichloroethane, a catalytic amount of acetic acid was added, stirred at room temperature overnight. Compound 19.1 (i.e. NS-1204) (301 mg, 79.4%) was obtained after concentration under reduced pressure and purification by silica gel column (P:E = 4:1 ~ 3:1).

[0299] Compound 19.1 (i.e. NS-1204): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.3, 2.0 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 3.82 (qd, J = 7.0, 1.0 Hz, 2H), 3.17 (d, J = 16.7 Hz, 1H), 2.92 (d, J = 16.7 Hz, 1H), 1.81 (m, 1H), 1.32 (s, 3H), 1.04 (m, 2H), 0.94 (t, J = 7.1 Hz, 3H), 0.87 (m, 2H). LC-MS: [M+H] + Calcd 379.06, 381.06, Found 378.8, 380.8.

[0300] Compound 19.1 (114 mg, 0.3 mmol) was dissolved in anhydrous tetrahydrofuran, cooled to 0 °C under nitrogen protection, sodium borohydride (23 mg, 0.6 mmol) was added in batches, slowly raised to room temperature, and stirred for 16 hours. Ammonium chloride aqueous solution was added under ice water bath, the aqueous phase was washed with dichloromethane three times, and the organic phases were combined. Compound 19.2 (i.e. NS-1208, 71 mg, 62.1%) was obtained after silica gel column purification (P:E = 2:1~1:1) under reduced pressure.

[0301] Compound 19.2 (i.e. NS-1208): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 5.96 (t, J = 4.8 Hz, 1H), 3.85 (m, 2H), 3.12 (d, J = 16.6 Hz, 1H), 2.89 (d, J = 16.5 Hz, 1H), 2.80 (m, 2H), 0.97 (t, J = 7.1 Hz, 3H), 0.90 (m, 1H), 0.39 (m, 2H), 0.15 (m, 1H), 0.09 (m, 1H). LC-MS: [M+H] + Calcd 381.07, 383.07, Found 380.8, 382.8.

[0302] Referring to the synthesis of compound 19.1 above, compounds 19.3~19.5 were obtained by reacting compound 19.1 with isobutyraldehyde, isoamyl aldehyde, propyl aldehyde, respectively.

[0303] Compound 19.3 (i.e. NS-1205): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 4.9 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.83 (q, J = 7.1 Hz, 2H), 3.18 (d, J = 16.7 Hz, 1H), 2.95 (d, J = 16.7 Hz, 1H), 2.69 (m, 1H), 1.34 (s, 3H), 1.17 (d, J = 6.9 Hz, 6H), 0.95 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 381.07, 383.07, Found 380.8, 382.8.

[0304] Compound 19.4 (i.e. NS-1206): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (t, J = 5.8 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 3.82 (q, J = 7.1 Hz, 2H), 3.18 (d, J = 16.7 Hz, 1H), 2.96 (d, J = 16.6 Hz, 1H), 2.34 (t, J = 6.3 Hz, 2H), 1.99 (dp, J = 13.4, 6.7 Hz, 1H), 1.35 (s, 3H), 1.00 (d, J = 6.7 Hz, 6H), 0.94 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 395.09, 397.09, Found 394.8, 396.8.

[0305] Compound 19.5 (i.e. NS-1207): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.92 (t, J = 4.8 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.83 (q, J = 7.1 Hz, 2H), 3.19 (d, J = 16.7 Hz, 1H), 2.96 (d, J = 16.7 Hz, 1H), 2.47 (m, 2H), 1.34 (s, 3H), 1.16 (t, J = 7.4 Hz, 3H), 0.96 (t, J = 7.1 Hz, 3H). LC-MS: [M+H]+ Calcd 367.06, 369.06, Found 366.8, 368.8.

[0306] Referring to the synthesis of compound 19.2, compound 19.3 was reduced by sodium borohydride to obtain compound 19.6.

[0307] Compound 19.6 (i.e. NS-1209): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.2, 2.0 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 5.88 (t, J = 5.6 Hz, 1H), 3.85 (m, 2H), 3.14 (d, J = 16.6 Hz, 1H), 2.89 (d, J = 16.6 Hz, 1H), 2.74 (m, 2H), 1.69 (dp, J = 13.3, 6.7 Hz, 1H), 1.26 (s, 3H), 0.96 (m, 9H). LC-MS: [M+H] + Calcd 383.09, 385.09, Found 382.8, 384.8.

[0308] Example 20. Synthesis of compounds 20.1-20.3

[0309] Each compound 26.1 (90 mg, 0.3 mmol) and triethylamine (4 mg, 0.03 mmol) were dissolved in 3 mL of ethanol, and were reacted with 1-octenone (63 mg, 0.5 mmol), 1-hexen-3-one (49 mg, 0.5 mmol), 1-penten-3-one (42 mg, 0.5 mmol) respectively in a sealed tube at 100 °C for 16 hours. Ethyl acetate was added for extraction, and the organic layers were combined. After drying over anhydrous sodium sulfate, concentration and purification on a silica gel column (P:E = 4:1-2; 1), 20.1-20.3 were obtained.

[0310] Compound 20.1 (i.e. NS-1210): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 0.1H), 6.93 (d, J = 8.3 Hz, 0.9H), 5.95 (t, J = 5.2 Hz, 0.9H), 3.85 (m, 2.2H), 3.14 (m, 2.8H), 2.90 (m, 1H), 2.76 (dd, J = 12.3, 7.0 Hz, 0.2H), 2.62 (td, J = 6.6, 3.1 Hz, 1.82H), 2.45 (t, J = 7.4 Hz, 0.2H), 2.40 (t, J = 7.3 Hz, 1.8H), 1.45 (m, 2H), 1.22 (m, 7H), 0.96 (t, J = 7.1 Hz, 3H), 0.86 (m, 3H). LC-MS: [M+H] + Calcd 453.13, 455.13, Found 452.9, 454.9.

[0311] Compound 20.2 (i.e. NS-1211): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (d, J = 8.3 Hz, 0.1H), 6.93 (d, J = 8.3 Hz, 0.9H), 5.95 (t, J = 5.2 Hz, 0.9H), 3.85 (m, 2.2H), 3.14 (m, 2.8H), 2.90 (m, 1H), 2.76 (dd, J = 12.3, 7.0 Hz, 0.2H), 2.62 (td, J = 6.6, 3.1 Hz, 1.82H), 2.45 (t, J = 7.4 Hz, 0.2H), 2.40 (t, J = 7.3 Hz, 1.8H), 1.45 (m, 2H), 1.22 (m, 7H), 0.96 (t, J = 7.1 Hz, 3H), 0.86 (m, 3H). LC-MS: [M+H] + Calcd 425.10, 427.10, Found 424.9, 426.9.

[0312] Compound 20.3 (i.e. NS-1212): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 2.0 Hz, 1H), 7.44 (dt, J = 8.3, 2.2 Hz, 1H), 7.06 (d, J = 8.4 Hz, 0.2H), 6.93 (d, J = 8.3 Hz, 1H), 5.94 (t, J = 5.3 Hz, 0.8H), 3.85 (m, 2.4H), 3.15 (m, 2.6H), 2.89 (m, 1H), 2.76 (dd, J = 11.5, 7.2 Hz, 0.4H), 2.64 (m, 1.6H), 2.48 (dd, J = 7.3, 1.4 Hz, 0.4H), 2.43 (q, J = 7.3 Hz, 1.6H), 1.27 (s, 2.4H), 1.24 (s, 0.6H), 0.95 (m, 6H). LC-MS: [M+H] + Calcd 411.08,413.08,Found 410.8,412.8.

[0313] Example 21. Synthesis of compound 21.1

[0314] Compound 5-1 (342 mg, 1 mmol) was dissolved in 5 mL of dichlorosulfoxide under nitrogen protection, a drop of DMF was added, after heating to reflux for 1 hour, the solvent was removed under reduced pressure, ethyl acetate and saturated sodium bicarbonate solution were added to separate, the organic phase was combined and dried over anhydrous sodium sulfate, and then concentrated to obtain compound 21-1 crude product. 21-1 was redissolved in dry DMF, and bromobutyronitrile (151 mg, 1 mmol) and potassium carbonate (138 mg, 1 mmol) were added, and stirred at room temperature for 2 hours. Ethyl acetate and water were added to separate, the organic phase was combined, dried over anhydrous sodium sulfate, and then concentrated, and purified by silica gel column (P:E = 3:1~2:1) to obtain compound 21.1 (i.e. NS-437) (68 mg, two-step yield, 15.8%)

[0315] Compound 21.1 (i.e. NS-437): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 1.9 Hz, 1H), 4.93 (s, 2H), 4.67 (hept, J = 6.4 Hz, 1H), 3.15 (d, J = 16.5 Hz, 1H), 2.92 (d, J = 16.4 Hz, 1H), 2.65 (qd, J = 7.2, 1.8 Hz, 2H), 1.33 (s, 3H), 1.00 (m, 6H), 0.93 (d, J = 6.2 Hz, 3H). LC-MS: [M+H] +Calcd 430.03 432.03, Found 430.0, 432.0.

[0316] Example 22. Synthesis of compounds 22.1 and 22.2

[0317] Potassium tert-butoxide (28 g, 0.25 mmol, 2.5 eq) was dissolved in 500 mL dry DMF under nitrogen protection, the temperature was reduced to -40 °C. 100 mL of p-bromonitrobenzene (20.2 g, 0.1 mmol, 1 eq) and methyl chloroacetate (12.0 g, 0.11 mmol, 1.1 eq) dry DMF mixed solution was added dropwise, after the end of dropwise addition, 30 minutes after the reaction solution was incubated at -20 °C, iodomethane (15.62 g, 0.11 mmol, 1.1 eq) was added dropwise. The reaction was slowly warmed to room temperature, extracted with ethyl acetate and water three times, the organic layer was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 5:1) to obtain compound 22-1 (16.1 g, 55.9%, colorless transparent syrup).

[0318] Compound 22-1 (2.88 g, 10 mmol, 1 eq) was dissolved in 50 mL of ethanol / tetrahydrofuran (2:1), ammonium chloride (4.3 g, 80 mmol, 8 eq) was added, and zinc powder (2.6 g, 40 mmol, 4 eq) was added in batches under ice bath conditions, and the reaction was slowly warmed to room temperature. The reaction was stirred at room temperature overnight. The reaction was removed by Buchner funnel, and the filtrate was removed after removing the organic solvent, extracted with ethyl acetate and water three times, the organic layer was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain compound 22-2 crude product. Compound 22-2 crude product was dissolved in dry DMF under nitrogen protection, and cooled to -40 °C. After the air in the system was replaced, diisopropylethylamine (1.78 g, 13.8 mmol, 3 eq) and bromomethyl methyl ether (0.75 g, 6.0 mmol, 1.3 eq) were added dropwise, and the reaction was carried out at -40 °C for 2 hours, then slowly warmed to room temperature, extracted with ethyl acetate and water three times, the organic layer was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 3:1~2:1) to obtain compound 22-3 (0.97 g, light yellow solid, 33.9%).

[0319] Compound 22-3 (0.97 g, 3.4 mmol) was dissolved in 30 mL of dry DMF, potassium carbonate (0.56 g, 4.1 mmol) and bromobutyronitrile (0.62 g, 4.1 mmol) were added and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was extracted with ethyl acetate and water three times. The organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column (P:E = 4:1 to 3:1) to give compound 22-4 (1.08 g, light yellow solid, 89.2%).

[0320] Compound 22-4 was dissolved in 15 mL of dichloromethane, 3 mL of trifluoroacetic acid was added and the reaction was allowed to proceed overnight. The solvent was removed under reduced pressure. The reaction mixture was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to give a light yellow crude product. The light yellow crude product was dissolved in DMF and reacted with N-methylpropylcarbamoyl chloride and N-methylisobutylcarbamoyl chloride in the presence of potassium bicarbonate to give compound 22.1 (i.e. NS-1145) and compound 22.2 (i.e. NS-1201) according to Reference Example 1.

[0321] Compound 22.1 (i.e. NS-1145): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 1.8 Hz, 1H), 7.45 (dd, J = 8.2, 1.9 Hz, 1H), 6.89 (d, J = 8.1 Hz, 0.5H), 6.83 (d, J = 8.2 Hz, 0.5H), 3.53 (d, J = 18.4 Hz, 1H), 3.42 (t, J = 6.5 Hz, 1H), 3.11 (d, J = 18.1 Hz, 1H), 3.10 (s, 1.5H), 2.96 (s, 1.5H), 2.36 (m, 2H), 1.71 (m, 1H), 1.58 (m, 1H), 1.29 (s, 3H), 0.97 (t, J = 7.1 Hz, 1.5H), 0.87 (t, J = 7.2 Hz, 1.5H), 0.81 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 411.08, 413.08, Found 410.8, 412.8.

[0322] Compound 22.2 (i.e. NS-1201): white solid, 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 1.5 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.7 Hz, 0.4H), 6.84 (d, J = 8.2 Hz, 0.6H), 4.16 (s, 0.4H), 3.96 (s, 0.6H), 3.54 (d, J = 18.6 Hz, 1H), 3.11 (d, J = 18.2 Hz, 1H), 2.95 (s, 1.8H), 2.80 (s, 1.2H), 2.37 (m, 2H), 1.53 (m, 2H), 1.29 (s, 3H), 1.20 (m, 3H), 0.91 (m, 3H), 0.81 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 425.10, 427.10, Found 424.9, 426.9.

[0323] Example 23. Synthesis of compounds 23.1-23.3

[0324] Compound 3-methylindolin-2-one (2.26 g, 10 mmol) was dissolved in 30 mL dry tetrahydrofuran under nitrogen protection, sodium hydride (440 mg, 11 mmol, 1.1 eq, 40% wrapped with mineral oil) was added in batches under ice water bath, after stirring for 1 hour, di-tert-butyl dicarbonate (2.4 g, 11 mmol, 1.1 eq) was added, after slowly recovering to room temperature, stirring overnight. 1 mL saturated ammonium chloride solution was added to quench the reaction. Extracted with ethyl acetate and water three times, combined the organic layer, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 4:1) to obtain compound 23-1 (2.07 g, colorless transparent syrup, 63.4%).

[0325] Referring to Example 22, compound 23-1 was reacted with bromobutyronitrile to generate compound 23-2 (2.3 g, colorless transparent syrup, 91.6%).

[0326] Compound 23-2 (396 mg, 1 mmol) was dissolved in 5 mL dichloromethane, 2 mL trifluoroacetic acid was added, after stirring overnight, the solvent was removed under reduced pressure. After separating with saturated sodium bicarbonate solution and ethyl acetate, the organic layer was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain a light yellow crude product. Referring to Example 10, the light yellow crude product was reacted with bromobutyronitrile, N-methylpropylformamidyl chloride and chloroacetyl methyl ethylamine under the action of potassium carbonate to generate compounds 23.1-23.3.

[0327] Compound 23.1 (i.e. NS-1133): colorless transparent syrup,1 H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 2.0 Hz, 1H), 7.37 (dd, J = 8.3, 2.1 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 4.70 (d, J = 18.1 Hz, 1H), 4.57 (d, J = 18.1 Hz, 1H), 3.45 (d, J = 18.2 Hz, 1H), 3.05 (d, J = 18.2 Hz, 1H), 2.61 (q, J = 7.3 Hz, 2H), 2.34 (m, 2H), 1.26 (s, 3H), 0.98 (t, J = 7.3 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 366.06, 368.06, Found 365.8, 367.8.

[0328] Compound 23.2 (i.e. NS-1169): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 1.7 Hz, 1H), 7.42 (dd, J = 8.4, 2.1 Hz, 1H), 6.95 (d, J = 9.1 Hz, 0.6H), 6.92 (d, J = 9.1 Hz, 0.4H), 3.59 (d, J = 18.5 Hz, 0.8H), 3.44 (br s, 2H), 3.14 (d, J = 18.5 Hz, 1.2H), 3.03 (s, 3H), 2.36 (m, 2H), 1.65 (m, 1.2H), 1.54 (m, 0.8H), 1.27 (s, 3H), 0.94 (t, J = 7.3 Hz, 1.8H), 0.80 (m, 4.2H). LC-MS: [M+H] + Calcd 395.09, 397.09, Found 394.8, 396.8.

[0329] Compound 23.3 (i.e. NS-1181): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 1.7 Hz, 1H), 7.42 (dd, J = 8.4, 2.1 Hz, 1H), 6.95 (d, J = 9.1 Hz, 0.6H), 6.92 (d, J = 9.1 Hz, 0.4H), 3.59 (d, J = 18.5 Hz, 0.8H), 3.44 (br s, 2H), 3.14 (d, J = 18.5 Hz, 1.2H), 3.03 (s, 3H), 2.36 (m, 2H), 1.65 (m, 1.2H), 1.54 (m, 0.8H), 1.27 (s, 3H), 0.94 (t, J = 7.3 Hz, 1.8H), 0.80 (m, 4.2H). LC-MS: [M+H] +Calcd 395.09,397.09,Found 394.8,396.8.

[0330] Example 24. Synthesis of compounds 24.1~24.3

[0331] A solution of 5-bromo-2-nitrobenzeneacetic acid methyl ester (2.74 g, 10 mmol, 1 eq) in allyl tert-butyl ester (6.4 g, 50 mmol, 5 eq) was added DBU (1.52 g, 10 mmol, 1 eq) under nitrogen protection. Stirring at 100 °C overnight, TLC monitoring reaction complete after adding ethyl acetate liquid-liquid extraction, the organic phase was combined, washed with brine, concentrated, and purified by silica gel column (P: E = 4: 1~3: 1) to obtain the target compound 24-1 (2.45 g, 60.9%).

[0332] Reference Example 1, compound 24-1 was methylated to obtain compound 24-2;

[0333] Reference Example 8, compound 24-2 was further reduced by zinc powder to close the ring to obtain compound 24-3;

[0334] Reference Example 1, compound 24-3 was reacted with iodomethane to obtain compound 24-4;

[0335] Reference Example 4, compound 24-4 was subjected to ester exchange under acidic conditions in a dry ethanol solution to obtain compound 24.1. Similarly, ester exchange under acid catalysis in a dry isopropanol solution to obtain compound 24.2.

[0336] Compound 24.1 (i.e. NS-624): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.3, 1.9 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 3.93 (m, 5H), 2.17 (m, 1H), 2.05 (m, 2H), 1.88 (m, 1H), 1.35 (s, 3H), 1.13 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 356.04 358.04,Found 355.8,357.8.

[0337] Compound 24.2 (i.e. NS-625): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 8.2, 1.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 4.77 (hept, J = 6.5 Hz, 1H), 3.94 (s, 3H), 2.15 (m, 1H), 2.02 (m, 2H), 1.85 (m, 1H), 1.34 (s, 3H), 1.12 (dd, J = 12.4, 6.2 Hz, 6H). LC-MS: [M+H] + Calcd 370.06, 372.06, Found 369.8, 371.8.

[0338] According to the above procedure, compound 24-3 was reacted with iodomethylcyclopropane, followed by ester exchange under acidic condition to give compound 24.3.

[0339] Compound 24.3 (i.e. NS-1263): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.98 (d, J = 7.4 Hz, 2H), 3.93 (q, J = 7.1 Hz, 2H), 2.16 (ddd, J = 12.2, 10.7, 5.8 Hz, 1H), 2.05 (m, 2H), 1.88 (ddd, J = 14.6, 10.5, 5.8 Hz, 1H), 1.34 (s, 3H), 1.20 (m, 1H), 1.12 (t, J = 7.1 Hz, 3H), 0.57 (m, 2H), 0.33 (m, 2H). LC-MS: [M+H] + Calcd 396.07, 398.07, Found 395.8, 397.8.

[0340] Example 25. Synthesis of compounds 25.1-25.3

[0341] According to Reference Example 10, compound 24-2 was reacted with tetrahydroxydiboron to reduce nitro group to amino group, followed by ring closure, and then reacted with bromoethyl methyl ether, 1-iodobutane and bromoethyl ethyl ether, respectively, to give compounds 25-1-25-3.

[0342] According to Reference Example 4, compounds 25-1-25-3 were subjected to ester exchange under catalysis of acid to give compounds 25.1-25.3, respectively.

[0343] Compound 25.1 (i.e. NS-1261): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.3, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.93 (m, 3H), 3.79 (dt, J = 14.5, 5.0 Hz, 1H), 3.54 (m, 2H), 3.22 (s, 3H), 2.12 (m, 1H), 1.99 (m, 2H), 1.73 (m, 1H), 1.30 (m, 3H), 1.12 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 384.07, 386.07, Found 383.8, 385.8.

[0344] Compound 25.2 (i.e. NS-1262): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.3, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.93 (m, 3H), 3.79 (dt, J = 14.5, 5.0 Hz, 1H), 3.54 (m, 2H), 3.22 (s, 3H), 2.12 (m, 1H), 1.99 (m, 2H), 1.73 (m, 1H), 1.30 (m, 3H), 1.12 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 382.09, 384.09, Found 381.8, 383.8.

[0345] Compound 25.3 (i.e. NS-1264): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.3, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.93 (m, 3H), 3.79 (dt, J = 14.5, 5.0 Hz, 1H), 3.54 (m, 2H), 3.22 (s, 3H), 2.12 (m, 1H), 1.99 (m, 2H), 1.73 (m, 1H), 1.30 (m, 3H), 1.12 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 398.09, 400.09, Found 397.8, 399.8.

[0346] Example 26. Synthesis of compounds 26.1 and 26.2

[0347] Referring to Example 1, compound 5-bromo-2-nitrobenzeneacetic acid methyl ester was reacted with allyl bromide and then with iodomethane to give compound 26-1;

[0348] Referring to Examples 8 and 1, compound 26-1 was reduced with zinc powder to give compound 26-2;

[0349] Compound 26-2 (296 mg, 1 mol), sodium periodate (742 mg, 3 mol) were dissolved in 10 mL water in tetrahydrofuran (20%) under ice water bath, 0.8 mL of osmium tetroxide (2.5 wt%) aqueous solution was added. After 2 hours of reaction at room temperature, the reaction was quenched with sodium thiosulfate solution. Ethyl acetate and water were added, the organic phase was separated, washed with brine, concentrated, and purified by silica gel column (P:E=2:1) to give compound 26-3 (203 mg, 68.1%). Compound 26-3 was dissolved in 5 mL of anhydrous methanol and tetrahydrofuran mixed solvent (1:1). Sodium borohydride (38 mg, 1 mol) was added portionwise under ice water bath, slowly warmed to room temperature, stirred for 2 hours, then quenched with dilute hydrochloric acid, ethyl acetate and water were added, the organic phase was separated, washed with brine, concentrated, and purified by silica gel column (P:E=2:1-1:1) to give compound 26-4 (188 mg, 92.0%).

[0350] Compound 26-4 (90 mg, 0.3 mmol) and pyridine (95 mg, 1.2 mmol) in dichloromethane were cooled to -30 °C under nitrogen protection, isobutyryl chloride (64 mg, 0.6 mmol) was added dropwise, the reaction was slowly warmed to room temperature, and then separated with ethyl acetate and water. The organic phase was combined, washed with dilute hydrochloric acid, sodium bicarbonate aqueous solution and saturated brine in turn. Anhydrous sodium sulfate was added for drying, concentrated, and purified by silica gel column (P:E=3:1) to give compound 26.1 (i.e. NS-614) (91 mg, 82.0%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 8.2, 1.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 3.93 (s, 3H), 3.88 (dt, J = 11.5, 5.7 Hz, 1H), 3.65 (ddd, J = 11.6, 7.9, 5.3 Hz, 1H), 2.22 (m, 3H), 1.35 (s, 3H), 0.96 (d, J = 3.5 Hz, 3H), 0.94 (d, J = 3.5 Hz, 3H). LC-MS: [M+H] +Calcd 370.06, 372.06, Found 369.8, 371.8.

[0351] Compound 26-4 (90 mg, 0.3 mmol) and pyridine (95 mg, 1.2 mmol) in dichloromethane were cooled to -30 °C under nitrogen protection, p-nitrophenyl chloroformate (66 mg, 0.33 mmol) was added, the reaction was slowly warmed to room temperature. The mixture was partitioned between ethyl acetate and water. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated, redissolved in dry tetrahydrofuran, 1 mL of dimethylamine in tetrahydrofuran (2 M) was added, stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, purified by silica gel column (P:E = 2:1) to obtain compound 26.2 (i.e. NS-613) (61 mg, 82.2%).

[0352] Compound 26.2 (i.e. NS-613): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.2, 1.9 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 3.92 (s, 3H), 3.82 (m, 1H), 3.63 (m, 1H), 2.69 (s, 3H), 2.59 (s, 3H), 2.23 (dddd, J = 22.2, 14.3, 9.5, 4.9 Hz, 2H), 1.34 (s, 3H). LC-MS: [M+H] + Calcd 371.05, 373.05, Found 370.8, 372.8.

[0353] Example 27. Synthesis of compounds 27.1-27.3

[0354] Compound 26-3 (148 mg, 0.5 mmol) was redissolved in 1,2-dichloroethane, 0.5 mL of dimethylamine in tetrahydrofuran (2 M), acetic acid (60 mg, 1 mmol) and sodium triacetoxyborohydride (297 mg, 1.4 mmol) were added, stirred at room temperature for 4 hours. The reaction was quenched by adding dilute hydrochloric acid, the pH was adjusted to 8-9 by saturated sodium bicarbonate solution, partitioned between dichloromethane and water. The organic phase was combined, dried over anhydrous sodium sulfate after washing with saturated brine, concentrated, purified by silica gel column (100% EA ~ DCM / MeOH = 10:1) to obtain compound 27.1 (i.e. NS-383) (114 mg, 69.7%). light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 3.87 (s, 3H), 2.08 (m, 1H), 1.97 (m, 1H), 1.93 (m, 1H), 1.88 (s, 6H), 1.82 (m, 1H), 1.29 (s, 3H). LC-MS: [M+H] + Calcd 327.06, 329.06, Found 326.8, 328.8.

[0355] Referring to the procedure described above, compound 26-3 was reductive aminated with 2-aminomethylthiazole to give compound 27.2 (i.e. NS-370): orange syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 7.79 (d, J = 3.3 Hz, 1H), 7.74 (d, J = 3.3 Hz, 1H), 7.40 (m, 2H), 7.17 (d, J = 8.7 Hz, 1H), 4.86 (d, J = 16.0 Hz, 1H), 4.74 (d, J = 16.0 Hz, 1H), 3.59 (s, 3H), 3.50 (m, 1H), 3.41 (m, 1H), 2.57 (dd, J = 12.9, 8.1 Hz, 1H), 2.03 (ddd, J = 12.6, 7.7, 4.7 Hz, 1H), 1.51 (s, 3H). LC-MS: [M+H] + Calcd 396.03, 398.03, Found 395.8, 397.

[0356] Referring to the synthesis of compound 26-2 in Example 26, compound 27-1 was prepared;

[0357] Referring to the synthesis of compound 27.1 described above, compound 27-1 was reductive aminated with dimethylamine to give compound 27.3 (i.e. NS-384): light yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4.88 (d, J = 15.9 Hz, 1H), 4.82 (d, J = 15.9 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.07 (m, 1H), 1.97 (m, 1H), 1.88 (m, 7H), 1.80 (ddd, J = 12.0, 7.1, 3.6 Hz, 1H), 1.30 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 399.08,401.08,Found 398.8,400.8.

[0358] Example 28. Synthesis of compounds 28.1 and 28.2

[0359] Compound 2-fluoro-4-bromonitrobenzene (2.2 g, 10 mmol, 1 eq) was dissolved in 25 mL dry DMF, potassium carbonate (2.76 g, 20 mmol, 2 eq) and methyl cyanoacetate (1.2 g, 12 mmol, 1.2 eq) were added, stirred at room temperature for 16 hours, extracted with ethyl acetate and saturated ammonium chloride solution three times, combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, removed the solvent under reduced pressure to obtain the crude compound 28-1. The crude compound 28-1 was dissolved in 40 ml dry DMF, under nitrogen protection, cooled to -10 °C, sodium hydride (480 mg, 12 mol, 1.2 eq, 40% wrapped in mineral oil) and iodomethane (1.7 g, 12 mmol, 1.2 eq) were added in batches, slowly raised to room temperature, stirred for 1 hour, quenched with saturated aqueous ammonium chloride solution. Extracted with ethyl acetate and water three times, combined the organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 2:1) to obtain compound 28-2 (2.12 g, 70.9%, brown syrup).

[0360] Referring to Example 8, compound 28-2 was ring-closed by zinc powder reduction to obtain compound 28-3.

[0361] Referring to Example 1, compound 28-3 reacted with ethyl bromoacetate to generate compound 28.1 (i.e. NS-699). Light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.85 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 353.01, 355.00, Found 352.8, 354.8.

[0362] Compound 28-3 (133 mg, 0.5 mmol) was dissolved in 2 mL of ethanol, 2 mL of 35% concentrated hydrochloric acid was added under ice water bath, stirred for 2 hours, the pH was adjusted to neutral with saturated sodium bicarbonate solution, and then extracted with ethyl acetate and saturated ammonium chloride solution three times, the organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 1:1) to obtain compound 28-4 (124 mg, 87.1%, white solid).

[0363] Referring to Example 1, compound 28-4 was reacted with ethyl bromoacetate in the presence of potassium bicarbonate to obtain compound 28.2 (i.e., NS-699).

[0364] Compound 28.2 (i.e., NS-700): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 1.8 Hz, 1H), 7.73 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 5.02 (d, J = 16.0 Hz, 1H), 4.97 (d, J = 16.0 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 1.85 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 371.02, 373.01, Found 370.8, 372.8.

[0365] Example 29. Synthesis of compounds 29.1-29.3

[0366] Compound 5-azaindole (5.9 g, 50 mmol, 1 eq) was dissolved in 50 mL dry DMF, cooled to -5 °C, sodium hydride (2.4 g, 60 mmol, 1.2 eq, 40% wrapped in mineral oil) was added, stirred for 0.5 h, then iodobutane (11 g, 60 mmol, 1.2 eq) was added dropwise, stirred at room temperature for 1 h, quenched with saturated ammonium chloride solution in ice water bath, extracted with ethyl acetate three times, combined the organic layers, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (DCM:MeOH = 20:1) to give compound 29-1 (8.0 g, 92%, brown syrup).

[0367] Compound 29-1 (8.0 g, 46 mmol, 1 eq) was dissolved in 65 mL of mixed solvents (Dioxane:THF:H2O = 5:5:3), N-bromosuccinimide (32 g, 180 mol, 3.9 eq) was added portionwise at room temperature, continued to stir for 3 h, quenched with excess saturated aqueous sodium bisulfite solution. Extracted with ethyl acetate and water three times, combined the organic layers, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (DCM:MeOH = 15:1) to give compound 29-2 (3.95 g, 45.2%, brown syrup).

[0368] Compound 29-2 (760 mg, 4 mmol, 1 eq) and ethyl bromoacetate (668 mg, 4 mmol, 1 eq) were dissolved in 15 mL dry DMF, cooled to -5 °C, sodium hydride (352 mg, 8.8 mmol, 2.2 eq, 40% wrapped in mineral oil) was added, stirred for 0.5 h, then iodomethane (568 mg, 4 mmol, 1 eq) was added dropwise at -5 °C, slowly raised to room temperature, stirred for 0.5 h, quenched with saturated ammonium chloride solution in ice water bath, extracted with ethyl acetate three times, combined the organic layers, washed the organic phase with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by thin layer chromatography (P:E = 2:1) to give compounds 29.1-29.3

[0369] Compound 29.1 (i.e. NS-1713): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.40 (d, J = 5.3 Hz, 1H), 7.14 (d, J = 5.3 Hz, 1H), 3.84 (qq, J = 10.9, 7.1 Hz, 2H), 3.69 (t, J = 7.3 Hz, 2H), 3.16 (d, J = 16.7 Hz, 1H), 2.94 (d, J = 16.7 Hz, 1H), 1.59 (m, 2H), 1.35 (m, 2H), 1.31 (s, 3H), 0.94 (m, 6H). LC-MS: [M+H] + Calcd 291.16, Found 291.1.

[0370] Compound 29.2 (i.e. NS-1733): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.39 (d, J = 5.3 Hz, 1H), 7.11 (d, J = 5.3 Hz, 1H), 3.84 (m, 4H), 3.66 (t, J = 7.2 Hz, 2H), 3.12 (d, J = 16.0 Hz, 2H), 2.90 (d, J = 16.0 Hz, 2H), 1.59 (m, 2H), 1.38 (m, 2H), 0.94 (m, 9H). LC-MS: [M+H] + Calcd 363.18, Found 363.1.

[0371] Compound 29.3 (i.e. NS-2043): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.40 (d, J = 5.3 Hz, 1H), 7.15 (d, J = 5.3 Hz, 1H), 3.68 (t, J = 7.0 Hz, 2H), 1.57 (m, 2H), 1.33 (s, 6H), 1.27 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 219.14, Found 219.1.

[0372] Example 30. Synthesis of compounds 30.1-30.3

[0373] Referring to Example 29, the flower compound 30-2 was synthesized using 5-bromo-6-azaindole as a raw material, and the compound 30-2 was sequentially reacted with bromoacetic acid ethyl ester and iodomethane under alkaline conditions to obtain compounds 30.1-30.3.

[0374] Compound 30.1 (i.e. NS-1762): white solid,1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.80 (s, 1H), 3.87 (m, 2H), 3.71 (t, J = 7.1 Hz, 2H), 3.25 (d, J = 17.2 Hz, 1H), 2.95 (d, J = 17.2 Hz, 1H), 1.59 (m, 2H), 1.34 (m, 2H), 1.28 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 369.07, 371.07, Found 369.0, 371.0.

[0375] Compound 30.2 (i.e. NS-2109): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.79 (s, 1H), 3.71 (t, J = 7.0 Hz, 2H), 1.59 (m, 2H), 1.31 (s, 6H), 1.26 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 297.05, 299.05, Found 297.0, 299.0.

[0376] Compound 30.3 (i.e. NS-2110): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.78 (s, 1H), 3.86 (m, 4H), 3.69 (t, J = 7.1 Hz, 2H), 3.12 (d, J = 16.3 Hz, 2H), 2.93 (d, J = 16.3 Hz, 2H), 1.59 (m, 2H), 1.37 (m, 2H), 0.98 (t, J = 7.1 Hz, 6H), 0.92 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 441.09, 443.09, Found 441.0, 443.0.

[0377] Example 31. Synthesis of compounds 31.1-31.3

[0378] Referring to Example 29, the compound 5-bromo-4-azaindole was used as a raw material to synthesize the compound 31-2, and the compound 31-2 was sequentially reacted with bromoacetic acid ethyl ester and iodomethane under alkaline conditions to obtain the compounds 31.1-31.3.

[0379] Reference Example 30, compound 31-2 was reduced with zinc powder and saturated ammonium chloride solution to give 31-3

[0380] Reference Example 29, crude compound 31-3 was sequentially reacted with bromoacetic acid ethyl ester and iodomethane to give compounds 31.1-31.3 after purification

[0381] Compound 31.1 (i.e. NS-1782): colorless syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.2 Hz, 1 H), 7.47 (d, J = 8.3 Hz, 1 H), 3.86 (m, 2 H), 3.71 (t, J = 7.1 Hz, 2 H), 3.03 (d, J = 17.1 Hz, 1 H), 2.96 (d, J = 17.2 Hz, 1 H), 1.57 (m, 2 H), 1.33 (dq, J = 14.7, 7.4 Hz, 2 H), 1.26 (s, 3 H), 0.99 (t, J = 7.1 Hz, 3 H), 0.91 (t, J = 7.3 Hz, 3 H). LC-MS: [M+H] + Calcd 369.07, 371.07, Found 369.0, 371.0.

[0382] Compound 31.2 (i.e. NS-2119): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 8.3 Hz, 1 H), 7.49 (d, J = 8.3 Hz, 1 H), 3.70 (t, J = 7.0 Hz, 2 H), 1.57 (m, 2 H), 1.28 (m, 8 H), 0.90 (t, J = 7.3 Hz, 3 H). LC-MS: [M+H] + Calcd 297.05, 299.05, Found 297.0, 299.0.

[0383] Compound 31.3 (i.e. NS-2120): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.3 Hz, 1 H), 7.44 (d, J = 8.3 Hz, 1 H), 3.85 (m, 4 H), 3.68 (t, J = 7.1 Hz, 2 H), 3.00 (d, J = 16.2 Hz, 2 H), 2.90 (d, J = 16.2 Hz, 2 H), 1.56 (m, 2 H), 1.35 (m, 2 H), 0.98 (t, J = 7.1 Hz, 6 H), 0.91 (t, J = 7.3 Hz, 3 H). LC-MS: [M+H] +Calcd 441.09, 443.09, Found 441.0, 443.0.

[0384] Example 32. Synthesis of compounds 32.1~32.3

[0385] Compound 5-bromoindoine (1.13 g, 5 mmol, 1 eq) was dissolved in 50 mL dry DMF, cooled to -5 °C, sodium hydride (240 mg, 6 mmol, 1.2 eq, 40% wrapped in mineral oil) was added, stirred for 0.5 h, 2-iodoethyl methyl ether (1.12 g, 6 mmol, 1.2 eq) was added dropwise, stirred at room temperature for 1 h, quenched with saturated ammonium chloride solution at 0 °C, extracted with ethyl acetate three times, combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P: E = 4: 1) to give compound 32-1 (1.23 g, 71.7%, orange red solid).

[0386] Compound 32-1 (1.23 g, 4.3 mmol, 1 eq) was dissolved in 20 mL dry THF, cooled to 0 °C, ethoxycarbonylmethylidene triphenylphosphonium (1.8 g, 5.2 mmol, 1.2 eq) was added in batches, continued to stir for 1 h, concentrated under reduced pressure, purified by silica gel column (P: E = 4: 1) to give 32-2 (1.19 g, 78.4%, orange red solid).

[0387] Compound 32-2 (176 mg, 0.5 mmol, 1 eq), anhydrous potassium carbonate (138 mg, 1 mmol, 2 eq) and formaldehyde aqueous solution (202 mg, 2.5 mmol, 5 eq, 40%) were dissolved in 5 mL toluene under nitrogen protection, tributylphosphine (121 mg, 0.6 mmol, 1.2 eq) was added dropwise, continued to stir for 1 h, concentrated under reduced pressure, purified by thin layer chromatography (P: E = 2: 1) to give 32-3 (212 mg) crude product.

[0388] Compound 32-3 (212 mg, 0.55 mmol, 1 eq) was dissolved in dichloromethane, p-toluenesulfonic acid monohydrate (230 mg, 1.2 mmol, 2.2 eq) was added, stirred at room temperature for 1 h, extracted with water and dichloromethane three times, combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P: E = 3: 1) to give compound 32.1

[0389] Referring to the synthesis of compound 32.1 above, compound 5-bromoindoine was reacted with iodo butane and 2-bromoethyl ethyl ether respectively, and then compound 32.2 and 32.3 were obtained by referring to the synthesis of compound 32.1

[0390] Compound 32.1 (i.e. NS-1715): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.4, 2.1 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.47 (d, J = 9.1 Hz, 1H), 4.44 (d, J = 9.1 Hz, 1H), 3.84 (t, J = 5.6 Hz, 2H), 3.55 (t, J = 5.5 Hz, 2H), 3.24 (s, 3H), 3.20 (d, J = 17.3 Hz, 1H), 2.78 (d, J = 17.3 Hz, 1H). LC-MS: [M+H] + Calcd 340.01, 342.01, Found 340.0, 342.0.

[0391] Compound 32.2 (i.e. NS-1716): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.45 (s, 2H), 3.66 (t, J = 7.1 Hz, 2H), 3.18 (d, J = 17.3 Hz, 1H), 2.78 (d, J = 17.3 Hz, 1H), 1.57 (m, 2H), 1.30 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 338.03, 340.03, Found 338.0, 340.0.

[0392] Compound 32.3 (i.e. NS-1717): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.48 (d, J = 9.0 Hz, 1H), 4.45 (d, J = 9.0 Hz, 1H), 3.84 (t, J = 5.6 Hz, 2H), 3.59 (t, J = 5.6 Hz, 2H), 3.43 (q, J = 7.0 Hz, 2H), 3.21 (d, J = 17.3 Hz, 1H), 2.77 (d, J = 17.3 Hz, 1H), 1.05 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] +Calcd 354.03,356.03,Found 354.0,356.0.

[0393] Example 33. Synthesis of compounds 33.1~33.3

[0394] Compound 32-2 (353 mg, 1 mmol, 1 eq), anhydrous potassium carbonate (276 mg, 2 mmol, 2 eq) and aqueous acetaldehyde (550 mg, 5 mmol, 5 eq, 40%) were dissolved in 10 mL of toluene under nitrogen protection, and tributylphosphine (243 mg, 1.2 mmol, 1.2 eq) was added dropwise, and stirring was continued for 1 hour, and concentrated under reduced pressure, and purified by thin layer chromatography preparation (P: E = 2: 1) to obtain compound 33.1.

[0395] Referring to Example 32 and the synthesis of compound 33.1 of this example, compounds 33.2, 33.3 were obtained

[0396] Compound 33.1 (i.e. NS-1718): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 2.0 Hz, 0.8H), 7.58 (dd, J = 8.4, 2.0 Hz, 0.2H), 7.54 (dd, J = 8.4, 2.1 Hz, 0.8H), 7.44 (d, J = 2.0 Hz, 0.2H), 7.18 (d, J = 8.5 Hz, 0.2H), 7.13 (d, J = 8.4 Hz, 0.8H), 4.89 (q, J = 6.4 Hz, 0.8H), 4.76 (q, J = 6.5 Hz, 0.2H), 3.95 (m, 1H), 3.79 (m, 1H), 3.54 (m, 2H), 3.40 (d, J = 17.1 Hz, 0.8H), 3.23 (s, 0.6H), 3.22 (s, 2.4H), 3.09 (d, J = 17.4 Hz, 0.2H), 3.03 (d, J = 17.3 Hz, 0.2H), 2.74 (d, J = 17.1 Hz, 0.8H), 1.09 (d, J = 6.8 Hz, 0.6H), 1.07 (d, J = 6.4 Hz, 2.4H). LC-MS: [M+H] + Calcd 354.03,356.03,Found 354.0,356.0.

[0397] Compound 33.2 (i.e. NS-1719): colorless syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 2.0 Hz, 0.75H), 7.59 (dd, J = 8.4, 2.0 Hz, 0.25H), 7.55 (dd, J = 8.4, 2.1 Hz, 0.75H), 7.47 (d, J = 2.0 Hz, 0.25H), 7.16 (d, J = 8.4 Hz, 0.25H), 7.11 (d, J = 8.4 Hz, 0.75H), 4.91 (q, J = 6.3 Hz, 0.75H), 4.77 (q, J = 6.5 Hz, 0.25H), 3.73 (m, 1H), 3.62 (m, 1H), 3.39 (d, J = 17.1 Hz, 0.75H), 3.06 (s, 0.5H), 2.75 (d, J = 17.1 Hz, 0.75H), 1.57 (m, 2H), 1.30 (m, 2H), 1.11 (d, J = 6.5 Hz, 0.75H), 1.08 (d, J = 6.4 Hz, 2.25H), 0.91 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 352.05, 354.05, Found 352.0, 354.0.

[0398] Compound 33.3 (i.e. NS-1721): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 2.0 Hz, 0.9H), 7.59 (dd, J = 8.4, 2.0 Hz, 0.1H), 7.55 (dd, J = 8.4, 2.0 Hz, 0.9H), 7.44 (d, J = 2.0 Hz, 0.1H), 7.20 (d, J = 8.5 Hz, 0.1H), 7.14 (d, J = 8.4 Hz, 0.9H), 4.90 (q, J = 6.4 Hz, 0.9H), 4.77 (q, J = 6.4 Hz, 0.1H), 3.96 (m, 1H), 3.82 (m, 0.1H), 3.75 (m, 0.9H), 3.59 (m, 2H), 3.41 (m, 3H), 3.10 (d, J = 17.3 Hz, 0.1H), 3.03 (d, J = 17.3 Hz, 0.1H), 2.74 (d, J = 17.1 Hz, 0.9H), 1.10 (d, J = 6.2 Hz, 0.3H), 1.09 (d, J = 6.4 Hz, 2.7H), 1.03 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 368.04, 370.04, Found 368.0, 370.0.

[0399] The advantageous effects of the present application are demonstrated by the following test examples.

[0400] Pharmacological data determination of the compounds of the present application

[0401] 1. Experimental method

[0402] The anesthetic effect of the compounds of the present application after tail vein injection in rats was tested (determination of the minimum anesthetic effective dose):

[0403] The experimental animals were 7-9 week old SD male rats, and the drugs were given by tail vein injection (the injection speed was 0.02 mL / s, and the injection volume was 0.6 mL per rat). The initial dose of each test compound was 1 mg / kg, and the actual dose was calculated according to the weight of each rat before the test. The increase or decrease of the subsequent dose was determined according to whether the experimental rats appeared righting reflex loss, and the lowest dose at which the righting reflex loss appeared was determined as the minimum anesthetic effective dose.

[0404] While testing whether the compounds of the present application have anesthetic effect after tail vein injection in rats, the analgesic effect of the compounds was also determined. Once it was determined that the compound had anesthetic effect (righting reflex loss≥30s), the reaction of the rat to noxious stimulation (holding the middle and outer 1 / 3 of the rat's tail with an alligator clip for 30s) was observed immediately after administration. If the rat showed no reaction within 30s, it was determined to have analgesic effect, otherwise it had no analgesic effect. If the compound had no anesthetic effect (righting reflex loss<30s), the rat was given noxious stimulation (holding the middle and outer 1 / 3 of the rat's tail with an alligator clip for 30s) 1 min after administration. If the rat showed no reaction within 30s, it was determined to have analgesic effect, otherwise it had no analgesic effect. In the present application, the dose at which analgesic effect began to appear was determined as the minimum analgesic effective dose.

[0405] The minimum anesthetic effective dose of the compounds of the present application was further classified as: A≤10 mg / kg; 10 mg / kg<B≤20 mg / kg; 20 mg / kg<C≤30 mg / kg; 30 mg / kg<D≤40 mg / kg; E>40 mg / kg.

[0406] The minimum analgesic effective dose of the compounds of the present application was further classified as: A≤10 mg / kg; 10 mg / kg<B≤20 mg / kg; 20 mg / kg<C≤30 mg / kg; 30 mg / kg<D≤40 mg / kg; E>40 mg / kg.

[0407] Pharmacological characteristics of equivalent doses:

[0408] In the above experiment, in addition to recording the dose at which the righting reflex disappears, the onset time and recovery time of the anesthetic effect from the start of self-administration, the duration of the righting reflex and the duration of the sedative effect, etc. can also be recorded. At the dose at which the compound of the present application causes the righting reflex to disappear, the effect of the compound on the respiration of the experimental animal can also be observed.

[0409] 2. Experimental results

[0410] Table 1. Pharmacological data of single intravenous injection of the compound of the present application

[0411] Table 2. Minimum analgesic effective dose of single intravenous injection of the compound of the present application

[0412] The experimental results show that the compound of the present application has high efficiency of anesthesia, sedation, hypnotic effect, can control status epilepticus, and also has analgesic effect.

Claims

1. A compound, a tautomer thereof, an endo form thereof, an exo form thereof, an enantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof, characterized in that, The structure of the compound is shown in formula I: L0 is selected from the group consisting of none, C 1-5 alkylene, C 2-5 alkenylene; R0is selected from cyano, COOR 01 , OCOR 01 , CONR 02 R 03 , OCONR 02 R 03 , NR 02 R 03 , OL9OR 01 , OL9R 01 , COR 01 , L9R 01 ; R 01 is selected from C 1-8 alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated oxacyclic, R 02 is selected from hydrogen, C 1-8 alkyl, R 03 is selected from hydrogen, C 1-8 alkyl, L8R 04 unsubstituted or substituted with one or more R L , or R 02 , R 03 are joined to form a 5-6 membered saturated azacyclic ring unsubstituted or substituted with one or more R 10 ; L8is selected from null, C 1-5 alkylene, R L is selected from 5-6 membered heteroaryl, R 04 are each independently selected from CONR 05 R 06 , C 1-8 alkyl, C 1-8 alkoxy, R 05 , R 06 are each independently selected from hydrogen, C 1-8 alkyl, R 10 are each independently selected from C 1-8 alkyl, L9is selected from null, C 1-5 alkylene; R1is selected from hydrogen, LR a ; L is selected from the group consisting of nothing, C 1-5 alkylene; R a substituted with one or more R a1 substituted with one or more R 1-8 substituted with one or more R a1 substituted with one or more R 1-8 substituted with one or more R a1 substituted with one or more R 2-8 substituted with one or more R b R c , COOR a24 ; R b is selected from hydrogen, C 1-8 alkyl, R c is selected from hydrogen, C 1-8 alkyl, or R b , R c form a 3-8 membered saturated nitrogen heterocycle; R a1 each independently is selected from halogen; R a2 is selected from C 1-8 alkyl; or R1is connected with L0R0to form a substituted or unsubstituted 3-5 membered heterocyclyl ring q3 substituted 3-5 membered heterocyclyl; said R q3 each independently selected from =0, C 1-5 alkyl, COOR q4 , R q4 selected from C 1-8 alkyl; Y1is selected from N, CR3; Y2is selected from N, CR4; Y3is selected from N, CR5; Y4is selected from N, CR2; and 0 or 1 of Y1, Y2, Y3and Y4is N; R2, R3, R4, R5are each independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C 3a substituted C 1-8 alkyl; R 3a each independently selected from halogen; Z is selected from C=0, C=S, C=CH2, CR r R s ; R r is selected from hydrogen, C 1-8 alkyl, R s is selected from hydrogen, C 1-8 alkyl; L1is selected from the group consisting of none, O, S, NR a3 , N=CH, C 1-5 alkylene; R a3 selected from hydrogen, C 1-8 alkyl; L2 is selected from none, unreplaced, or replaced by one or more R values. x Replacement C 1-5 Alkylene, unsubstituted or with one or more R x Replacement C 2-5 Ideonyl; R x Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, hydroxyl groups; A is selected from nothing, OCO, CONH, O, S, SO, SO2; L3is selected from the group consisting of none, C 1-5 alkylene; R6is selected from hydrogen, unsubstituted or substituted with one or more R 6a substituted C 1-8 alkyl, unsubstituted or substituted with one or more R 6a substituted C 1-8 alkoxy, unsubstituted or substituted with one or more R 6a substituted C 2-8 alkenyl, unsubstituted or substituted with one or more R 6a substituted C 2-8 alkynyl, NR7R8, unsubstituted or substituted with one or more R 6a substituted 3-8 membered saturated cycloalkyl, unsubstituted or substituted with one or more R 6a substituted 3-8 membered saturated heterocyclyl, OCOR 6b , unsubstituted or substituted with one or more R v substituted phenyl, unsubstituted or substituted with one or more R v substituted 5-6 membered heteroaryl, OL4R y ; R 6a each independently selected from C 1-8 alkyl, C 1-8 alkoxy, halogen, hydroxyl; R 6b is selected from C 1-8 alkyl; R7is selected from hydrogen, C 1-8 alkyl, L5R z1 ; R8is selected from C 1-8 alkyl, C 1-8 alkoxy, 3-8 membered saturated cycloalkyl, 5-6 membered unsaturated heteroaryl, 5-6 membered saturated heteroaryl, 5-6 membered heteroaryl substituted with one or more R v substituted 5-6 membered heteroaryl, L7R z3 ; or R7, R8are linked to form a substituted or unsubstituted 3-8 membered saturated nitrogen heterocycle; 7a substituted 3-8 membered saturated nitrogen heterocycle; R 7a each independently selected from C 1-8 alkyl; R v each independently selected from C 1-8 alkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkoxy, halogen-substituted C 1-8 alkoxy, halogen, CN, CONR v1 R v2 ; R v1 is selected from hydrogen, C 1-8 alkyl, R v2 is selected from hydrogen, C 1-8 alkyl; L5is selected from C 1-5 alkylene; R z1 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R w1 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R w1 each independently selected from the group consisting of OR w2 , R w2 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R 1-5 alkyl, 3-8 membered saturated cycloalkyl; L7is selected from C 1-5 alkylene; R z3 is selected from the group consisting of 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, which is unsubstituted or substituted by one or more R w5 is selected from the group consisting of 5-6 membered heteroaryl, 3-8 membered saturated cycloalkyl, which is unsubstituted or substituted by one or more R w5 each independently selected from OR w6 , R w6 is selected from the group consisting of C 1-8 alkyl, 3-8 membered saturated cycloalkyl; L4 is selected from the group consisting of none, C 1-5 alkylene; R y selected from the group consisting of hydrogen, C 1-8 alkyl, phenyl.

2. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of claim 1, characterized in that, The structure of the compound is shown as formula II-1, formula II-2, formula II-3, formula II-4, or formula II-5: L0is selected from the group consisting of none, C 1-4 alkylene, C 2-4 alkenylene; R0is selected from cyano, COOR 01 , OCOR 01 , CONR 02 R 03 , OCONR 02 R 03 , NR 02 R 03 , OL9OR 01 , OL9R 01 , COR 01 , L9R 01 ; R 01 is selected from C 1-6 alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated oxacyclic, R 02 is selected from hydrogen, C 1-6 alkyl, R 03 is selected from hydrogen, C 1-6 alkyl, L8R 04 unsubstituted or substituted with one or more R L , or R 02 , R 03 are joined to form a 6 membered saturated azacyclic ring unsubstituted or substituted with one or more R 10 ; L8is selected from null, C 1-3 alkylene, R L is selected from 5-6 membered heteroaryl, R 04 are each independently selected from CONR 05 R 06 , C 1-6 alkyl, C 1-6 alkoxy, R 05 , R 06 are each independently selected from hydrogen, C 1-6 alkyl, R 10 are each independently selected from C 1-5 alkyl, L9is selected from null, C 1-3 alkylene; R1is selected from hydrogen, LR a ; L is selected from the group consisting of nothing, C 1-5 alkylene; R a selected from the group consisting of unsubstituted or substituted C a1 alkyl, 3-6 membered saturated cycloalkyl, COOR 1-5 alkyl, 3-6 membered saturated cycloalkyl, COOR a2 ; R a1 each independently selected from the group consisting of halogen; R a2 selected from the group consisting of C 1-5 alkyl; or R1is connected with L0R0to form a substituted or unsubstituted 3-5 membered saturated or partially unsaturated ring, which is unsubstituted or substituted with one or more R q3 substituted 3-5 membered saturated or partially unsaturated ring, which is unsubstituted or substituted with one or more R q3 each independently selected from =0, C 1-5 alkyl, COOR q4 , R q4 selected from C 1-5 alkyl; R2, R3, R4, R5are each independently selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C 3a substituted C 1-5 alkyl; R 3a each independently selected from halogen; L1is selected from the group consisting of none, O, S, NR a3 , N=CH, C 1-5 alkylene; R a3 selected from hydrogen, C 1-5 alkyl; L2 is selected from none, unreplaced, or replaced by one or more R values. x Replacement C 1-5 Alkylene, unsubstituted or with one or more R x Replacement C 2-5 Ideonyl; R x Each independently selected from C 1-5 Alkyl, C 1-5 Alkyl groups, hydroxyl groups; A is selected from nothing, OCO, CONH, O, S, SO, SO2; L3is selected from the group consisting of none, C 1-5 alkylene; R6is selected from hydrogen, unsubstituted or substituted with one or more R 6a substituted C 1-5 alkyl, unsubstituted or substituted with one or more R 6a substituted C 1-5 alkoxy, unsubstituted or substituted with one or more R 6a substituted C 2-5 alkenyl, unsubstituted or substituted with one or more R 6a substituted C 2-5 alkynyl, NR7R8, unsubstituted or substituted with one or more R 6a substituted 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R 6a substituted 3-6 membered saturated heterocyclyl, OCOR 6b , unsubstituted or substituted with one or more R v substituted phenyl, unsubstituted or substituted with one or more R v substituted 5-6 membered heteroaryl, OL4R y ; R 6a each independently selected from C 1-5 alkyl, C 1-5 alkoxy, halogen, hydroxyl; R 6b is selected from C 1-5 alkyl; R7is selected from hydrogen, C 1-5 alkyl, L5R z1 ; R8is selected from C 1-5 alkyl, C 1-5 alkoxy, 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R v substituted 5-6 membered heteroaryl, L7R z3 ; or R7, R8are linked to form a substituted or unsubstituted 3-6 membered saturated nitrogen heterocycle; 7a substituted 3-6 membered saturated nitrogen heterocycle; R 7a each independently selected from C 1-5 alkyl; R v each independently selected from C 1-5 alkyl, halogen-substituted C 1-5 alkyl, C 1-5 alkoxy, halogen-substituted C 1-5 alkoxy, halogen, CN, CONR v1 R v2 ; R v1 selected from hydrogen, C 1-5 alkyl, R v2 selected from hydrogen, C 1-5 alkyl; L5is selected from C 1-5 alkylene; R z1 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R w1 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R w1 each independently selected from the group consisting of OR w2 , R w2 is selected from the group consisting of C 1-5 alkyl, 3-6 membered saturated cycloalkyl; L7is selected from C 1-5 alkylene; R z3 is selected from the group consisting of 5-6 membered heteroaryl, 3-6 membered saturated cycloalkyl, each independently optionally substituted with one or more R w5 is selected from the group consisting of 5-6 membered heteroaryl, 3-6 membered saturated cycloalkyl, each independently optionally substituted with one or more R w5 is each independently selected from the group consisting of OR w6 , R w6 is selected from the group consisting of C 1-5 alkyl, 3-6 membered saturated cycloalkyl; L4 is selected from the group consisting of none, C 1-5 alkylene; R y selected from the group consisting of hydrogen, C 1-5 alkyl, phenyl.

3. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterium derivative of claim 2, characterized in that, The structure of the compound is shown as formula III-1, formula III-2, formula III-3, formula III-4, or formula III-5: b is selected from 0, 1 or 2; R 01 selected from C 1-4 alkyl; L1, L2, A, R6, R1, R2, R3, R4, R5are as described in claim 2.

4. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of claim 2, characterized in that, The structure of the compound is shown in formula IV: b is selected from 0, 1 or 2; R 02 selected from hydrogen, C 1-4 alkyl, R 03 selected from hydrogen, C 1-4 alkyl, unsubstituted or substituted by one or more R 04 L8R L , or R 02 , R 03 form a 6-membered saturated nitrogen heterocycle, unsubstituted or substituted by one or more R 10 L8 is selected from nothing, C 1-2 alkylene, R L selected from R 04 each independently selected from the group consisting of CONR 05 R 06 , C 1-4 alkyl, C 1-4 alkoxy, R 05 , R 06 each independently selected from the group consisting of hydrogen, C 1-4 alkyl, R 10 each independently selected from the group consisting of C 1- 4alkyl; L1, L2, A, R6, R1, R2, R3, R4, R5are as described in claim 2.

5. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of claim 2, characterized in that, The structure of the compound is as shown in formula V: b is selected from 0, 1 or 2; R 01 selected from C 1-4 alkyl, NR 02 R 03 ; R 02 selected from hydrogen, C 1-4 alkyl, R 03 selected from hydrogen, C 1-4 alkyl, unsubstituted or substituted by one or more R 04 L8R L , or R 02 , R 03 form a 6-membered saturated nitrogen heterocycle, unsubstituted or substituted by one or more R 10 L8 is selected from nothing, C 1-2 alkylene, R L selected from R 04 each independently selected from the group consisting of CONR 05 R 06 , C 1-4 alkyl, C 1-4 alkoxy, R 05 , R 06 each independently selected from the group consisting of hydrogen, C 1-4 alkyl, R 10 each independently selected from the group consisting of C 1- 4alkyl; L1, L2, A, R6, R1, R2, R3, R4, R5are as described in claim 2.

6. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of claim 2, characterized in that, The structure of the compound is as shown in formula VI: b is selected from 0, 1, 2 or 3; a is selected from 0 or 1; R 01 selected from hydrogen, unsubstituted or mono- or di-substituted L8R 04 ; L8 is selected from null, C L alkylene, R 1-5 ; L8 is selected from null, C L alkylene, R 1-8 ; L8 is selected from null, C 1-8 alkylene, R 04 each independently selected from C 1-8 alkyl, C 1-8 alkoxy; L1, L2, A, R6, R1, R2, R3, R4, R5are as described in claim 2.

7. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of claim 2, characterized in that, The structure of the compound is as shown in formula VII-1, VII-2, VII-3, VII-4, VII-5: X1is selected from N, CR A ; X2is selected from N, CR B ; X1, X2are not simultaneously N; R A , R B each independently is selected from the group consisting of hydrogen, halogen, C 3a 1-6alkyl which is unsubstituted or substituted by one or more R 1-8 each independently is selected from the group consisting of halogen; and 3a each independently is selected from the group consisting of halogen; and L1, L2, A, R6, R1, R2, R3, R4, R5are as described in claim 2.

8. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative according to any one of claims 1 to 7, characterized in that, The The structure of L1is selected from the group consisting of none, O, S, NR a3 , N=CH, C 1-3 alkylene; R a3 selected from hydrogen, C 1-3 alkyl; L2 is selected from none, unreplaced, or replaced by one or more R values. x Replacement C 1-3 Alkylene, unsubstituted or with one or more R x Replacement C 2-3 Ideonyl; R x Each independently selected from C 1-8 Alkyl, C 1-8 Alkyl groups, hydroxyl groups; L3is selected from the group consisting of none, C 1-3 alkylene; R6is selected from hydrogen, unsubstituted or substituted with one or more R 6a substituted C 1-5 alkyl, unsubstituted or substituted with one or more R 6a substituted C 1-5 alkoxy, unsubstituted or substituted with one or more R 6a substituted C 2-3 alkenyl, unsubstituted or substituted with one or more R 6a substituted C 2-3 alkynyl, NR t R u , unsubstituted or substituted with one or more R 6a substituted 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R 6a substituted 3-6 membered saturated heterocyclyl, OCOR 6b , phenyl, one or more R v substituted phenyl, 5-6 membered nitrogen heteroaryl, one or more R v substituted 5-6 membered nitrogen heteroaryl; R 6a each independently selected from C 1-3 alkyl, C 1-3 alkoxy, halogen, hydroxyl; R 6b selected from C 1-3 alkyl; R v each independently selected from C 1-3 alkyl, halogen-substituted C 1-3 alkyl, C 1-3 alkoxy, halogen-substituted C 1-3 alkoxy, halogen, CONR v1 R v2 ; R v1 selected from hydrogen, C 1-5 alkyl, R v2 selected from hydrogen, C 1-5 alkyl; R t selected from hydrogen, C 1-3 alkyl, R u selected from hydrogen, C 1-3 alkyl.

9. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative according to any one of claims 1 to 7, characterized in that, Said In: L1is selected from the group consisting of none, O, S, NR a3 、 N=CH, C 1-3 alkylene; R a3 selected from hydrogen, C 1-3 alkyl; L2is selected from nothing, unsubstituted or substituted C x substituted C 1-3 alkylene, unsubstituted or substituted C x substituted C 2-3 alkenylene; R x each independently selected from C 1-3 alkyl, C 1-3 alkoxy, hydroxy; A is selected from nothing, OCO, CONH, O, S, SO, SO2; R6is selected from hydrogen, unsubstituted or substituted with one or more R 6a substituted C 1-5 alkyl, unsubstituted or substituted with one or more R 6a substituted C 1-5 alkoxy, unsubstituted or substituted with one or more R 6a substituted C 2-3 alkenyl, unsubstituted or substituted with one or more R 6a substituted C 2-3 alkynyl, NR t R u , unsubstituted or substituted with one or more R 6a substituted 3-5 membered saturated cycloalkyl, unsubstituted or substituted with one or more R 6a substituted 3-5 membered saturated heterocyclyl, OCOR 6b , phenyl, one or more R v substituted phenyl, 5-6 membered nitrogen heteroaryl, one or more R v substituted 5-6 membered nitrogen heteroaryl, OL4R y ; R 6a each independently selected from C 1-3 alkyl, C 1-3 alkoxy, halogen, hydroxyl; R 6b is selected from C 1-3 alkyl; R t selected from hydrogen, C 1-3 alkyl, L5R z1 , R u selected from hydrogen, C 1-3 alkyl, L6R z2 ; L5is selected from C 1-3 alkylene; R z1 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R w1 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R w1 each independently selected from the group consisting of OR w2 , R w2 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R 1-3 alkyl, 3-5 membered saturated cycloalkyl; L6is selected from C 1-3 alkylene; R z2 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R w3 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R w3 each independently selected from the group consisting of OR w4 , R w4 is selected from the group consisting of an unsubstituted or substituted 5-6 membered heteroaryl; R 1-3 alkyl, 3-5 membered saturated cycloalkyl; L4 is selected from the group consisting of none, C 1-3 alkylene; R y selected from the group consisting of hydrogen, C 1-3 alkyl, phenyl; R v each independently selected from C 1-3 alkyl, halogen-substituted C 1-3 alkyl, C 1-3 alkoxy, halogen-substituted C 1-3 alkoxy, halogen, CN, CONR v1 R v2 ; R v1 selected from hydrogen, C 1-3 alkyl, R v2 selected from hydrogen, C 1-3 alkyl.

10. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of claim 9, characterized in that, The The structure of the compound is: c is selected from 0, 1, 2 or 3, and R6is as described in claim 9.

11. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of any one of claims 1-7, characterized in that, The The structure of L1is selected from the group consisting of none, O, S, NR a3 、 N=CH, C 1-3 alkylene; R a3 selected from hydrogen, C 1-3 alkyl; L2is selected from the group consisting of none, C 1-3 alkylene; R7is selected from hydrogen, C 1-3 alkyl; R8is selected from C 1-4 alkyl, C 1-4 alkoxy, 3-4 membered saturated cycloalkyl, one or more R v substituted 5-6 membered nitrogen heteroaryl, L7R z3 ; or R7, R8are linked to form a substituted or unsubstituted 4-6 membered saturated nitrogen heterocycle; 7a substituted 4-6 membered saturated nitrogen heterocycle; R 7a each independently selected from C 1-3 alkyl; R v each independently selected from C 1-3 alkyl, halogen-substituted C 1-3 alkyl, C 1-3 alkoxy, halogen-substituted C 1-3 alkoxy, halogen, CN, CONR v1 R v2 ; R v1 selected from hydrogen, C 1-3 alkyl, R v2 selected from hydrogen, C 1-3 alkyl; L7is selected from C 1-3 alkylene; R z3 is selected from the group consisting of 5-6 membered heteroaryl, 3-4 membered saturated cycloalkyl, which is unsubstituted or substituted by one or more R w5 is selected from the group consisting of 5-6 membered heteroaryl, 3-4 membered saturated cycloalkyl, which is unsubstituted or substituted by one or more R w5 each independently is selected from the group consisting of OR w6 , R w6 is selected from the group consisting of C 1-3 alkyl, 3-5 membered saturated cycloalkyl.

12. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of any one of claims 1-7, characterized in that, The The structure of L1is selected from the group consisting of none, O, S, NR a3 , N=CH, C 1-3 alkylene; R a3 selected from hydrogen, C 1-3 alkyl; L2is selected from the group consisting of none, C 1-3 alkylene; R6is selected from hydrogen, unsubstituted or substituted with one or more R 6a substituted C 1-4 alkyl, unsubstituted or substituted with one or more R 6a substituted C 1-4 alkoxy, NR7R8; R 6a each independently selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, hydroxyl; R7is selected from hydrogen, C 1-4 alkyl; R8is selected from C 1-4 alkyl; or R7, R8are joined to form a substituted or unsubstituted 3-6 membered saturated nitrogen heterocycle; 7a substituted 3-6 membered saturated nitrogen heterocycle; R 7a each independently selected from C 1-4 alkyl.

13. The compound of claim 1, a tautomer thereof, an endo form thereof, an exo form thereof, an enantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof, characterized in that, The compound is selected from one of the following compounds:

14. The compound, its tautomer, its mesomer, its racemate, its enantiomer, its diastereomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative of any one of claims 1-13, characterized in that, the pharmaceutically acceptable salt is selected from citrate, hydrofluoride, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, nosylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, xinafoate or p-toluenesulfonate.

15. A pharmaceutical composition comprising, It is a preparation obtained by adding a pharmaceutically acceptable adjuvant to the active ingredient which is the compound, the tautomer thereof, the mesomer thereof, the racemate thereof, the enantiomer thereof, the diastereomer thereof, the pharmaceutically acceptable salt thereof, the solvate thereof, the prodrug thereof, the metabolite thereof or the deuterated derivative thereof of any one of claims 1 to 14.

16. Use of the compound, the tautomer thereof, the mesomer thereof, the racemate thereof, the enantiomer thereof, the diastereomer thereof, the pharmaceutically acceptable salt thereof, the solvate thereof, the prodrug thereof, the metabolite thereof or the deuterated derivative thereof of any one of claims 1 to 14 in the manufacture of a medicament having analgesic effect, and / or, having anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus.

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