Compound, and preparation method therefor and use thereof

Abstract

The present invention belongs to the technical field of medicine. Provided are a compound, and a preparation method therefor and the use thereof. The compound has a structure as shown in formula I. The compound of the present invention not only has efficient sedative, hypnotic and / or anesthetic effects, and the ability to control status epilepticus, but also exhibits an analgesic effect, and can reduce or avoid the use of opioid analgesics 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 pruritus caused by opioid analgesics.

Description

A compound, and 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, and 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 drug currently used in clinical practice. It has the advantages of rapid onset of anesthetic induction, rapid recovery, 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 effects. If a compound has sedative, hypnotic, and / or anesthetic effects, can control status epilepticus, and also has analgesic effects, it can achieve more perfect analgesia, significantly reduce the use 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 of other drugs during combined anesthesia, speed up the recovery of the patient's self-sedation, hypnotic, and / or anesthesia state, and increase the safety of the patient. Therefore, there is an urgent need to develop a drug that not only has sedative, hypnotic, and / or anesthetic effects, can control status epilepticus, but also has analgesic effects. SUMMARY

[0003] The present application provides a compound, and 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, and the structure of the compound is shown in formula I:

[0005] L0 is selected from the group consisting of nothing, O, S, C 1-5 alkylene, L 01 -L 02 -L 03 ; L 01 selected from the group consisting of nothing, C 1-5 alkylene, L 02 selected from the group consisting of CONH, NHCO, NR a0 , CO, L 03 selected from the group consisting of nothing, C 1-5 alkylene, R a0 selected from the group consisting of hydrogen, C 1-8 alkyl;

[0006] R0 is selected from the group consisting of unsubstituted or substituted by one or more R q1substituted aryl, unsubstituted or substituted by one or more R q1 substituted heteroaryl, unsubstituted or substituted by one or more R q1 substituted fused ring, unsubstituted or substituted by one or more R q2 substituted saturated nitrogen-containing heterocyclyl;

[0007] said R q1 each independently selected from -O, =O, halogen, C 1-8 alkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyl, halogen-substituted C 1-8 alkoxy, halogen-substituted C 1c R 1d , NR 1c R 1d , COR 1e ; said R q2 each independently selected from -O, halogen, C 1-8 alkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyl, halogen-substituted C 1-8 alkoxy, amino protecting group, NR 1c R 1d , COR 1e ; R 1c selected from hydrogen, C 1-8 alkyl, amino protecting group, R 1d selected from hydrogen, C 1-8 alkyl, amino protecting group, R 1e selected from hydrogen, C 1-8 alkyl;

[0008] R1is selected from hydrogen, LR a ;

[0009] L is selected from null, C 1-5 alkylene;

[0010] R a is selected from unsubstituted or substituted by one or more R a1 C 1-8 alkyl, unsubstituted or substituted by one or more R a1 C 1-8 alkoxy, unsubstituted or substituted by one or more R a1 C 2-8 alkenyl, hydroxyl, N3, CN, NO2, halogen, 3-8 membered saturated cycloalkyl, NR b R c , COOR a2 ; R b selected from hydrogen, C 1-8 alkyl, Rc selected from hydrogen, C 1-8 alkyl, or R b , R c to form a 3-8 membered saturated nitrogen heterocycle; R a1 each independently selected from halogen; R a2 selected from C 1-8 alkyl;

[0011] 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;

[0012] R2, R3, R4, R5are each independently selected from hydrogen, halogen, unsubstituted or substituted C 3a alkyl, unsubstituted or substituted by one or more R 1-8 alkyl, unsubstituted or substituted by one or more R 3a alkyl, unsubstituted or substituted by one or more R 1-8 alkoxy, NO2, CN, COOR h , OR h , SO2OM, SO2NR h R i , CONR h R i , OCONR h R i , NR h R i , CONHR j ; R 3a each independently selected from halogen; R j selected from unsubstituted or substituted by one or more R k 5-6 membered heteroaryl, phenyl, R k each independently selected from CONR h R i ; R h selected from hydrogen, C 1-8 alkyl, R i selected from hydrogen, C 1-8 alkyl; M is selected from hydrogen, a metal atom;

[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] L1is selected from none, O, S, NR a3 , N=CH, C 1-5 alkylene; Ra3 selected from hydrogen, C 1-8 alkyl;

[0015] L2 is selected from the absence, 5-6 membered saturated nitrogen heterocyclyl, unsubstituted or substituted with one or more R x substituted C 1-5 alkylene, unsubstituted or substituted with one or more R x substituted C 2-5 alkenylene, unsubstituted or substituted with one or more R x substituted C 2-5 alkynylene; R x each independently selected from C 1-8 alkyl, C 1-8 alkoxy, hydroxyl, halogen;

[0016] A is selected from the absence, COL3, NR a6 L3, COOL3, OCOL3, CONR a6 L3, OL3, SL3, SOL3, SO2L3;

[0017] R a6 selected from hydrogen, C 1-8 alkyl;

[0018] L3 is selected from the absence, C 1-5 alkylene;

[0019] R6 is selected from hydrogen, hydroxyl, 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, L 10 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, unsubstituted or substituted with one or more R 6a substituted 3-6 membered non-aromatic unsaturated nitrogen 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 1-8alkyl, halo-substituted C 6b selected from C 1-8 alkyl; L 10 selected from C 1-5 alkylene;

[0020] R7is selected from hydrogen, halo- or unhalo-substituted C 1-8 alkyl, L5R z1 ;

[0021] R8is selected from halo- or unhalo-substituted C 1-8 alkyl, C 1-8 alkoxy, C 2-5 alkenyl, C 2-5 alkynyl, 3-8 membered saturated cycloalkyl, 5-6 membered heteroaryl which is unsubstituted or substituted by one or more R v , L7R z3 ;

[0022] or R7, R8are linked to form a 3-8 membered saturated nitrogen-containing heterocyclic ring, a 5-6 membered non-aromatic unsaturated nitrogen-containing heterocyclic ring, a 5-6 membered nitrogen-containing heteroaryl, a 3-8 membered saturated nitrogen-containing heterocyclic ring fused to a benzene ring, which is unsubstituted or substituted by one or more R 7a ;

[0023] R 7a each independently selected from C 1-8 alkyl, C 1-8 alkoxy, phenyl, COOR 6d ; R 6d selected from C 1-8 alkyl;

[0024] R v each independently selected from C 1-8 alkyl, halo-substituted C 1-8 alkyl, C 1-8 alkoxy, halo-substituted C 1-8 alkoxy, halo, CN, CONR v1 R v2 ; R v1 selected from hydrogen, C 1-8 alkyl, R v2 selected from hydrogen, C 1-8 alkyl;

[0025] L5is selected from C 1-5 alkylene; R z1 selected from 5-6 membered heteroaryl which is unsubstituted or substituted by one or more R w1 ; R w1 each independently selected from OR w2 , R w2 selected from C 1-5 alkyl, 3-8 membered saturated cycloalkyl;

[0026] L7 is selected from C 1-5 Alkylene; R z3 Selected from those that have not been replaced or have been replaced by one or more R w5 Substituted groups include: 5-6 membered heteroaryl groups, 3-8 membered saturated cycloalkyl groups; R w5 Each independently selected from OR w6 R w6 Selected from C 1-8 Alkyl groups, 3-8 membered saturated cycloalkyl groups;

[0027] L4 is selected from none, C 1-5 Alkylene; R y Selected from hydrogen, C 1-8 Alkyl, phenyl.

[0028] Furthermore, the structure of the compound is shown in Formula II-1, Formula II-2, Formula II-3, Formula II-4, or Formula II-5:

[0029] R1 is selected from hydrogen, LR a ;

[0030] L is selected from none, C 1-2 Alkylene;

[0031] R a Selected from those that have not been replaced or have been replaced by one or more R a1 Replacement C 1-3 Alkyl, unsubstituted or with one or more R a1 Replacement C 1-3 Alkyl group, unsubstituted or with one or more R groups a1 Replacement C 2-3 Alkenyl, hydroxyl, N3, CN, NO2, halogen, 3-4 member saturated cycloalkyl, NR b R c COOR a2 ;R b Selected from hydrogen, C 1-3 Alkyl, R c Selected from hydrogen, C 1-3 Alkyl, or R b R c The linkage forms a 3-4 member saturated nitrogen heterocycle; R a1 Each is independently selected from halogens; R a2 Selected from C 1-3 alkyl;

[0032] R2 is selected from hydrogen, CONHR d ;R d Selected from those that have not been replaced or have been replaced by one or more R e Substituted groups include: 5-6 azirroyl, phenyl; R eEach independently selected from CONR f R g ;R f Selected from hydrogen, C 1-3 Alkyl, R g Selected from hydrogen, C 1-3 alkyl;

[0033] R3 is selected from hydrogen, halogen, unsubstituted or surrounded by one or more R3 groups. 3a Replacement C 1-3 Alkyl, unsubstituted or with one or more R 3a Replacement C 1-3 Alkoxy, NO2, CN, COOR h OR h SO2OM, SO2NR h R i CONR h R i NR h R i CONHR j ;R 3a Each is independently selected from halogens; R j Selected from those that have not been replaced or have been replaced by one or more R k Substituted groups include: 5-6 azirroaryl, phenyl, R k Each independently selected from CONR h R i ;R h Selected from hydrogen, C 1-3 Alkyl, R i Selected from hydrogen, C 1-3 Alkyl group; M is selected from hydrogen or metal atoms;

[0034] R4 is selected from hydrogen, C 1-3 Alkoxy, COOR m OR m OCONR m R n ;R m Selected from hydrogen, C 1-3 Alkyl, R n Selected from hydrogen, C 1-3 alkyl;

[0035] R5 is selected from hydrogen, OCONR p R q ;R p Selected from hydrogen, C 1-3 Alkyl, R q Selected from hydrogen, C 1-3 alkyl;

[0036] L1 is selected from None, O, S, NR a3 , N=CH, C 1-5 alkylene; R a3 selected from hydrogen, C 1-5 alkyl;

[0037] L2 is selected from the absence, 5-6 membered saturated nitrogen heterocyclyl, C x substituted C 1-5 alkylene, unsubstituted or substituted with one or more R x substituted C 2-5 alkenylene, unsubstituted or substituted with one or more R x substituted C 2-5 alkynylene; R x each independently selected from C 1-5 alkyl, C 1-5 alkoxy, hydroxyl, halogen;

[0038] A is selected from the absence, COL3, NR a6 L3, COOL3, OCOL3, CONR a6 L3, OL3, SL3, SOL3, SO2L3;

[0039] R a6 selected from hydrogen, C 1-5 alkyl;

[0040] L3 is selected from the absence, C 1-5 alkylene;

[0041] R6 is selected from hydrogen, hydroxyl, C 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, L 10 NR7R8, unsubstituted or substituted with one or more R 6a 3-6 membered saturated cycloalkyl, unsubstituted or substituted with one or more R 6a 3-6 membered saturated heterocyclyl, unsubstituted or substituted with one or more R 6a 3-6 membered non-aromatic unsaturated nitrogen heterocyclyl, OCOR 6b , unsubstituted or substituted with one or more R v phenyl, unsubstituted or substituted with one or more R v 5-6 membered heteroaryl, OL4R y ; R 6a each independently selected from C1- 5-alkyl, C 1-5 Alkoxy, halogen, hydroxyl; R 6b Selected from C 1-5 Alkyl; L 10 Selected from C 1-3 Alkylene;

[0042] R7 is selected from hydrogen, halogenated, or non-halogenated C. 1-5 Alkyl, L5R z1 ;

[0043] R8 is selected from halogenated or non-halogenated C. 1-5 Alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, C 1-5 Alkoxy, 3-6 membered saturated cycloalkyl, unsubstituted or with one or more R v Substituted 5-6 aryl heteroaryl, L7R z3 ;

[0044] Alternatively, the connection of R7 and R8 forms a structure that is not replaced or is formed by one or more R... 7a The following groups are substituted: 3-6 membered saturated nitrogen-containing heterocycles, 5-6 membered non-aromatic unsaturated nitrogen-containing heterocyclic groups, 5-6 membered nitrogen-containing heteroaryl groups, and 3-6 membered saturated nitrogen-containing heterocyclic benzobenzene rings;

[0045] R 7a Each independently selected from C 1-5 Alkyl, C 1-5 Alkoxy, phenyl, COOR 6d ;R 6d Selected from C 1-5 alkyl;

[0046] R v Each independently selected from C 1-5 Alkyl, halogen-substituted C 1-5 Alkyl, C 1-5 alkoxy- or 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;

[0047] L5 is selected from C 1-5 Alkylene; R z1 Selected from those that have not been replaced or have been replaced by one or more R w1 Substituted 5-6 aryl groups; R w1 Each independently selected from OR w2 R w2 Selected from C1-5 Alkyl groups, 3-6 membered saturated cycloalkyl groups;

[0048] L7 is selected from C 1-5 Alkylene; R z3 Selected from those that have not been replaced or have been replaced by one or more R w5 Substituted groups include: 5-6 membered heteroaryl groups, 3-6 membered saturated cycloalkyl groups; R w5 Each independently selected from OR w6 R w6 Selected from C 1-5 Alkyl groups, 3-6 membered saturated cycloalkyl groups;

[0049] L4 is selected from none, C 1-5 Alkylene; R y Selected from hydrogen, C 1-5 Alkyl, phenyl;

[0050] L0 and R0 are as described above.

[0051] Furthermore, in the compound, The structure is selected from L 2c COL3R6, L 2c COOL3R6, L 2c CONR a6 L3R6, L 2d NR a6 L3R6, L 2d OCOL3R6, L 2d OL3R6, L 2d SL3R6, L 2d SOL3R6, L 2d SO2L3R6;

[0052] in, The structure is selected from

[0053] G x Selected from O or S;

[0054] a is selected from 0, 1, 2, or 3; A1 is selected from none or 0;

[0055] b is selected from 0, 1, 2, or 3; A2 is selected from none or O, S, SO, SO2, NHL3, A3L3, unsubstituted, or substituted by one or more R. x Replacement C 1-3 Alkylene; A3 is selected from 5-6 membered saturated nitrogen heterocyclic groups; L3 is selected from none, C 1-3 Alkylene; R x Each independently selected from C 1-3 Alkyl, C 1-3 Alkyl groups, hydroxyl groups;

[0056] for when for At that time, R a3 It is none;

[0057] The structure is selected from

[0058] R b4 Selected from hydrogen, C 1-5 Alkyl, R b5 For L 2a A4R6; L 2a Selected from none, C 1-3 Alkylene, C 2-3 Ideonyl group, A4 is selected from none, CO; or R b4 R b5 The linkage forms 3-6 member saturated nitrogen heterocycles;

[0059] L 2b Selected from none, C 1-3 Alkylene, A5 is selected from none, CO;

[0060] A6 is selected from None, CO, NR a6 ;R a6 Selected from hydrogen, C 1-3 alkyl;

[0061] R 6c Selected from those that have not been replaced or have been replaced by one or more R 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 Substituted 3-6 saturated cycloalkyl groups, unsubstituted or with one or more R groups v Substituted phenyl, unsubstituted or with one or more R v Substituted 5-6 aryl groups;

[0062] L 2c Selected from none, not replaced, or replaced by one or more R x Replacement C 1-5 Alkylene, unsubstituted or with one or more R x Replacement C 2-5 alkenyl, unsubstituted or with one or more R x Replacement C 2-5 Ethyne group;

[0063] L 2d Selected from those that have not been replaced or have been replaced by one or more R xsubstituted C 1-5 alkylene, unsubstituted or substituted by one or more R x substituted C 2-5 alkenylene, unsubstituted or substituted by one or more R x substituted C 2-5 alkynylene;

[0064] R x each independently selected from C 1-5 alkyl, C 1-5 alkoxy, hydroxy;

[0065] R a6 selected from hydrogen, C 1-5 alkyl;

[0066] L3is selected from none, C 1-5 alkylene;

[0067] R6is as described hereinbefore.

[0068] Further, the compound has a structure as shown in Formula III-1, Formula III-2, Formula III-3, Formula III-4, or Formula III-5:

[0069] wherein, the structure of

[0070] G x selected from O or S;

[0071] ais selected from 0, 1, 2, or 3; A1is selected from none or O;

[0072] bis selected from 0, 1, 2, or 3; A2is selected from none or O, S, SO, SO2, NHL3, A3L3, unsubstituted or substituted by one or more R x substituted C 1-3 alkylene; A3is selected from 5-6 membered saturated nitrogen heterocyclyl; L3is selected from none, C 1-3 alkylene; R x each independently selected from C 1-3 alkyl, C 1-3 alkoxy, hydroxy;

[0073] R6, R1, R2, R3, R4, R5, L0, R0are as described hereinbefore.

[0074] Further, the compound has a structure as shown in Formula IV-1, Formula IV-2, Formula IV-3, Formula IV-4, or Formula IV-5:

[0075] wherein, is when For R a3 is nothing;

[0076] the structure of A4R6is selected from

[0077] R b4 is selected from hydrogen, C 1-5 alkyl, R b5 is L 2a A4R6; L 2a is selected from nothing, C 1-3 alkylene, C 2-3 alkenylene, A4is selected from nothing, CO; or R b4 , R b5 are joined to form a 3-6 membered saturated nitrogen heterocycle;

[0078] L 2b is selected from nothing, C 1-3 alkylene, A5is selected from nothing, CO;

[0079] A6is selected from nothing, CO, NR a6 ; R a6 is selected from hydrogen, C 1-3 alkyl;

[0080] R 6c is selected from C 6a alkyl which is unsubstituted or substituted by one or more R 1-5 , C 6a alkoxy which is unsubstituted or substituted by one or more R 1-5 , 3-6 membered saturated cycloalkyl which is unsubstituted or substituted by one or more R 6a , phenyl which is unsubstituted or substituted by one or more R v , 5-6 membered heteroaryl which is unsubstituted or substituted by one or more R v ;

[0081] L 10 , R7, R8, R6, R1, R2, R3, R4, R5, L0, R0are as described hereinbefore.

[0082] Further, in the compounds, the structure of A4R6is selected from L 2c COL3R6, L 2c COOL3R6, L 2c CONR a6 L3R6, L 2d NR a6 L3R6, L 2d OCOL3R6, L 2d OL3R6, L 2dSL3R6, L 2d SOL3R6, L 2d SO2L3R6;

[0083] L 2c selected from none, unsubstituted or substituted with one or more R x substituted C 1-5 alkylene, unsubstituted or substituted with one or more R x substituted C 2-5 alkenylene, unsubstituted or substituted with one or more R x substituted C 2-5 alkynylene;

[0084] L 2d selected from unsubstituted or substituted with one or more R x substituted C 1-5 alkylene, unsubstituted or substituted with one or more R x substituted C 2-5 alkenylene, unsubstituted or substituted with one or more R x substituted C 2-5 alkynylene;

[0085] R x each independently selected from C 1-5 alkyl, C 1-5 alkoxy, hydroxy;

[0086] R a6 selected from hydrogen, C 1-5 alkyl;

[0087] L3 is selected from none, C 1-5 alkylene;

[0088] R6 is as previously described.

[0089] Further, in the compound, the structure of which is shown in Formula X-1:

[0090] In Formula X-1, L0 is selected from none, C 1-5 alkylene;

[0091] B ring is selected from phenyl, 5-6 membered heteroaryl;

[0092] b is selected from 0, 1, 2 or 3;

[0093] R 1b each independently selected from hydrogen, -O, halogen, C 1-8 alkyl, halogen substituted C 1-8 alkyl, C 1-8 alkoxy, halogen substituted C 1-8 alkoxy, CONR1c R 1d NR 1c R 1d COR 1e ;R 1c Selected from hydrogen, C 1-8 alkyl and amino protecting groups, R 1d Selected from hydrogen, C 1-8 alkyl and amino protecting groups, R 1e Selected from hydrogen, C 1-8 alkyl;

[0094] Alternatively, in the compound, The structure is shown in equation X-2:

[0095] In equation X-2, L0 is selected from none, C 1-5 Alkylene;

[0096] The C ring is selected from a 6-membered saturated nitrogen-containing heterocyclic group, R 07 Selected from hydrogen, =O, C 1-8 Alkyl, C 1-8 Alkoxy, NR 08 R 09 R 08 Selected from hydrogen, C 1-8 alkyl and amino protecting groups, R 09 Selected from hydrogen, C 1-8 Alkyl and amino protecting groups;

[0097] Alternatively, in the compound, The structure is shown in equation X-3:

[0098] In formula X-3, L0 is selected from 0, O, and S, and the D ring is a benzo5-membered heterocycle; R q1 Selected from hydrogen, C 1-8 alkyl.

[0099] Furthermore, in equation X-1, L0 is selected from none, C 1-4 Alkylene;

[0100] b is selected from 0, 1, 2, or 3;

[0101] Ring B is selected from phenyl or 5-6 membered heteroaryl groups;

[0102] R 1b Each element is independently selected from hydrogen, -O, halogens, and C. 1-6 Alkyl, halogen-substituted C 1-6 Alkyl, C 1-6 alkoxy- or halogen-substituted C 1-6 Alkoxy, CONR 1c R 1dNR 1c R 1d COR 1e ;R 1c Selected from hydrogen, C 1-6 alkyl and amino protecting groups, R 1d Selected from hydrogen, C 1-6 alkyl and amino protecting groups, R 1e Selected from hydrogen, C 1-6 alkyl;

[0103] Alternatively, as shown in equation X-2 The structure is

[0104] L0 is selected from none, C 1-3 Alkylene;

[0105] X2 is selected from NH, CH2, O, and S;

[0106] R 07 Selected from hydrogen, =O, C 1-4 Alkyl, C 1-4 Alkoxy, NR 08 R 09 R 08 Selected from hydrogen, C 1-4 alkyl and amino protecting groups, R 09 Selected from hydrogen, C 1-4 Alkyl or amino protecting groups.

[0107] Furthermore, in equation X-1, L0 is selected from none, C 1-2 Alkylene;

[0108] b is selected from 0, 1, 2, or 3;

[0109] Ring B is selected from phenyl, 5-6-membered heteroaryl, and the 5-6-membered heteroaryl is selected from...

[0110] X1 is selected from N and NO;

[0111] R 1b Each element is independently selected from hydrogen, -O, halogens, and C. 1-3 Alkyl, halogen-substituted C 1-3 Alkyl, C 1-3 alkoxy- or halogen-substituted C 1-3 Alkoxy, CONR 1c R 1d NR 1c R 1d COR 1e ;R 1c Selected from hydrogen, C 1-3 alkyl and amino protecting groups, R1d selected from hydrogen, C 1-3 alkyl, an amino protecting group, R 1e selected from hydrogen, C 1-3 alkyl;

[0112] Alternatively, in Formula X-2, L0is selected from the absence of, C 1-2 alkylene;

[0113] selected from

[0114] R 07 selected from hydrogen, =0, C 1-4 alkyl, C 1-4 alkoxy, NR 08 R 09 , R 08 selected from hydrogen, C 1-4 alkyl, an amino protecting group, R 09 selected from hydrogen, C 1-4 alkyl, an amino protecting group;

[0115] Alternatively, in Formula X-3, L0is selected from the absence of, C 1-2 alkylene, D ring is R q1 selected from hydrogen, C 1-4 alkyl.

[0116] Further, B ring is when Formula X-1 is is

[0117] Further, the compound is selected from one of the following compounds:

[0118] 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, edisylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene-2-carboxylate, oxalate, palmitate, pamoate, phosphate, monohydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, xinafoate, or p-toluenesulfonate.

[0119] 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.

[0120] 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 preparation of a drug having analgesic effect, and / or, having anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus.

[0121] "Having analgesic effect, and / or, having anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus" includes the following three cases: (1) having analgesic effect; (2) having anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus; (3) having both anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus and analgesic effect.

[0122] "Having both anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus and analgesic effect" in the present application refers to no response to noxious stimuli or increasing the response threshold to noxious stimuli when the compound of the present application produces sedative, hypnotic and / or anesthetic effect.

[0123] "Drug having sedative effect" in the present application refers to a drug which is effective in helping sleep and effective in improving sleep. That is, it can avoid the serious harm of insomnia to the human body, treat insomnia, and improve sleep quality.

[0124] The "drug having a hypnotic effect" according to the present application means a drug that induces sleepiness and promotes sleep. That is, it has an inhibitory effect on the central nervous system, and a small dose induces sedation, and an overdose causes general anesthesia.

[0125] 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 by a drug, and the characteristic of the inhibition is the loss of sensation, particularly pain sensation. Preferably, the anesthetic effect is general anesthesia.

[0126] The "general anesthesia" according to the present application, abbreviated as GA, means a temporary inhibition of the central nervous system by an anesthetic drug, and the clinical manifestations are loss of consciousness, loss of general pain sensation, amnesia, reflex inhibition, and skeletal muscle relaxation.

[0127] The "status epilepticus" according to the present application means that the consciousness is not completely recovered between successive seizures of epilepsy, and the seizures frequently recur, or the seizures last for more than 30 minutes without stopping on their own. If not treated in time, long-term seizures can cause irreversible brain damage due to high fever, circulatory failure, or excitotoxic damage to neurons, resulting in a high rate of disability and mortality, and thus status epilepticus is a common emergency in internal medicine.

[0128] Definitions of terms used in the present application: Unless otherwise indicated, the initial definition of a group or term provided herein applies throughout this specification; for terms not specifically defined herein, the meaning given to them by one of ordinary skill in the art in light of the disclosure and context will prevail.

[0129] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix C a～b Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C 1-5 Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C 1-5 Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C 1-5 Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C 2-3 Alkenyl means any alkenyl group containing "a" to "b" carbon atoms. For example, C

[0130] Halogen is fluorine, chlorine, bromine, or iodine.

[0131] Metal atoms include monovalent alkali metal atoms, such as sodium.

[0132] Amino protecting groups include, but are not limited to, Bz (benzoyl), Cbz (benzyloxycarbonyl), Boc (tert-butyloxycarbonyl), Fmoc (9-fluorenylmethoxycarbonyl), Alloc (allyloxycarbonyl), Teoc (trichloroethoxycarbonyl).

[0133] More than one means one or more than one, and so on.

[0134] 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 contains both configurations.

[0135] 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 contains "cis, i.e. Z type" and "trans, i.e. E type".

[0136] Compared with the prior art, the compound provided by the present application has the following beneficial effects:

[0137] 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.

[0138] 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, replacements or changes can be made without departing from the above basic technical idea of the present application.

[0139] The above content of the present application will be further described in detail through the specific embodiments below. However, this should not be understood as limiting the scope of the above subject matter of the present application to the following embodiments. Any technology realized based on the above content of the present application belongs to the scope of the present application. DETAILED DESCRIPTION

[0140] The raw materials and equipment used in the present application are known products, which are obtained by purchasing commercially available products.

[0141] The following are the preparation method and structural characterization data of the compound.

[0142] The following are the preparation method and structural characterization data of the compound.

[0143] Example 1. Synthesis of compound 1.1, 1.2

[0144] Synthesis of compound 1-1

[0145] Sodium hydride (5.6 g, 0.14 mol, 1.4 eq, 40% wrapped in mineral oil) was suspended in 200 mL dry DMF under nitrogen protection, cooled to -40 °C, and 2-pyridineacetic acid methyl ester (22.6 g, 0.15 mol, 1.5 eq) was added dropwise. After slowly rising to 0 °C and stirring for 1 h, a solution of 2-fluoro-4-bromonitrobenzene (22.0 g, 0.10 mol, 1 eq) in 100 mL dry DMF was added dropwise. After slowly rising to room temperature and stirring for 2 h, the reaction was quenched by adding saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate and water three times, and the organic layers were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 4:1 ~ 3:1) to give compound 1-1 (30.5 g, yellow solid, 86.9%).

[0146] Synthesis of compound 1-2

[0147] Sodium hydride (3.8 g, 95.6 mol, 1.1 eq, 40% wrapped in mineral oil) was suspended in 200 mL dry DMF under nitrogen protection, cooled to -10 °C, and iodomethane (14.8 g, 104.3 mmol, 1.2 eq) was added. Then a solution of 1-1 (30.5 g, 86.9 mmol, 1 eq) in 100 mL dry DMF was added dropwise. After slowly rising to room temperature and stirring for 1 h, the reaction was quenched by adding saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate and water three times, and the organic layers were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 4:1) to give compound 1-2 (30.1 g, white solid, 94.9%).

[0148] Synthesis of compound 1-3

[0149] Method 1.

[0150] A solution of 30 mL of compound 1-2 (3.6 g, 10 mmol, 1 eq) and 4,4'-dipyridyl (78 mg, 0.5 mmol, 0.05 eq) in DMF was cooled to -10 °C, and tetrahydroxyboron (2.24 g, 25 mol, 2.5 eq) solid was added slowly in batches. After continuing to stir for 2 h, the temperature was slowly raised to room temperature, and stirring was continued for 2 h. The reaction mixture was extracted with ethyl acetate and water three times, and the organic layers were 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 give compound 1-3 (3.07 g, white solid, 96.5%).

[0151] Method 2.

[0152] Compound 1-2 (3.6 g, 10 mmol, 1 eq) was dissolved in 50 mL of tetrahydrofuran, 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. The reaction was slowly warmed to room temperature and stirred overnight at room temperature. The reaction liquid was removed from the insoluble material through a Buchner funnel. After removing the organic solvent from the filtrate, ethyl acetate and water were added to extract three times, the organic layers were combined, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 2:1) to obtain compound 1-3 (2.73 g, white solid, 85.8%).

[0153] Synthesis of compound 1.1

[0154] Compound 1-3 (128 mg, 0.4 mmol, 1 eq) was dissolved in 1 mL of dry dichloromethane under nitrogen protection, pyridine (320 mg, 4 mmol, 10 eq) and a catalytic amount of DMAP were added, isopropyl chloroformate (245 mg, 2 mmol, 5 eq) was added dropwise under ice bath conditions, the reaction was slowly warmed to room temperature, the solvent was removed, ethyl acetate and water were added to extract three times, the organic layers were 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 1.1 (i.e. NS-40) (47 mg, 29.2%, colorless transparent syrup). 1 HNMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 4.5 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.51 (m, 3H), 7.34 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.01 (m, 1H), 1.81 (s, 3H), 1.25 (d, J = 6.3 Hz, 6H). LC-MS: [M+H] + Calcd 405.04, 407.04, Found 405.0, 407.0.

[0155] According to the operation of compound 1, compound 1-3 (64 mg, 0.2 mmol, 1 eq), pyridine (32 mg, 0.4 mmol, 2 eq), and isobutyryl chloride (26 mg, 0.24 mmol, 1.2 eq) were used to synthesize compound 1.2 (i.e. NS-41) (71 mg, 91.5%, light yellow syrup). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.5 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.52 (m, 3H), 7.34 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 3.05 (m, 1H), 1.84 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H). LC-MS: [M+H] + Calcd 389.04, 391.04, Found 389.0, 391.0.

[0156] Example 2. Synthesis of compounds 2.1-2.15

[0157] Compound 1-3 (64 mg, 0.2 mmol, 1 eq) was dissolved in 1 mL dry DMF, potassium bicarbonate (40 mg, 0.4 mmol, 2 eq) and dimethylcarbamoyl chloride (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, 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) to obtain compound 2.1 (i.e. NS-42) (53 mg, 68.1%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.5 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.52 (m, 3H), 7.34 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 3.05 (m, 1H), 1.84 (s, 3H), 1.29 (d, J = 7.0 Hz, 6H). LC-MS: [M+H] + Calcd 390.04, 392.04, Found 390.0, 392.0.

[0158] Synthesis of compound 2.2

[0159] Methyl ethyl amine (118 mg, 2 mmol, 1 eq) was dissolved in 3 mL dry tetrahydrofuran, 1 mL of triphosgene (237 mg, 0.8 mmol, 0.4 eq) in tetrahydrofuran was added dropwise under ice bath conditions, slowly warmed to room temperature, extracted with methyl tert-butyl ether and water three times, combined organic layers, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to obtain chloroformyl methyl ethyl amine crude 1-4.

[0160] Referring to the synthesis of compound 2.1 above, 1-4 crude and compound 1-3 (64 mg, 0.2 mmol, 1 eq) were used as starting materials to synthesize compound 2.2 (i.e. NS-193) under the condition of potassium carbonate (138 mg, 1 mmol, 5 eq). White solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 3.4 Hz, 1H), 7.85 (td, J = 7.7, 1.4 Hz, 1H), 7.53 (dd, J = 10.5, 2.3 Hz, 3H), 7.36 (dd, J = 7.1, 5.2 Hz, 1H), 7.00 (dd, J = 16.4, 8.3 Hz, 1H), 3.52 (q, J = 7.0 Hz, 1H), 3.37 (q, J = 7.0 Hz, 1H), 3.12 (s, 2H), 2.98 (s, 2H), 1.84 (s, 1.5H), 1.28 (t, J = 6.9 Hz, 1.5H), 1.15 (t, J = 7.0 Hz, 1.5H). LC-MS: [M+H] + Calcd 404.05, 406.05, Found 404.0, 406.0.

[0161] Following the procedure for the synthesis of compound 2.2, the corresponding chloroformamides were synthesized using methyl isopropylamine (146 mg, 2 mmol), methyl propylamine (146 mg, 2 mmol), diethylamine (146 mg, 2 mmol), N-methyl isobutylamine (174 mg, 2 mmol), methyl cyclopropylamine (142 mg, 2 mmol), ethyl propylamine (174 mg, 2 mmol), ethyl isopropylamine (174 mg, 2 mmol), ethyl cyclopropylmethylamine (198 mg, 2 mmol), tetrahydropyrrole (142 mg, 2 mmol), N-methyl piperazine (200 mg, 2 mmol), methyl isobutylamine (174 mg, 2 mmol), cyclobutylamine hydrochloride (186 mg, 2 mmol), 3,3-dimethylcyclobutylamine hydrochloride (232 mg, 2 mmol) as starting materials, respectively, and reacted with compound 1-3 to give compounds 2.3-2.15.

[0162] Compound 2.3 (i.e. NS-194), white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 3.2 Hz, 1H), 7.85 (td, J = 7.9, 1.0 Hz, 1H), 7.53 (m, 3H), 7.36 (dd, J = 7.1, 4.9 Hz, 1H), 7.01 (s, 1H), 4.45 (s, 0.34H), 4.21 (s, 0.66H), 3.00 (s, 2H), 2.86 (s, 1H), 1.85 (s, 3H), 1.28 (s, 2H), 1.19 (s, 4H). LC-MS: [M+H] + Calcd 418.07, 420.07, Found 418.1, 420.1.

[0163] Compound 2.4 (i.e. NS-196), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.1 Hz, 1H), 7.85 (td, J = 7.8, 1.3 Hz, 1H), 7.52 (m, 3H), 7.36 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 6.98 (dd, J = 27.9, 8.2 Hz, 1H), 3.44 (t, J = 7.2 Hz, 1H), 3.29 (t, J = 7.2 Hz, 1H), 3.13 (s, 1.5H), 2.98 (s, 1.5H), 1.72 (m, 1H), 1.59 (m, 1H), 0.98 (t, J = 7.2 Hz, 1.5H), 0.88 (t, J = 7.4 Hz, 1.5H). LC-MS: [M+H] + Calcd 418.07, 420.07, Found 418.1, 420.1.

[0164] Compound 2.5 (i.e. NS-197), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 3.1 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.52 (m, 3H), 7.36 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 3.49 (q, J = 7.1 Hz, 2H), 3.34 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 6.5 Hz, 3H), 1.15 (t, J = 6.4 Hz, 3H). LC-MS: [M+H] + Calcd 418.07, 420.07, Found 418.1, 420.1.

[0165] Compound 2.6 (i.e. NS-207), white solid:1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.85 (t, J = 7.3 Hz, 1H), 7.52 (m, 3H), 7.35 (dd, J = 6.8, 4.9 Hz, 1H), 7.02 (d, J = 8.3 Hz, 0.55H), 6.91 (d, J = 8.3 Hz, 0.45H), 3.31 (d, J = 7.8 Hz, 1.1H), 3.15 (d, J = 7.8 Hz, 0.9H), 3.14 (s, 1.65H), 2.97 (s, 1.35H), 2.04 (m, 1H), 1.84 (s, 0.45H), 0.99 (d, J = 5.1 Hz, 2.7H), 0.89 (dd, J = 6.5, 2.1 Hz, 3.3H). LC-MS: [M+H] + Calcd 432.08, 434.08 Found 432.1, 434.1.

[0166] Compound 2.7 (i.e. NS-215), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.52 (m, 3H), 7.36 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 2.97 (s, 3H), 2.90 (br s, 1H), 1.84 (s, 3H), 0.88 (br s, 4H). LC-MS: [M+H] + Calcd 416.05, 418.05, Found 416.0, 418.0.

[0167] Compound 2.8 (i.e. NS-216), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.85 (t, J = 7.4 Hz, 1H), 7.53 (m, 3H), 7.36 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.94 (t, J = 7.7 Hz, 1H), 3.44 (m, 2H), 3.30 (m, 2H), 1.84 (s, 3H), 1.73 (q, J = 8.1 Hz, 1H), 1.59 (q, J = 7.7 Hz, 1H), 1.29 (t, J = 7.2 Hz, 1.5H), 1.15 (t, J = 6.6 Hz, 1.5H), 0.97 (t, J = 7.1 Hz, 1.5H), 0.88 (t, J = 7.3 Hz, 1.5H). LC-MS: [M+H] +Calcd 432.08, 434.08, Found 432.1, 434.1.

[0168] Compound 2.9 (i.e. NS-217), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.52 (m, 3H), 7.35 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 4.32 (s, 0H), 4.11 (s, 1H), 3.42 (s, 2H), 1.84 (s, 3H), 1.31 (brs, 3H), 1.22 (brs, 3H). LC-MS: [M+H] + Calcd 432.08, 434.08, Found 432.1, 434.1.

[0169] Compound 2.10 (i.e. NS-218), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 3.4 Hz, 1H), 7.84 (td, J = 7.7, 1.4 Hz, 1H), 7.52 (m, 3H), 7.35 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 0.5H), 6.96 (d, J = 7.9 Hz, 0.5H), 3.38 (d, J = 6.0 Hz, 1H), 3.22 (d, J = 6.8 Hz, 1H), 3.19 (s, 1.5H), 3.03 (s, 1.5H), 1.84 (s, 3H), 1.22 (brs, 1H), 1.06 (brs, 1H), 0.58 (d, J = 7.2 Hz, 1H), 0.52 (m, 1H), 0.40 (d, J = 3.4 Hz, 1H), 0.28 (d, J = 4.2 Hz, 1H). LC-MS: [M+H] + Calcd 430.07, 432.07, Found 430.1, 432.1.

[0170] Compound 2.11 (i.e. NS-219), white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.2 Hz, 1H), 7.84 (td, J = 7.8, 1.7 Hz, 1H), 7.51 (m, 3H), 7.35 (ddd, J = 7.4, 4.8, 0.8 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 3.62 (m, 2H), 3.41 (t, J = 6.7 Hz, 2H), 1.94 (m, 4H), 1.84 (s, 3H). LC-MS: [M+H] + Calcd 416.05, 418.05, Found 416.0, 418.0.

[0171] Compound 2.12 (i.e. NS-220), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.2 Hz, 1H), 7.85 (td, J = 7.8, 1.7 Hz, 1H), 7.53 (m, 3H), 7.36 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 3.68 (br s, 2H), 3.46 (br s, 2H), 2.42 (br s, 4H), 2.26 (s, 3H), 1.84 (s, 3H). LC-MS: [M+H] + Calcd 445.08, 447.08, Found 445.1, 447.1.

[0172] Compound 2.13 (i.e. NS-221), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.85 (t, J = 7.3 Hz, 1H), 7.52 (dd, J = 9.1, 4.9 Hz, 3H), 7.36 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.00 (d, J = 7.5 Hz, 0.6H), 6.92 (d, J = 9.5 Hz, 0.4H), 4.19 (m, 0.4H), 3.97 (m, 0.6H), 2.97 (s, 1.8H), 2.82 (s, 1.2H), 1.84 (s, 3H), 1.55 (m, 2H), 1.26 (br s, 1.2H), 1.17 (d, J = 6.6 Hz, 1.8H), 0.96 (m, 1.2H), 0.85 (m, 1.8H). LC-MS: [M+H] + Calcd 432.08, 434.08, Found 432.1, 434.1.

[0173] Compound 2.14 (i.e. NS-272), white solid:1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 4.2 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.51 (m, 3H), 7.35 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.31 (br s, 2H), 4.10 (br s, 2H), 2.37 (dd, J = 15.1, 7.6 Hz, 2H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 402.04, 404.04, Found 402.0, 404.0.

[0174] Compound 2.15 (i.e. NS-273), white solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 4.1 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.53 (dd, J = 8.3, 1.9 Hz, 1H), 7.49 (m, 2H), 7.35 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 3.99 (br s, 2H), 3.78 (br s, 2H), 1.83 (br s, 3H), 1.33 (br s, 6H). LC-MS: [M+H] + Calcd 430.07, 432.07, Found 430.1, 432.1.

[0175] Example 3. Synthesis of compounds 3.1-3.3

[0176] N-(2-hydroxyethyl) methanesulfonamide (194 mg, 2 mmol, 1 eq) was suspended in 5 mL dry pyridine, p-nitrophenyl chloroformate (482 mg, 2.4 mmol, 1.2 eq) in dichloromethane was added under ice bath condition, after slowly raised to room temperature, stirred for 4 hours, extracted with ethyl acetate and dilute hydrochloric acid three times, the organic layer was combined, the organic phase was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 3:1) to obtain compound 3-1 (341 mg, light yellow solid, 75.4%).

[0177] Compound 1-3 (64 mg, 0.2 mmol, 1 eq) and 3-1 (226 mg, 1 mmol, 5 eq) were dissolved in 1 mL of dry DMF, potassium carbonate (138 mg, 1 mmol, 5 eq) was added, and stirring was performed at 80 °C for 16 hours. Ethyl acetate and water were added, and liquid-liquid extraction was performed three times. The organic layers were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 3:1 ~ 2:1) to obtain compound 3.1 (i.e., NS-195) (67 mg, 82.5%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.3 Hz, 1H), 7.86 (td, J = 7.7, 1.6 Hz, 1H), 7.54 (m, 3H), 7.37 (dd, J = 7.5, 4.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 3.84 (s, 3H), 3.32 (s, 3H), 1.86 (s, 3H). LC-MS: [M+H] + Calcd 406.03, 408.03, Found 406.0, 408.0.

[0178] Synthesis of compound 3.2

[0179] N-methylhydroxylamine hydrochloride (1.67 g, 20 mmol, 1 eq) was dissolved in 20 mL of water, and a tetrahydrofuran solution of Boc2O (4.36 g, 20 mmol, 1 eq) was added. A saturated aqueous solution of sodium carbonate (6.36 g, 60 mmol, 3 eq) was added dropwise. After stirring at room temperature for 2 hours, ethyl acetate and water were added, and liquid-liquid extraction was performed three times. The organic layers were 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 Boc-protected N-methylhydroxylamine (1.47 g, 40.5%).

[0180] Boc-protected N-methylhydroxylamine (736 mg, 5 mmol) and iodoethane (936 mg, 6 mmol) were dissolved in 10 mL of dry DMF, under nitrogen protection, and cooled in an ice-water bath. Sodium hydride (240 mg, 6 mmol, 40% wrapped in mineral oil) was added in portions. After stirring for 30 minutes, the mixture was allowed to warm to room temperature. After stirring at room temperature for 1 hour, the reaction was quenched by the addition of 5 mL of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate and water three times. The organic layers were combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 4:1 to 3:1) to give compound Boc-N-methylethylhydroxylamine. The resulting compound was dissolved in 20 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 3 hours, and concentrated to give N-methyl-O-ethylhydroxylamine trifluoroacetate 3-2 (310 mg, 35.8%).

[0181] Compound 3.2 (i.e., NS-205) was obtained according to the synthetic procedure of compound 3.1. White solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 3.8 Hz, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (dt, J = 14.8, 7.4 Hz, 3H), 7.37 (dd, J = 7.0, 5.3 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.32 (m, 3H), 1.86 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 420.05, 422.05, Found 420.0, 422.0.

[0182] Compound 3.3 (i.e., NS-206) was obtained according to the synthetic procedure of compound 3.1 above. White solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 3.8 Hz, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (dt, J = 14.8, 7.4 Hz, 3H), 7.37 (dd, J = 7.0, 5.3 Hz, 1H), 7.06 (d, J = 8.9 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.32 (m, 3H), 1.86 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 434.06, 436.06, Found 434.1, 436.1.

[0183] Example 4. Synthesis of compounds 4.1-4.7

[0184] Compound 1-3 (64 mg, 0.2 mmol, 1 eq) was dissolved in 1 mL of dry DMF, potassium bicarbonate (40 mg, 0.4 mmol, 2 eq) and 2-bromoethyl acetate (43 mg, 0.24 mmol, 1.2 eq) were added, stirred at room temperature for 1 hour, extracted with ethyl acetate and water three times, the organic layers were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 3:1) to give compound 4.1 (i.e. NS-27) (68 mg, 85.0%). Pale yellow syrup: 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 1H), 7.49 (dt, J = 8.0, 0.9 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.31 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.99 (m, 1H), 4.93 (t, J = 8.0 Hz, 2H), 1.78 (s, 3H), 1.17 (t, J = 6.3 Hz, 6H). LC-MS: [M+H] + Calcd 419.05, 421.05, Found 419.0, 421.0.

[0185] Following the above procedure, each compound 1-3 (64 mg, 0.2 mmol, 1 eq) was reacted with 2-bromoethyl acetate (40 mg, 0.24 mmol, 1.2 eq), 2-bromobutanone (37 mg, 0.24 mmol, 1.2 eq), bromomethyl isopropyl ketone (40 mg, 0.24 mmol, 1.2 eq), bromomethyl cyclopropyl ketone (39 mg, 0.24 mmol, 1.2 eq), 2-bromoacetophenone (48 mg, 0.24 mmol, 1.2 eq), 2-bromoacetodimethylamine (40 mg, 0.24 mmol, 1.2 eq) to give compounds 4.2-4.7.

[0186] Compound 4.2 (i.e. NS-28, RO-10): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.46 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 1H), 7.50 (dt, J = 8.0, 0.9 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.97 (d, J = 15.7 Hz, 1H), 4.92 (d, J = 15.8 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 1.78 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 405.04, 407.04, Found 405.0, 407.0.

[0187] Compound 4.3 (i.e. NS-61): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.84 (td, J = 7.7, 1.6 Hz, 1H), 7.55 (dd, J = 8.3, 1.7 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.33 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 5.02 (s, 2H), 2.57 (q, J = 7.2 Hz, 2H), 1.80 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H). LC-MS: [M+H] + Calcd 389.04, 391.04, Found 389.0, 391.0.

[0188] Compound 4.4 (i.e. NS-63): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.56 (dd, J = 8.3, 1.9 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 5.18 (d, J = 16.9 Hz, 1H), 5.12 (d, J = 16.9 Hz, 1H), 2.80 (hept, J = 6.9 Hz, 1H), 1.80 (s, 3H), 1.05 (dd, J = 6.9, 3.4 Hz, 6H). LC-MS: [M+H] + Calcd 403.06, 405.06, Found 403.1, 405.1.

[0189] Compound 4.5 (i.e. NS-270): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (m, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 5.22 (d, J = 16.9 Hz, 1H), 5.17 (d, J = 16.9 Hz, 1H), 2.23 (ddd, J = 12.2, 7.7, 4.7 Hz, 1H), 1.80 (s, 3H), 0.97 (m, 4H). LC-MS: [M+H] + Calcd 401.04, 403.04, Found 401.0, 403.0.

[0190] Compound 4.6 (i.e. NS-271): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.9 Hz, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.82 (td, J = 7.8, 1.7 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 7.56 (m, 3H), 7.51 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.31 (m, 2H), 5.76 (d, J = 16.6 Hz, 1H), 5.71 (d, J = 16.5 Hz, 1H), 1.81 (s, 3H). LC-MS: [M+H]+ Calcd 437.04, 439.04, Found 437.0, 440.0.

[0191] Compound 4.7 (i.e. NS-62): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.7, 0.9 Hz, 1H), 7.84 (td, J = 7.7, 1.6 Hz, 1H), 7.53 (m, 2H), 7.44 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 7.5, 4.8 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 4.98 (s, 2H), 2.99 (s, 3H), 2.85 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 404.05, 406.05, Found 404.0, 406.0.

[0192] Example 5. Synthesis of compounds 5.1-5.17

[0193] Methyl-n-propylamine (71 mg, 1 mmol, 1 eq) was dissolved in dry tetrahydrofuran under nitrogen protection, the temperature was reduced to -30 degrees Celsius, diisopropylethylamine (129 mg, 1 mmol, 1 eq) and chloroacetyl chloride (113 mg, 1 mmol, 1 eq) were added in turn, after stirring in ice bath for 1 hour, the reaction was quenched with water, methyl tert-butyl ether was added to separate the liquid, the organic phase was combined and concentrated to obtain 68 mg of compound 5-1 crude product. Compound 5-1 and compound 1-3 (64 mg, 0.2 mmol, 1 eq) were dissolved in 1 mL of dry DMF, potassium bicarbonate (60 mg, 0.6 mmol, 3 eq) and a catalytic amount of tetrabutylammonium iodide were added, stirred at room temperature for 1 hour, 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 = 2:1-1:1) to obtain compound 5.1 (i.e. NS-210) (69 mg, 80.0%, colorless transparent syrup). 1H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 4.1 Hz, 1H), 7.84 (ddd, J = 9.6, 5.8, 1.9 Hz, 1H), 7.54 (dd, J = 8.3, 1.8 Hz, 1H), 7.49 (dd, J = 7.9, 2.3 Hz, 1H), 7.44 (t, J = 2.1 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.26 (dd, J = 8.3, 2.1 Hz, 1H), 4.99 (m, 2H), 3.26 (m, 2H), 2.97 (s, 1.7H), 2.83 (s, 1.3H), 1.54 (m, 0.9H), 1.47 (m, 1.1H), 0.84 (t, J = 7.2 Hz, 1.3H), 0.80 (t, J = 7.2 Hz, 1.7H). LC-MS: [M+H] + Calcd 432.08, 434.08, Found 432.1, 434.1.

[0194] Following the procedure described above, chloroacetyl chloride was reacted with methylisopropylamine (73 mg, 1 mmol), tetrahydropyrrole (71 mg, 1 mmol), diethylamine (73 mg, 1 mmol), methylethylamine (59 mg, 1 mmol), N-methylisobutylamine (87 mg, 1 mmol), methylcyclopropylamine (71 mg, 1 mmol), methylcyclopropylmethylamine (99 mg, 1 mmol), cyclobutylamine hydrochloride (93 mg, 1 mmol), 3,3-dimethylcyclobutylamine hydrochloride (121 mg, 1 mmol), N-methylpiperazine (100 mg, 1 mmol), methylisobutylamine (87 mg, 1 mmol), ethylpropylamine (87 mg, 1 mmol), ethylisopropylamine (73 mg, 1 mmol), dimethylhydroxylamine hydrochloride (96.5 mg, 1 mmol), N-methyl-O-ethylhydroxylamine trifluoroacetate (188 mg, 1 mmol), N-methyl-O-isopropylhydroxylamine trifluoroacetate (202 mg, 1 mmol) to generate the corresponding chloroformamides, which were then reacted with compound 1-3 (64 mg, 0.2 mmol, 1 eq) successively to give compounds 5.2-5.17 successively.

[0195] Compound 5.2 (i.e. NS-211): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 3.8 Hz, 1H), 7.83 (td, J = 7.7, 1.9 Hz, 1H), 7.54 (dd, J = 8.3, 1.8 Hz, 1H), 7.50 (m, 1H), 7.44 (t, J = 2.5 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 5.01 (d, J = 1.6 Hz, 0.7H), 4.95 (s, 1.3H), 4.62 (m, 0.65H), 4.02 (m, 0.35H), 2.82 (s, 1.95H), 2.71 (s, 1.05H), 1.80 (s, 3H), 1.15 (dd, J = 9.6, 6.6 Hz, 2.2H), 1.04 (t, J = 6.7 Hz, 3.8H). LC-MS: [M+H] + Calcd 432.08, 434.08, Found 432.1, 434.1.

[0196] Compound 5.3 (i.e. NS-212): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 3.9 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (dd, J = 8.3, 1.9 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 7.0, 4.9 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 4.88 (s, 2H), 3.45 (t, J = 6.8 Hz, 2H), 1.88 (m, 2H), 1.78 (m, 5H). LC-MS: [M+H] + Calcd 430.07, 432.07, Found 430.1, 432.1.

[0197] Compound 5.4 (i.e. NS-213): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.52 (s, 1H), 7.51 (m, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.97 (s, 1H), 4.97 (s, 1H), 3.30 (m, 4H), 1.79 (d, J = 7.4 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 432.08, 434.08, Found 432.1, 434.1.

[0198] Compound 5.5 (i.e. NS-263): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 4.5 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.52 (ddd, J = 11.5, 8.1, 2.7 Hz, 2H), 7.44 (s, 1H), 7.33 (dd, J = 7.4, 4.8 Hz, 1H), 7.26 (dd, J = 8.3, 2.7 Hz, 1H), 4.98 (m, 2H), 2.98 (s, 1.7H), 2.83 (s, 1.3H), 1.80 (s, 3H), 1.11 (t, J = 7.1 Hz, 1.3H), 1.01 (t, J = 7.1 Hz, 1.7H). LC-MS: [M+H] + Calcd 418.07, 420.07, Found 418.1, 420.1.

[0199] Compound 5.6 (i.e. NS-264): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J = 4.4 Hz, 1H), 7.83 (ddd, J = 7.8, 5.9, 2.0 Hz, 1H), 7.54 (dt, J = 8.3, 2.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 2.3 Hz, 1H), 7.33 (dd, J = 6.8, 4.8 Hz, 1H), 7.27 (dd, J = 8.3, 4.5 Hz, 1H), 5.02 (m, 2H), 3.14 (m, 2H), 2.97 (s, 1.8H), 2.83 (s, 1.2H), 1.90 (dt, J = 13.6, 6.8 Hz, 1H), 1.80 (s, 1.2H), 1.79 (s, 1.8H), 0.83 (m, 6H). LC-MS: [M+H] + Calcd 446.10, 448.10, Found 446.1, 448.1.

[0200] Compound 5.7 (i.e. NS-265): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 3.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (m, 2H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 4.7, 4.2, 1.4 Hz, 2H), 5.21 (d, J = 14.6 Hz, 1H), 5.10 (d, J = 14.7 Hz, 1H), 2.83 (s, 3H), 2.77 (m, 1H), 1.80 (s, 3H), 0.80 (m, 4H). LC-MS: [M+H] + Calcd 430.07, 432.07, Found 430.1, 432.1.

[0201] Compound 5.8 (i.e. NS-266): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 5.7 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.54 (dd, J = 8.3, 1.7 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 1.9 Hz, 1H), 7.33 (dd, J = 7.3, 5.3 Hz, 1H), 7.26 (dd, J = 8.3, 1.8 Hz, 1H), 5.00 (s, 2H), 3.21 (m, 2H), 3.04 (s, 1.8H), 2.91 (s, 1.2H), 1.80 (s, 3H), 0.97 (m, 1H), 0.49 (d, J = 7.7 Hz, 0.8H), 0.43 (d, J = 8.0 Hz, 1.2H), 0.26 (d, J = 4.6 Hz, 0.8H), 0.22 (d, J = 4.4 Hz, 1.2H). LC-MS: [M+H] + Calcd 444.08, 446.08, Found 444.1, 446.1.

[0202] Compound 5.9 (i.e. NS-267): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (t, J = 5.7 Hz, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.54 (dd, J = 8.3, 1.7 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 1.9 Hz, 1H), 7.33 (dd, J = 7.3, 5.3 Hz, 1H), 7.26 (dd, J = 8.3, 1.8 Hz, 1H), 5.00 (s, 2H), 3.21 (m, 2H), 3.04 (s, 1.8H), 2.91 (s, 1.2H), 1.80 (s, 3H), 0.97 (m, 1H), 0.49 (d, J = 7.7 Hz, 0.8H), 0.43 (d, J = 8.0 Hz, 1.2H), 0.26 (d, J = 4.6 Hz, 0.8H), 0.22 (d, J = 4.4 Hz, 1.2H). LC-MS: [M+H] + Calcd 416.05, 418.05, Found 416.0, 418.0.

[0203] Compound 5.10 (i.e. NS-268): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (m, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.72 (s, 2H), 3.91 (s, 2H), 3.58 (s, 2H), 1.80 (s, 3H), 1.22 (s, 3H), 1.19 (s, 3H). LC-MS: [M+H] + Calcd 444.08, 446.08, Found 444.1, 446.1.

[0204] Compound 5.11 (i.e. NS-286): yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 3.8 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (dd, J = 8.3, 1.9 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.34 (dd, J = 7.5, 4.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.99 (s, 2H), 3.46 (m, 4H), 2.30 (m, 4H), 2.19 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 459.10, 461.10, Found 459.1, 461.1.

[0205] Compound 5.12 (i.e. NS-287): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (td, J = 4.9, 2.3 Hz, 1H), 7.83 (m, 1H), 7.52 (m, 2H), 7.45 (m, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 5.01 (m, 2H), 4.42 (dd, J = 14.8, 7.0 Hz, 0.6H), 3.71 (br s, 0.4H), 2.78 (s, 1.8H), 2.68 (d, J = 0.9 Hz, 1.2H), 1.80 (s, 3H), 1.45 (m, 2H), 1.13 (dd, J = 9.8, 6.5 Hz, 1.2H), 1.02 (t, J = 6.8 Hz, 1.8H), 0.76 (m, 3H). LC-MS: [M+H] +Calcd 446.10, 448.10, Found 446.1, 448.1.

[0206] Compound 5.13 (i.e. NS-291): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 4.7 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.53 (dd, J = 8.3, 1.7 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.34 (J = 7.5, 4.8, 0.9 Hz,), 7.27 (dd, J = 8.3, 1.6 Hz, 1H), 5.01 (dd, J = 13.7, 4.0 Hz, 1H), 4.96 (dd, J = 13.7, 4.0 Hz, 1H), 3.29 (t, J = 7.0 Hz 2H), 3.22 (t, J = 7.0 Hz, 2H), 1.80 (s, 3H), 1.50 (m, 2H), 1.11 (t, J = 7.1 Hz, 1.5H), 1.01 (t, J = 7.1 Hz, 1.5H), 0.85 (t, J = 7.0 Hz, 1.5H), 0.80 (t, J = 7.0 Hz, 1.5H). LC-MS: [M+H] + Calcd 446.10, 448.10, Found 446.1, 448.1.

[0207] Compound 5.14 (i.e. NS-292): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.33 (dd, J = 7.1, 5.2 Hz, 1H), 7.26 (t, J = 9.1 Hz, 1H), 4.97 (m, 2H), 4.41 (hept, J = 6.3 Hz, 0.5H), 4.00 (hept, J = 6.3 Hz, 0.5H), 3.24 (m, 2H), 1.80 (s, 3H), 1.11 (m, 9H). LC-MS: [M+H] + Calcd 446.10, 448.10, Found 446.1, 448.1.

[0208] Compound 5.15 (i.e. NS-288): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.8, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.53 (m, 2H), 7.44 (d, J = 1.9 Hz, 1H), 7.32 (m, 2H), 5.09 (s, 2H), 3.69 (s, 3H), 3.13 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 420.05, 422.05, Found 420.0, 422.0.

[0209] Compound 5.16 (i.e. NS-289): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.8, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.53 (m, 2H), 7.44 (d, J = 1.9 Hz, 1H), 7.32 (m, 2H), 5.09 (s, 2H), 3.69 (s, 3H), 3.13 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 434.06, 436.06, Found 434.1, 436.1.

[0210] Compound 5.17 (i.e. NS-290): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 7.7, 5.8 Hz, 2H), 5.11 (d, J = 15.4 Hz, 1H), 5.06 (d, J = 15.5 Hz, 1H), 4.19 (hept, J = 6.3 Hz, 1H), 3.13 (s, 3H), 1.80 (s, 3H), 1.17 (d, J = 6.2 Hz, 3H), 1.14 (d, J = 6.2 Hz, 3H). LC-MS: [M+H] + Calcd 448.08, 450.08, Found 448.1, 450.1.

[0211] Example 6 Synthesis of compounds 6.1-6.5

[0212] Synthesis of compound 6.1

[0213] A solution of intermediate 1-3 (636 mg, 2 mmol, 1 eq) in allyl tert-butyl ester (2.56 g, 20 mmol, 10 eq) under N2protection, DMAP (244 mg, 2 mmol, 1 eq) was added. Stirring at 100 °C overnight, TLC monitoring reaction complete, ethyl acetate partition extraction was added, 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 6-1 (958 mg, 96.6%).

[0214] Compound 6-1 (67 mg, 0.15 mmol) was dissolved in 1.5 mL of dry ethanol, 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 reaction complete, remove the organic solvent. Saturated sodium bicarbonate solution and ethyl acetate partition was added, the organic phase was combined, washed with brine, concentrated, and purified by silica gel column (P:E = 3:1) to obtain the target compound 6.1 (i.e. NS-307) (51 mg, 81.3%, colorless transparent syrup). 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.7, 1.0 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.55 (m, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4.44 (t, J = 5.8 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 2.86 (t, J = 5.9 Hz, 2H), 1.80 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 419.05, 421.05, Found 419.0, 421.0.

[0215] Synthesis of compound 6.2

[0216] Compound 6-1 (89 mg, 0.2 mmol) was dissolved in 2 mL of dry dichloromethane, and 0.4 mL of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 18 hours. After the reaction was complete as detected by TLC, the organic solvent was removed under reduced pressure to obtain compound 6-2. Under nitrogen protection, thionyl chloride and a catalytic amount of DMF were added, and the mixture was refluxed for 2 hours. The organic solvent was then removed under reduced pressure. Under nitrogen protection, the crude product was redissolved in dry tetrahydrofuran, cooled to -30 °C, and 1 mL of a 2 M solution of dimethylamine in tetrahydrofuran was added dropwise. After 30 minutes, the organic solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography (P:E = 2:1) to obtain the target compound 6.2 (i.e., NS-209) (51 mg, 81.3%, pale yellow syrup). 1 H NMR (400MHz, DMSO-d6) δ8.49(ddd,J=4.8,1.8,0.8Hz,1H,1H),7.85(td,J=7.8,1.9Hz,1H),7.54(m,2H),7.44(d,J=1.9Hz,1H),7. 33(ddd,J=7.5,4.8,0.9Hz,1H),7.22(d,J=8.3Hz,1H),4.43(t,J=5.9Hz,2H),2.97(s,3H),2.85(m,5H),1.80(s,3H).LC-MS:[M+H] + Calcd 418.07,420.07,Found418.1,420.1.

[0217] Synthesized compound 6.3–6.5

[0218] Following the synthetic procedure for compound 6.2, compound 6-1 (89 mg, 0.2 mmol) was reacted with N-methylisobutylamine (174 mg, 2 mmol), N-methyl-2-butanamine (174 mg, 2 mmol), and N-methylisopropylamine (146 mg, 2 mmol) to generate compounds 6.3–6.5.

[0219] Compound 6.3 (i.e., NS-308): pale yellow syrup. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (m, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 7.3, 4.9 Hz, 1H), 7.21 (dd, J = 8.3, 2.3 Hz, 1H), 4.44 (t, J = 5.6 Hz, 2H), 3.16 (d, J = 7.5 Hz, 1.2H), 3.11 (d, J = 7.5 Hz, 0.8H), 2.96 (s, 1.8H), 2.88 (t, J = 5.6 Hz, 2H), 2.85 (s, 1.2H), 1.90 (m, 1H), 1.80 (s, 3H), 0.85 (m, 6H). LC-MS: [M+H] + Calcd 460.12, 462.12, Found 460.1, 462.1.

[0220] Compound 6.4 (i.e. NS-313): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 4.0 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (dd, J = 6.0, 4.2 Hz, 2H), 7.43 (d, J = 1.6 Hz, 1H), 7.33 (dd, J = 7.4, 4.8 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.48 (m, 2.6H), 3.81 (dd, J = 14.6, 6.6 Hz, 0.4H), 2.88 (m, 2H), 2.76 (d, J = 1.8 Hz, 1.8H), 2.67 (d, J = 2.3 Hz, 1.2H), 1.79 (d, J = 13.8 Hz, 3H), 1.43 (m, 2H), 1.04 (m, 3H), 0.77 (m, 3H). LC-MS: [M+H] + Calcd 460.12, 462.12, Found 460.1, 462.1.

[0221] Compound 6.5 (i.e. NS-314): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 3.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 7.3, 4.9 Hz, 1H), 7.22 (dd, J = 8.2, 4.8 Hz, 1H), 4.72 (hept, J = 6.3 Hz, 0.56H), 4.46 (m, 2H), 4.10 (hept, J = 6.3 Hz, 0.44H), 2.89 (dd, J = 11.1, 5.7 Hz, 0.88H), 2.82 (dd, J = 9.1, 5.8 Hz, 1.12H), 2.78 (s, 1.68H), 2.71 (s, 1.32H), 1.80 (s, 3H), 1.07 (m, 6H). LC-MS: [M+H] + Calcd 446.10, 448.10, Found 446.1, 448.1.

[0222] Example 7. Synthesis of compounds 7.1-7.30

[0223] Synthesis of compounds 7.1-7.26

[0224] Following the procedure of Example 4, each of compounds 1-3 (64 mg, 0.2 mmol, 1 eq) was reacted with methyl iodide (43 mg, 0.3 mmol, 1.5 eq), 1-iodobutane (55 mg, 0.3 mmol, 1.5 eq), 1-iodopropane (51 mg, 0.3 mmol, 1.5 eq), 1-iodoisobutane (55 mg, 0.3 mmol, 1.5 eq), bromoethyl methyl ether (42 mg, 0.3 mmol, 1.5 eq), bromoethyl ethyl ether (46 mg, 0.3 mmol, 1.5 eq), bromoethyl isopropyl ether (51 mg, 0.3 mmol, 1.5 eq), bromomethyl methyl ether (38 mg, 0.3 mmol, 1.5 eq), bromomethyl ethyl ether (42 mg, 0.3 mmol, 1.5 eq), bromomethyl isopropyl ether (46 mg, 0.3 mmol, 1.5 eq), iodomethyl cyclopropane (55 mg, 0.3 mmol, 1.5 eq), 2-iodopropane (51 mg, 0.3 mmol, 1.5 eq), dimethylamino chloroethane hydrochloride (44 mg, 0.3 mmol, 1.5 eq), 2-dimethylamino chloropropane (37 mg, 0.3 mmol, 1.5 eq), benzyl bromide (52 mg, 0.3 mmol, 1.5 eq), 3-(iodomethyl)oxetane (60 mg, 0.3 mmol, 1.5 eq), allyl bromide (37 mg, 0.3 mmol, 1.5 eq), epibromohydrin (41 mg, 0.3 mmol, 1.5 eq), 1-iodoisopentane (60 mg, 0.3 mmol, 1.5 eq), methyl allyl iodide (55 mg, 0.3 mmol, 1.5 eq), 1-bromo-3-methyl-2-butene (45 mg, 0.3 mmol, 1.5 eq), 1-bromo-2-butene (41 mg, 0.3 mmol, 1.5 eq), bromopropargyl (36 mg, 0.3 mmol, 1.5 eq), 1-fluoro-2-iodoethane (52 mg, 0.3 mmol, 1.5 eq), 1-bromo-3-fluoropropane (42 mg, 0.3 mmol, 1.5 eq), 2-iodo-1,1,1-trifluoroethane (63 mg, 0.3 mmol, 1.5 eq) to give compounds 7.1-7.26.

[0225] Compound 7.1 (i.e. NS-750): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (m, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 4.00 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 333.02, 335.0, Found 333.0, 335.0.

[0226] Compound 7.2 (i.e. NS-751): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (dd, J = 6.4, 1.7 Hz, 1H), 7.52 (d, J = 4.3 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 4.20 (t, J = 6.6 Hz, 2H), 1.80 (s, 3H), 1.73 (m, 2H), 1.49 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 375.06, 377.06, Found 375.1, 377.1.

[0227] Compound 7.3 (i.e. NS-752): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (dd, J = 6.5, 1.6 Hz, 1H), 7.51 (d, J = 4.5 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.7 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.16 (t, J = 6.6 Hz, 2H), 1.80 (s, 3H), 1.75 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 361.05, 363.05, Found 361.0, 363.0.

[0228] Compound 7.4 (i.e. NS-753): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.8 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.53 (m, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 7.5, 4.8 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 3.98 (dd, J = 15.2, 8.8 Hz, 2H), 2.07 (hep, J = 6.6 Hz, 1H), 1.79 (s, 3H), 1.04 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 375.06, 377.06, Found 375.1, 377.1.

[0229] Compound 7.5 (i.e. NS-754): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.8 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.53 (m, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 7.5, 4.8 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 3.98 (dd, J = 15.2, 8.8 Hz, 2H), 2.07 (hep, J = 6.6 Hz, 1H), 1.79 (s, 3H), 1.04 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 377.04, 379.04, Found 377.0, 379.0.

[0230] Compound 7.6 (i.e. NS-761): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.55 (dd, J = 8.3, 2.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4.34 (t, J = 4.3 Hz, 2H), 3.70 (m, 2H), 3.46 (m, 2H), 1.80 (s, 3H), 1.11 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 391.06, 393.06, Found 391.1, 393.1.

[0231] Compound 7.7 (i.e. NS-762): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.55 (dd, J = 8.3, 2.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4.34 (t, J = 4.3 Hz, 2H), 3.70 (m, 2H), 3.46 (m, 2H), 1.80 (s, 3H), 1.11 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 405.07, 407.07, Found 405.1, 407.1.

[0232] Compound 7.8 (i.e. NS-755): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (dd, J = 8.3, 2.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 5.21 (d, J = 7.3 Hz, 1H), 5.19 (d, J = 7.3 Hz, 1H), 3.61 (s, 3H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 363.03, 365.03, Found 363.0, 365.0

[0233] Compound 7.9 (i.e. NS-759): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.47 (m, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 5.24 (m, 2H), 3.90 (q, J = 7.0 Hz, 2H), 1.81 (s, 3H), 1.15 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 377.04, 379.04, Found 377.0, 379.0.

[0234] Compound 7.10 (i.e. NS-760): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (m, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 5.27 (s, 2H), 4.20 (hept, J = 6.1 Hz, 1H), 1.80 (s, 3H), 1.15 (dd, J = 8.3, 6.2 Hz, 6H). LC-MS: [M+H] +Calcd 391.06, 393.06, Found 391.1, 393.1.

[0235] Compound 7.11 (i.e. NS-756): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.52 (dd, J = 8.2, 2.0 Hz, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 4.04 (m, 2H), 1.80 (s, 3H), 1.23 (pd, J = 7.7, 3.9 Hz, 1H), 0.55 (m, 2H), 0.36 (m, 2H). LC-MS: [M+H] + Calcd 373.05, 375.05, Found 373.0, 375.0.

[0236] Compound 7.12 (i.e. NS-765): 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 4.7 Hz, 1H), 7.85 (td, J = 7.8, 1.7 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.4, 1.9 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 7.5, 4.8 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.61 (dt, J = 12.3, 6.2 Hz, 1H), 1.80 (s, 3H), 1.33 (dd, J = 6.1, 2.2 Hz, 6H). LC-MS: [M+H] + Calcd 361.05, 363.05, Found 361.0, 363.0.

[0237] Compound 7.13 (i.e. NS-798): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (m, 2H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 4.28 (t, J = 5.4 Hz, 2H), 2.63 (q, J = 5.4 Hz, 2H), 2.22 (s, 6H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 390.07, 392.07, Found 390.1, 392.1.

[0238] Compound 7.14 (i.e. NS-799): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 2.4 Hz, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (m, 2H), 7.45 (m, 1H), 7.33 (dd, J = 7.5, 4.8 Hz, 1H), 7.12 (td, J = 7.9, 3.7 Hz, 1H), 4.57 (m, 0.4H), 4.24 (dt, J = 9.9, 6.4 Hz, 0.6H), 4.08 (m, 0.6H), 2.98 (dt, J = 13.2, 6.7 Hz, 0.4H), 2.66 (dd, J = 13.3, 6.9 Hz, 0.4H), 2.38 (ddd, J = 7.5, 4.4, 2.2 Hz, 0.6H), 2.25 (d, J = 4.1 Hz, 3.6H), 2.20 (d, J = 4.1 Hz, 2.4H), 1.80 (s, 3H), 1.31 (dd, J = 6.3, 1.9 Hz, 1.2H), 1.06 (dd, J = 6.6, 5.3 Hz, 1.8H). LC-MS: [M+H] + Calcd 404.09, 406.09, Found 404.1, 406.1.

[0239] Compound 7.15 (i.e. NS-774): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.4 Hz, 1H), 8.52 (d, J = 4.4 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.56 (dd, J = 6.3, 3.0 Hz, 2H), 7.56 (dd, J = 6.3, 3.0 Hz, 2H), 7.43 (m, 6H), 7.43 (m, 6H), 7.34 (dd, J = 7.4, 4.8 Hz, 1H), 7.34 (dd, J = 7.4, 4.8 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.23 (s, 2H), 5.23 (s, 2H), 1.78 (s, 3H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 409.05, 411.05, Found 409.0, 411.0.

[0240] Compound 7.16 (i.e. NS-777): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.86 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (m, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.70 (dd, J = 7.8, 6.2 Hz, 2H), 4.47 (m, 4H), 3.45 (m, 1H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 389.04, 391.04, Found 389.0, 391.0.

[0241] Compound 7.17 (i.e. NS-778): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (m, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.12 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.44 (dd, J = 17.1, 1.4 Hz, 1H), 5.35 (d, J = 10.2 Hz, 1H), 4.72 (d, J = 6.7 Hz, 2H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 359.03, 361.03, Found 359.0, 361.0.

[0242] Compound 7.18 (i.e. NS-779): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (m, 1H), 7.84 (m, 1H), 7.53 (m, 2H), 7.45 (m, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.14 (t, J = 8.3 Hz, 1H), 4.55 (m, 1H), 4.01 (ddd, J = 13.0, 12.1, 7.7 Hz, 1H), 3.40 (ddt, J = 9.7, 4.9, 2.5 Hz, 1H), 2.82 (t, J = 4.4 Hz, 1H), 2.66 (ddd, J = 6.7, 5.0, 2.6 Hz, 1H), 1.81 (d, J = 3.0 Hz, 3H). LC-MS: [M+H] + Calcd 375.03, 377.03, Found 375.0, 377.0.

[0243] Compound 7.19 (i.e. NS-780): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.53 (m, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 4.23 (m, 2H), 1.85 (m, 4H), 1.65 (q, J = 6.8 Hz, 2H), 0.95 (dd, J = 6.6, 0.8 Hz, 6H). LC-MS: [M+H]+ Calcd 389.08, 391.08, Found 389.1, 391.1.

[0244] Compound 7.20 (i.e. NS-1224): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.53 (dd, J = 8.3, 2.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 5.12 (m, 1H), 5.07 (m, 1H), 4.63 (s, 2H), 1.93 (s, 3H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 373.05, 375.05, Found 373.0, 375.0.

[0245] Compound 7.21 (i.e. NS-1226): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 2.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 5.50 (m, 1H), 4.71 (d, J = 7.7 Hz, 2H), 1.78 (s, 3H), 1.71 (s, 3H), 1.65 (s, 3H). LC-MS: [M+H] + Calcd 387.06, 389.06, Found 387.1, 389.1.

[0246] Compound 7.22 (i.e. NS-1227): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 7.84 (ddd, J = 7.8, 5.7, 1.8 Hz, 1H), 7.49 (m, 3H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.09 (d, J = 8.3 Hz, 0.25H), 7.06 (d, J = 8.3 Hz, 0.75H), 5.86 (m, 1H), 5.75 (m, 1H), 4.80 (d, J = 7.3 Hz, 0.5H), 4.64 (d, J = 6.9 Hz, 1.5H), 1.79 (s, 0.75H), 1.78 (s, 2.25H), 1.65 (d, J = 5.9 Hz, 2.25H), 1.63 (d, J = 1.6 Hz, 0.75H). LC-MS: [M+H] + Calcd 373.05, 375.05, Found 373.0, 375.0.

[0247] Compound 7.23 (i.e. NS-1230): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 5.01 (dd, J = 15.5, 2.3 Hz, 1H), 4.96 (dd, J = 15.4, 2.2 Hz, 1H), 3.75 (t, J = 2.4 Hz, 1H), 1.82 (s, 3H). LC-MS: [M+H] + Calcd 357.02, 359.01, Found 357.0, 359.0.

[0248] Compound 7.24 (i.e. NS-1701): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.55 (m, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.6, 4.8, 0.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.83 (m, 1H), 4.71 (m, 1H), 4.52 (dd, J = 4.6, 2.9 Hz, 1H), 4.44 (dd, J = 4.6, 2.9 Hz, 1H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 365.02, 367.02, Found 365.0, 367.0.

[0249] Compound 7.25 (i.e. NS-1702): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.55 (m, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.6, 4.8, 0.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.83 (m, 1H), 4.71 (m, 1H), 4.52 (dd, J = 4.6, 2.9 Hz, 1H), 4.44 (dd, J = 4.6, 2.9 Hz, 1H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 379.04, 381.04, Found 379.0, 381.0.

[0250] Compound 7.26 (i.e. NS-1688): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.55 (m, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.6, 4.8, 0.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.83 (m, 1H), 4.71 (m, 1H), 4.52 (dd, J = 4.6, 2.9 Hz, 1H), 4.44 (dd, J = 4.6, 2.9 Hz, 1H), 1.81 (s, 3H). LC-MS: [M+H] +Calcd 401.00, 403.00, Found 401.0, 403.0.

[0251] Synthesis of compounds 7.27-7.30

[0252] Compound 1-3 (96 mg, 0.3 mmol, 1 eq) and triphenylphosphine (118 mg, 0.45 mmol, 1.5 eq) were dissolved in 1 ml 3-methyl-2-butanol under nitrogen protection, the temperature was reduced to -5 °C, and diethyl azodicarboxylate (78 mg, 0.45 mmol, 1.5 eq) was added dropwise, the reaction was slowly raised to room temperature, and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the target compound 7.27 (i.e. NS-757) was obtained after silica gel column purification (P:E = 3:1): 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 4.7 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.52 (ddd, J = 8.2, 6.3, 3.5 Hz, 2H), 7.43 (dd, J = 3.7, 1.9 Hz, 1H), 7.32 (dd, J = 7.5, 4.8 Hz, 1H), 7.02 (dd, J = 8.3, 1.6 Hz, 1H), 4.32 (m, 1H), 2.01 (tt, J = 13.6, 6.8 Hz, 1H), 1.79 (s, 3H), 1.22 (dd, J = 6.3, 2.9 Hz, 3H), 1.03 (d, J = 6.3 Hz, 3H), 1.02 (d, J = 5.4 Hz, 3H). LC-MS: [M+H]+ Calcd 389.08, 391.08, Found 389.1, 391.1.

[0253] Referring to the above synthesis, compound 1-3 (96 mg, 0.3 mmol, 1 eq) was reacted with 1 mL of 1-cyclopropylethanol, 4,4,4-trifluorobutanol, 3,3,3- trifluoropropyl alcohol, respectively, to generate compounds 7.28-7.30.

[0254] Compound 7.28: (i.e. NS-758): 1H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J = 4.1 Hz, 1H), 7.86 (tdd, J = 7.8, 3.6, 1.9 Hz, 1H), 7.52 (m, 2H), 7.45 (dd, J = 7.7, 1.9 Hz, 1H), 7.34 (dd, J = 7.3, 4.9 Hz, 1H), 7.12 (dd, J = 8.3, 5.5 Hz, 1H), 3.79 (m, 1H), 1.80 (d, J = 1.8 Hz, 3H), 1.41 (d, J = 6.3 Hz, 3H), 1.08 (m, 1H), 0.51 (m, 1H), 0.37 (m, 2H), 0.24 (qd, J = 9.0, 4.8 Hz, 1H). LC-MS: [M+H]+ Calcd 387.06, 389.06, Found 387.1, 389.1.

[0255] Compound 7.29 (i.e. NS-1686): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.86 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (m, 2H), 7.47 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 4.28 (t, J = 6.3 Hz, 2H), 2.58 (m, 2H), 1.98 (m, 2H), 1.80 (s, 3H). LC-MS: [M+H]+ Calcd 429.03, 431.03, Found 429.0, 431.0.

[0256] Compound 7.30 (i.e. NS-1687): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.86 (td, J = 7.8, 1.9 Hz, 1H), 7.57 (dd, J = 8.2, 1.9 Hz, 2H), 7.48 (d, J = 1.9 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.44 (m, 2H), 2.91 (qt, J = 11.5, 6.0 Hz, 2H), 1.82 (s, 3H). LC-MS: [M+H]+ Calcd 415.02, 417.02, Found 415.0, 417.0.

[0257] Example 8. Synthesis of compound 8.1

[0258] Compound 8-1 was synthesized according to the method of Example 7.

[0259] Compound 8-1 (112 mg, 0.3 mmol) was dissolved in dry tetrahydrofuran, dimethylamine tetrahydrofuran solution (1.5 mL, 2M) was added, and the tube was heated to 60°C for 16 hours. After concentration, the target compound 8.1 (i.e. NS-306) (64 mg, 52.7%, light yellow syrup) was obtained after purification by silica gel column (100% EA ~ DCM / MeOH = 10:1). 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (t, J = 4.6 Hz, 1H), 7.85 (td, J = 7.7, 1.5 Hz, 1H), 7.55 (m, 2H), 7.45 (m, 1H), 7.33 (m, 1H), 7.19 (dd, J = 8.3, 4.6 Hz, 1H), 5.02 (dd, J = 9.5, 4.8 Hz, 1H), 4.29 (td, J = 9.8, 2.8 Hz, 1H), 4.06 (ddd, J = 10.1, 7.1, 5.0 Hz, 1H), 3.96 (m, 1H), 2.32 (m, 2H), 2.19 (s, 3H), 2.18 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 420.08,422.08,Found 420.1,422.1.

[0260] Example 9. Synthesis of compounds 9.1~9.6

[0261] 50 mL of compound 1-2 (3.64 g, 10 mol, 1 eq) and 4,4'-dipyridine (78 mg, 0.5 mol, 0.05 eq) in DMF were 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 = 2:1 ~ 1:1) to obtain compound 9-1 (2.83 g, 93.7%).

[0262] Compound 9-1 (60 mg, 0.2 mmol, 1 eq) was dissolved in 1 mL 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, combined organic layers, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 3:1) to obtain compound 9.1 (i.e. NS-58) (58 mg, 77.5%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 3.3 Hz, 1H), 7.87 (td, J = 7.8, 1.7 Hz, 1H), 7.64 (s, 1H), 7.46 (dd, J = 8.6, 1.8 Hz, 2H), 7.31 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 3.06 (s, 3H), 3.03 (s, 3H), 1.82 (s, 3H). LC-MS: [M+H] + Calcd 374.04, 376.04, Found 374.0, 376.0.

[0263] Another strategy to synthesize compound 9-1:

[0264] Compound 1-3 (64 mg, 0.2 mmol, 1 eq) was dissolved in 1 mL dry DMF, potassium carbonate (84 mg, 0.6 mmol, 3 eq) and 2-bromoacetate (1.2 eq) or 2-bromoketone were added, stirred at room temperature 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 = 3:1) to obtain compound 9-1.

[0265] According to the above procedure, chloroformic methylethylamine (73 mg, 0.6 mmol, 3 eq), chloroformic methylisopropylamine (82 mg, 0.6 mmol, 3 eq) and N-methyl-2-butylamine (90 mg, 0.6 mmol, 3 eq) synthesized in example 2 were reacted with compound 9-1 (60 mg, 0.2 mmol, 1 eq) to obtain compounds 9.2-9.4.

[0266] Compound 9.2 (i.e. NS-64): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.89 (t, J = 7.7 Hz, 1H), 7.65 (br s, 1H), 7.49 (d, J = 7.3 Hz, 2H), 7.33 (dd, J = 7.1, 5.1 Hz, 1H), 7.06 (d, J = 8.5 Hz, 0.66H), 7.01 (d, J = 8.2 Hz, 0.34H), 3.50 (q, J = 7.0 Hz, 2H), 3.07 (s, 1H), 3.03 (s, 2H), 1.84 (s, 3H), 1.21 (t, J = 7.0 Hz, 2H), 1.11 (t, J = 6.4 Hz, 1H). LC-MS: [M+H] + Calcd 388.06, 390.06, Found 388.0, 390.0.

[0267] Compound 9.3 (i.e. NS-65): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.89 (t, J = 6.8 Hz, 1H), 7.68 (br s, 1H), 7.48 (d, J = 7.9 Hz, 2H), 7.33 (dd, J = 7.1, 5.1 Hz, 1H), 7.05 (d, J = 8.2 Hz, 0.66H), 7.00 (d, J = 8.2 Hz, 0.34H), 4.52 (m, 1H), 2.94 (s, 1H), 2.90 (s, 2H), 1.84 (s, 3H), 1.22 (s, 4H), 1.14 (s, 2H). LC-MS: [M+H] + Calcd 402.07, 404.07, Found 402.1, 404.1.

[0268] Compound 9.4 (i.e. NS-1091): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (m 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.71 (dd, J = 22.9, 7.4 Hz, 1H), 7.49 (m, 2H), 7.33 (m, 1H), 7.06 (d, J = 11.1 Hz, 0.4H), 6.97 (d, J = 8.2 Hz, 0.6H), 4.30 (m, 1H), 2.89 (s, 1.8H), 2.86 (s, 1.2H), 1.84 (s, 3H), 1.55 (br s, 2H), 1.20 (m, 3H), 0.91 (t, J = 6.9 Hz, 1.8H), 0.69 (m, 1.2H). LC-MS: [M+H] +Calcd 416.09,418.09,Found 416.1,418.1.

[0269] Under nitrogen protection, 4-aminopyridinecarboxamide (274 mg, 2 mmol, 1 eq) and diisopropylethylamine (650 mg, 5 mmol, 2.5 eq) were dissolved in 10 mL of dry tetrahydrofuran. 1 mL of triphosgene (237 mg, 0.8 mmol, 0.4 eq) in tetrahydrofuran was added dropwise under ice bath conditions. The mixture was slowly heated to room temperature and stirred for 1 hour. Compound 9-1 (151 mg, 0.5 mmol, 0.25 eq) and diisopropylethylamine (260 mg, 2 mmol, 1 eq) were added. After stirring at room temperature for 4 hours, the mixture was extracted three times with ethyl acetate and water. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (P:E = 1:1 to 1:3) to obtain the target compound 9.5 (i.e., NS-503) (41.2 mg, 17.7%, pale yellow solid). 1 H NMR (400MHz, DMSO-d6) δ10.69 (s, 1H), 8.50 (dd, J=4.8, 0.9Hz, 1H), 8.02 (d, J= 5.6Hz,1H),7.81(td,J=7.8,1.9Hz,1H),7.43(d,J=8.0Hz,1H),7.38(dd,J=8. 2,2.1Hz,1H),7.30(dt,J=5.8,1.4Hz,2H),7.22(d,J=2.2Hz,1H),6.88(d,J=8 .2Hz,1H),6.59(dd,J=5.5,2.4Hz,1H),6.28(s,2H),1.73(s,3H).LC-MS:[M+H] + Calcd 466.04,468.04, Found 466.0,468.0.

[0270] Following the above procedure, compound 9-1 (151 mg, 0.5 mmol, 0.25 eq) and (R)-(1-ethyl isocyanate)benzene (89 mg, 0.6 mmol, 0.3 eq) react to produce compound 9.6.

[0271] Compound 9.6 (i.e., NS-1697): white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 7.3 Hz, 1H), 8.47 (ddd, J = 4.8, 1.6, 0.8 Hz, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.88 (tdd, J = 7.9, 6.2, 1.8 Hz, 1H), 7.64 (dd, J = 8.0, 3.3 Hz, 1H), 7.51 (dt, J = 8.7, 2.0 Hz, 1H), 7.45 (m, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.34 (m, 1H), 7.29 (m, 1H), 5.06 (p, J = 7.0 Hz, 1H), 1.89 (d, J = 5.7 Hz, 3H), 1.53 (dd, J = 6.9, 2.1 Hz, 3H). LC-MS: [M+H] + Calcd 450.07, 452.07, Found 450.1, 452.1.

[0272] Example 10. Synthesis of compounds 10.1-10.10

[0273] Compound 9-1 (60 mg, 0.2 mmol, 1 eq) was dissolved in 1 mL dry DMF, potassium carbonate (56 mg, 0.4 mmol, 2 eq) and 1-bromo-3-methyl-2-butanone (40 mg, 0.24 mmol, 1.2 eq) were added, stirred at room temperature for 1 hour, extracted with ethyl acetate and water three times, the organic layers were 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-39) (61 mg, 78.8%, light yellow solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.47 - 7.38 (m, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.84 (s, 2H), 2.91 - 2.83 (m, 1H), 1.77 (s, 3H), 1.12 (d, J = 0.8 Hz, 3H), 1.10 (d, J = 0.8 Hz, 3H). LC-MS: [M+H] + Calcd 387.06, 389.06, Found 387.1, 389.1.

[0274] Following the above procedure, compound 9-1 (60 mg, 0.2 mmol, 1 eq) was reacted with bromomethylcyclopropyl ketone (39 mg, 0.24 mmol, 1.2 eq), bromomethyl tert-butyl ketone (43 mg, 0.24 mmol, 1.2 eq), 2-bromobutane (36 mg, 0.24 mmol, 1.2 eq), 2-bromopropanone (33 mg, 0.24 mmol, 1.2 eq), ethyl bromoacetate (40 mg, 0.24 mmol, 1.2 eq), N,N-dimethyl-bromoacetamide (40 mg, 0.24 mmol, 1.2 eq), isopropyl bromoacetate (44 mg, 0.24 mmol, 1.2 eq), 2-bromoacetophenone (48 mg, 0.24 mmol, 1.2 eq) and chloroacetamide (23 mg, 0.24 mmol, 1.2 eq) to give compounds 10.2-10.10, respectively.

[0275] Compound 10.2 (i.e. NS-52): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.43 (dd, J = 8.4, 2.1 Hz, 1H), 7.40 (dt, J = 8.0, 1.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.91 (s, 2H), 2.23 (m, 1H), 1.76 (s, 3H), 1.00 (m, 2H), 0.93 (m, 2H). LC-MS: [M+H] + Calcd 385.05, 387.05, Found 385.0, 387.0.

[0276] Compound 10.3 (i.e. NS-53): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.80 (td, J = 7.7, 1.9 Hz, 1H), 7.43 (dd, J = 8.4, 2.1 Hz, 1H), 7.40 (dt, J = 8.0, 1.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 4.92 (s, 2H), 1.77 (s, 3H), 1.22 (s, 12H). LC-MS: [M+H] +Calcd 401.08, 403.08, Found 401.1, 403.1.

[0277] Compound 10.4 (i.e. NS-54): White solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.38 (m, 2H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.66 (d, J = 2.0 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.76 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 389.05, 391.05, Found 389.0, 391.0.

[0278] Compound 10.5 (i.e. NS-55): Pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.79 (td, J = 7.7, 1.9 Hz, 1H), 7.42 (m, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.75 (s, 2H), 2.24 (s, 3H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 359.03, 361.03, Found 359.0, 361.0.

[0279] Compound 10.6 (i.e. NS-56): Colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.37 (m, 2H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 17.8 Hz, 1H), 4.63 (d, J = 17.8 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 1.76 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 389.04, 391.03, Found 389.0, 391.0.

[0280] Compound 10.7 (i.e. NS-66): White solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.37 (m, 2H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 17.8 Hz, 1H), 4.63 (d, J = 17.8 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 1.76 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 388.06, 390.06, Found 388.1, 390.1.

[0281] Compound 10.8 (i.e. NS-78): White solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.37 (m, 2H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.68 (d, J = 17.8 Hz, 1H), 4.63 (d, J = 17.8 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 1.76 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] +Calcd 403.06, 405.06, Found 403.1, 405.1.

[0282] Compound 10.9 (i.e. NS-294): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 4.5 Hz, 1H), 8.13 (d, J = 7.4 Hz, 2H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.76 (t, J = 7.4 Hz, 1H), 7.63 (t, J = 7.7 Hz, 2H), 7.45 (dd, J = 11.2, 8.8 Hz, 3H), 7.34 (dd, J = 7.1, 5.0 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 5.47 (s, 3H), 1.84 (s, 3H). LC-MS: [M+H] + Calcd 421.05, 423.05, Found 421.0, 423.0.

[0283] Compound 10.10 (i.e. NS-1705): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 0.9 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.73 (br s, 1H), 7.47 (m, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 2H), 6.99 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 16.9 Hz, 1H), 4.37 (d, J = 16.9 Hz, 1H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 360.03, 362.03, Found 360.0, 360.0.

[0284] Example 11. Synthesis of compounds 11.1-11.10

[0285] 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 separated, and the aqueous phase was extracted with dichloromethane. The organic phase was combined and washed with saturated potassium carbonate solution, 1 N dilute hydrochloric acid, and saturated brine solution. After drying over anhydrous sodium sulfate, the mixture was concentrated to obtain the epoxide 11-1. Compound 11-1 was dissolved in dry DMF, compound 9-1 (90 mg, 0.3 mmol, 1 eq) and potassium carbonate (50 mg, 0.36 mmol, 1.2 eq) were added under nitrogen protection, and the mixture was stirred at 70 °C for 16 hours. The mixture was extracted with ethyl acetate and water three times, and the organic phase was combined and washed with saturated brine solution. After drying over anhydrous sodium sulfate, the mixture was concentrated and purified by silica gel column chromatography (P:E = 2:1) to obtain compound 11-2 (93 mg, 70.9%).

[0286] Compound 11-2 was dissolved in dichloromethane, and the dess-martin reagent (108 mg, 0.26 mmol) was added portionwise and stirred overnight. After the addition of ethyl acetate, the mixture was filtered through celite, and the filtrate was stirred with sodium thiosulfate solution for 1 hour, and then separated. The organic phase was dried over sodium sulfate and concentrated, and then purified by silica gel column chromatography (P:E = 3:1) to obtain compound 11.1 (i.e., NS-330) (87 mg, 94.0%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 4.2 Hz, 1H), 7.80 (td, J = 7.8, 1.5 Hz, 1H), 7.44 (dd, J = 8.4, 1.9 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 7.31 (m, 6H), 6.95 (d, J = 8.4 Hz, 1H), 4.88 (s, 2H), 4.03 (s, 2H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 435.06, 437.06, Found 434.8, 436.8.

[0287] Following the above procedure, compound 11.2~11.10 were obtained by using p- methylallylbenzene (132 mg, 1 mmol), p-methoxyallylbenzene (148 mg, 1 mmol), p- methoxyphenylstyrene (134 mg, 1 mmol), p-methylphenylstyrene (118 mg, 1 mmol), m- chlorostyrene (140 mg, 1 mmol), p-chlorostyrene (140 mg, 1 mmol), o-chlorostyrene (140 mg, 1 mmol), m-fluorostyrene (122 mg, 1 mmol), p-fluorostyrene (122 mg, 1 mmol) as starting materials, respectively, followed by epoxidation, reaction with compound 9-1, and epoxide ring opening and oxidation of hydroxyl group.

[0288] Compound 11.2 (i.e. NS-331): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.15 (m, 4H), 6.93 (d, J = 8.4 Hz, 1H), 4.85 (s, 2H), 3.98 (d, J = 16.8 Hz, 1H), 3.94 (d, J = 16.8 Hz, 1H), 2.30 (s, 3H), 1.77 (s, 3H). LC-MS: [M+H] + Calcd 449.08, 451.08, Found 449.1, 451.1.

[0289] Compound 11.3 (i.e. NS-332): pale yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.43 (dd, J = 8.3, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.18 (m, 2H), 6.92 (m, 3H), 4.84 (s, 2H), 3.93 (s, 2H), 3.75 (s, 3H), 1.77 (s, 3H). LC-MS: [M+H] + Calcd 465.07, 467.07, Found 465.1, 467.1.

[0290] Compound 11.4 (i.e. NS-333): White solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 4.7 Hz, 1H), 8.10 (d, J = 8.8 Hz, 2H), 7.83 (td, J = 7.8, 1.7 Hz, 1H), 7.44 (m, 3H), 7.34 (dd, J = 7.5, 4.8 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 5.40 (s, 2H), 3.90 (s, 3H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 451.06, 453.06, Found 451.1, 453.1.

[0291] Compound 11.5 (i.e. NS-334): White solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 3.9 Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (m, 5H), 7.34 (dd, J = 6.6, 4.9 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 5.42 (s, 3H), 2.45 (s, 3H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 435.06, 437.06, Found 435.1, 437.1.

[0292] Compound 11.6 (i.e. NS-401): White solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 8.15 (t, J = 1.7 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.83 (ddd, J = 7.7, 4.7, 1.8 Hz, 2H), 7.66 (t, J = 7.9 Hz, 1H), 7.43 (m, 3H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 5.49 (s, 2H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 455.01, 457.01, Found 455.0, 457.0.

[0293] Compound 11.7 (i.e. NS-402): White solid, 1H NMR (400 MHz, DMSO-d6) δ 8.55 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.44 (m, 3H), 7.34 (dd, J = 6.6, 4.9 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 5.47 (s, 2H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 455.01, 457.01, Found 455.0, 457.0.

[0294] Compound 11.8 (i.e. NS-403): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.64 (d, J = 3.7 Hz, 2H), 7.54 (m, 1H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 7.41 (dd, J = 11.8, 5.0 Hz, 2H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.31 (s, 2H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 455.01, 457.01, Found 455.0, 457.0.

[0295] Compound 11.9 (i.e. NS-404): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 4.7, 0.8 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 9.6 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.69 (td, J = 7.9, 5.9 Hz, 1H), 7.62 (td, J = 8.4, 1.7 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 9.6 Hz, 2H), 7.34 (ddd, J = 7.4, 4.9, 0.7 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 5.48 (s, 2H), 1.84 (s, 3H). LC-MS: [M+H] +Calcd 439.04, 441.04, Found 439.0, 441.0.

[0296] Compound 11.10 (i.e. NS-405): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 8.22 (m, 2H), 7.46 (m, 5H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 5.47 (s, 2H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 439.04, 441.04, Found 439.0, 441.0.

[0297] Example 12. Synthesis of compounds 12.1 and 12.2

[0298] Following Reference Example 11, compound 9-1 (180 mg, 0.6 mmol) was subjected to epoxide ring opening with butadiene monoxide (140 mg, 2 mmol) under basic condition to give hydroxyl compound 12.1 (197 mg, 88.1%, white solid) (i.e. NS-192). 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 3.9 Hz, 1H), 7.79 (ddd, J = 7.8, 3.5, 1.8 Hz, 1H), 7.46 (dd, J = 8.4, 1.9 Hz, 1H), 7.39 (t, J = 8.2 Hz, 1H), 7.35 (t, J = 2.4 Hz, 1H), 7.31 (dd, J = 7.2, 4.9 Hz, 1H), 7.17 (dd, J = 8.4, 2.8 Hz, 1H), 5.91 (m, 1H), 5.30 (dd, J = 8.1, 5.0 Hz, 1H), 5.23 (ddt, J = 17.1 7.4, 1.2 Hz, 1H), 5.09 (ddt, J = 10.4, 5.7, 1.2 Hz, 1H), 4.35 (m, 1H), 3.76 (d, J = 5.8 Hz, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 373.05, 375.05, Found 373.0, 375.0.

[0299] Following the synthesis of compound 11.1 in Example 11, compound 12.1 (74 mg, 0.2 mmol) was oxidized to give compound 12.2 (i.e. NS-76) (61 mg, 82.5%, white solid). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 4.0 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.43 (m, 3H), 7.33 (dd, J = 7.1, 5.2 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.58 (dd, J = 17.7, 10.0 Hz, 1H), 6.50 (dd, J = 17.7, 1.5 Hz, 1H), 6.13 (dd, J = 10.0, 1.5 Hz, 1H), 5.03 (s, 2H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 371.03, 373.03, Found 371.0, 373.0.

[0300] Example 13. Synthesis of compounds 13.1-13.3

[0301] Compound 9-1 (180 mg, 0.6 mmol), epibromohydrin (90 mg, 0.3 mmol), potassium carbonate (69 mg, 0.5 mmol) were stirred at 80 °C for 16 h under nitrogen protection. The mixture was extracted with ethyl acetate and water for three times. The organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified on silica gel column (P:E = 2:1) to give compound 13.1 (i.e. NS-558, 180 mg, 83.3 %). White solid: 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 4.0 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.43 (m, 3H), 7.33 (dd, J = 7.1, 5.2 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.58 (dd, J = 17.7, 10.0 Hz, 1H), 6.50 (dd, J = 17.7, 1.5 Hz, 1H), 6.13 (dd, J = 10.0, 1.5 Hz, 1H), 5.03 (s, 2H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 359.03, 361.03, Found 359.0, 361.0.

[0302] Compound 13-3 was dissolved in dichloromethane, trifluoroacetic acid was added, and the reaction was allowed to proceed at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 8-9 by the addition of sodium bicarbonate, and the solution was purified by C18 reverse phase column to give compound 13.2 (i.e. NS-299). Pale yellow solid, yield 70%.

[0303] Compound 13-3 was dissolved in dichloromethane, trifluoroacetic acid was added, and the reaction was allowed to proceed at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 8-9 by the addition of sodium bicarbonate, and the solution was purified by C18 reverse phase column to give compound 13.2 (i.e. NS-299). Pale yellow solid, yield 70%.

[0304] Compound 13-3 was dissolved in dichloromethane, trifluoroacetic acid was added, and the reaction was allowed to proceed at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 8-9 by the addition of sodium bicarbonate, and the solution was purified by C18 reverse phase column to give compound 13.2 (i.e. NS-299). Pale yellow solid, yield 70%. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.55 (dd, J = 4.8, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.35 (ddd, J = 7.5, 4.9, 0.9 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.96 (s, 2H), 4.37 (m, 2H), 2.61 (t, J = 5.3 Hz, 3H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 388.06, 390.06, Found 388.0, 390.0.

[0305] Compound 13-3 was dissolved in dichloromethane, trifluoroacetic acid was added, and the reaction was allowed to proceed at room temperature for 16 hours. The solvent was removed under reduced pressure, and the residue was dissolved in water. The pH was adjusted to 8-9 by the addition of sodium bicarbonate, and the solution was purified by C18 reverse phase column to give compound 13.2 (i.e. NS-299). Pale yellow solid, yield 70%. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (m, 1H), 7.80 (m, 1H), 7.46 (ddd, J = 8.5, 4.5, 2.1 Hz, 1H), 7.42 (dd, J = 12.1, 8.1 Hz, 1H), 7.35 (t, J = 1.8 Hz, 1H), 7.31 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.88 (d, J = 4.7 Hz, 1H), 3.93 (m, 1H), 3.85 (m, 1H), 3.65 (ddd, J = 16.3, 14.0, 7.4 Hz, 1H), 2.30 (m, 2H), 2.18 (s, 3H), 2.18 (s, 3H), 1.76 (d, J = 4.2 Hz, 3H). LC-MS: [M+H] + Calcd 404.09, 406.09, Found 404.0, 406.0.

[0306] Example 14. Synthesis of compounds 14.1-14.3

[0307] Under nitrogen protection, 1,2-pentanediol (208 mg, 2 mmol) was dissolved in 10 mL of dry pyridine solution, and (381 mg, 2 mmol) was added in batches under ice bath condition. After 2 hours of reaction under ice bath, 2 mL of aqueous sodium carbonate solution was used to terminate the reaction. Ethyl acetate and water were used to extract three times, and the organic layers were combined. The organic phase was washed with dilute hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 2:1) to obtain 2-hydroxy-pentyl-4-methylbenzenesulfonate (213 mg, 41.3%).

[0308] Under nitrogen protection, 2-hydroxy-pentyl-4-methylbenzenesulfonate (129 mg, 0.5 mmol), 9-1 (90 mg, 0.3 mmol, 1 eq), potassium carbonate (69 mg, 0.5 mmol), and a catalytic amount of tetrabutylammonium iodide were stirred at 80°C for 16 hours. Ethyl acetate and water were used to extract three times, and the organic layers were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 2:1) to obtain compound 14-1 (72 mg, 61.8%).

[0309] Compound 14-1 was dissolved in dichloromethane, and dess-martin reagent (91 mg, 0.22 mmol) was added in batches and oxidized overnight. After adding ethyl acetate, the mixture was filtered through diatomite, and the filtrate was stirred with sodium thiosulfate solution for 1 hour, then separated. The organic layer was dried over sodium sulfate and concentrated, and then purified by silica gel column (P:E = 3:1) to obtain compound 14.1 (i.e. NS-261) (65 mg, 90.7%, colorless transparent syrup).1 H NMR (400 MHz, DMSO-d6) δ 8.53 (J = 7.8, 3.5, 1.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.44 (m, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.32 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.75 (s, 2H), 2.61 (t, J = 7.0 Hz, 2H), 1.79 (s, 3H), 1.56 (h, J = 7.3 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 387.06, 389.06, Found 387.0, 389.0.

[0310] Following the above procedure, the corresponding p-toluenesulfonate esters were synthesized using 1,2-heptanediol and 1,2-hexanediol as starting materials, respectively, and after reaction with 9-1, further oxidation gave compounds 14.2, 14.3, respectively.

[0311] Compound 14.2 (i.e. NS-302): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.7, 0.9 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (m, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.76 (s, 2H), 2.63 (t, J = 7.2 Hz, 2H), 1.79 (s, 3H), 1.55 (m, 2H), 1.29 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 387.06, 389.06, Found 387.0, 389.0.

[0312] Compound 14.3 (i.e. NS-303): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.7, 0.9 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (m, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.33 (ddd, J = 7.4, 4.8, 0.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.76 (s, 2H), 2.63 (t, J = 7.4 Hz, 2H), 1.79 (s, 3H), 1.53 (m, 2H), 1.31 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 401.08, 403.08, Found 401.0, 403.0.

[0313] Example 15. Synthesis of compound 15.1

[0314] Compound 10.6 (194 mg, 0.5 mmol, 1 eq) was dissolved in 5 mL of ethanol, 0.5 mL of sodium hydroxide (40 mg, 1 mmol, 2 eq) aqueous solution was added dropwise, stirred at room temperature for 5 hours, adjusted to pH 2-3, added water and dichloromethane to separate, the organic layer was combined. After drying over anhydrous sodium sulfate, concentrated to syrup. Resuspended in 2.5 mL of dried thionyl chloride under nitrogen protection, added a catalytic amount of DMF, the reaction was heated to reflux for 1 hour, then the solvent was removed under reduced pressure. Resuspend the residue in dry dichloromethane under nitrogen protection, drop into a solution of 4-aminopyridine carboxamide (82 mg, 0.6 mmol, 1.2 eq) in dry pyridine cooled to -40 °C. The reaction slowly returned to room temperature and continued to stir for 16 hours. Added dichloromethane and hydrochloric acid solution to separate, the organic phase was combined and washed with saturated sodium bicarbonate solution and brine. Dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (100% EA ~ DCM / MeOH = 10:1) to obtain 15.1 (i.e. NS-504) (43 mg, 21.1%, white solid). 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.56 (dd, J = 4.8, 0.9 Hz, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.4 Hz, 1H), 7.83 (td, J = 7.7, 1.8 Hz, 1H), 7.77 (dd, J = 5.5, 2.2 Hz, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.74 (s, 2H), 1.82 (s, 3H). LC-MS: [M+H] + Calcd 480.06, 482.06, Found 480.0, 482.0.

[0315] Example 16. Synthesis of compounds 16.1-16.11

[0316] To a solution of intermediate 9-1 (606 mg, 2 mmol, 1 eq) in allyl tert-butyl ester (2.56 g, 20 mmol, 10 eq) under N2protection, DMAP (244 mg, 2 mmol, 1 eq) was added. 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 give the target compound 16.1 (817 mg, 95.1%). Compound 16.1 (i.e. NS-418) (72 mg, 61.8%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.98 (t, J = 7.1 Hz, 2H), 2.63 (t, J = 6.9 Hz, 2H), 1.75 (s, 3H), 1.35 (s, 9H). LC-MS: [M+H] + Calcd 431.09, 433.09, Found 431.0, 433.0.

[0317] Compound 16.1 (817 mg, 1.9 mmol) was dissolved in 20 mL of dry dichloromethane, 4 mL of trifluoroacetic acid was added dropwise, stirred at room temperature for 18 hours, TLC detection reaction was complete, the organic solvent was removed under reduced pressure to obtain 16-1.

[0318] Compound 16-1 (75 mg, 0.2 mmol) and potassium bicarbonate (40 mg, 0.4 mmol) were added to 2 mL of dry DMF solvent, respectively added methyl iodide (43 mg, 0.3 mmol), 1-iodobutane (55 mg, 0.3 mmol), 1-iodopropane (51 mg, 0.3 mmol), bromoethyl methyl ether (56 mg, 0.2 mmol), 2-iodopropane (51 mg, 0.2 mmol), 2-iodobutane (55 mg, 0.2 mmol), stirred at room temperature overnight, 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 = 3:1) to obtain compounds 16.2-16.9 (83%-94%).

[0319] Compound 16.2 (i.e. NS-57): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.7, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.4, 4.8, 0.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.02 (t, J = 7.0 Hz, 2H), 3.57 (s, 3H), 2.71 (t, J = 7.0 Hz, 2H), 1.74 (s, 3H). LC-MS: [M+H] + Calcd 389.04, 391.04, Found 389.0, 391.0.

[0320] Compound 16.3 (i.e. NS-409): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (t, J = 5.7 Hz, 2H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.00 (dt, J = 17.1, 6.8 Hz, 4H), 2.71 (t, J = 6.9 Hz, 2H), 1.74 (s, 3H), 1.47 (m, 2H), 1.25 (dt, J = 14.5, 7.5 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 431.09, 433.09, Found 431.0, 433.0.

[0321] Compound 16.4 (i.e. NS-410): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (t, J = 5.7 Hz, 2H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.00 (dt, J = 17.1, 6.8 Hz, 4H), 2.71 (t, J = 6.9 Hz, 2H), 1.74 (s, 3H), 1.47 (m, 2H), 1.25 (dt, J = 14.5, 7.5 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 417.07, 419.07, Found 417.0, 419.0.

[0322] Compound 16.5 (i.e. NS-411): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.7, 0.9 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.02 (dt, J = 7.2, 4.6 Hz, 4H), 2.70 (t, J = 6.9 Hz, 2H), 1.74 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 403.06, 405.06, Found 403.0, 405.0.

[0323] Compound 16.6 (i.e. NS-412): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.9, 0.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.11 (m, 2H), 4.03 (t, J = 7.0 Hz, 2H), 3.47 (dd, J = 5.6, 4.0 Hz, 2H), 3.23 (s, 3H), 2.73 (t, J = 7.1 Hz, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 433.07, 435.07, Found 433.0, 435.0.

[0324] Compound 16.7 (i.e. NS-416): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.49 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.31 (dd, J = 6.8, 4.9 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.85 (hept, J = 6.3 Hz, 1H), 4.02 (t, J = 6.6 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 1.75 (s, 3H), 1.13 (d, J = 2.8 Hz, 3H), 1.11 (d, J = 2.8 Hz, 3H). LC-MS: [M+H] + Calcd 417.07, 419.07, Found 417.0, 419.0.

[0325] Compound 16.8 (i.e. NS-417): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.7 Hz, 1H), 7.79 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 (dd, J = 7.5, 5.1 Hz, 2H), 7.31 (dd, J = 7.2, 5.1 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.71 (h, J = 6.3 Hz, 1H), 4.01 (t, J = 7.1 Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H), 1.74 (s, 3H), 1.47 (m, 2H), 1.09 (dd, J = 6.3, 1.8 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 431.09, 433.09, Found 431.0, 433.0.

[0326] Compound 16.9 (i.e. NS-423): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 3.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.1, 5.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.79 (t, J = 5.6 Hz, 1H), 4.02 (m, 4H), 3.54 (dd, J = 10.4, 5.4 Hz, 2H), 2.73 (t, J = 7.0 Hz, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 419.05, 421.05, Found 419.0, 421.0.

[0327] Following Example 6, 16-1 (75 mg, 0.2 mmol) was reacted with dimethylamine (0.2 mL, 0.4 mmol, 2M), hydroxylamine hydrochloride (25 mg, 0.4 mmol) respectively to synthesize 16.10, 16.11.

[0328] Compound 16.10 (i.e. NS-204): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 3.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.1, 5.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.79 (t, J = 5.6 Hz, 1H), 4.02 (m, 4H), 3.54 (dd, J = 10.4, 5.4 Hz, 2H), 2.73 (t, J = 7.0 Hz, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 402.07, 404.07, Found 402.0, 404.0.

[0329] Compound 16.11 (i.e. NS-262): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.7, 0.9 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.4, 4.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.00 (td, J = 6.9, 2.7 Hz, 2H), 3.64 (s, 3H), 3.08 (s, 3H), 2.78 (t, J = 6.8 Hz, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 418.07, 420.07, Found 418.0, 420.0.

[0330] Example 17. Synthesis of compounds 17.1-17.4

[0331] Reference Example 13. Compound 9-1 (90 mg, 0.3 mmol) was used as a raw material to react with 4-iodo-2-butanol in the presence of potassium carbonate to obtain compound 17-1; Reference Example 14, compound 17-1 was further oxidized by Dess-Martin reagent to obtain compound 17.1 (i.e. NS-199). Colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.7, 0.9 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.4, 4.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.00 (td, J = 6.9, 2.7 Hz, 2H), 3.64 (s, 3H), 3.08 (s, 3H), 2.78 (t, J = 6.8 Hz, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 373.05, 375.05, Found 373.0, 375.0.

[0332] To a solution of compound 9-1 (90 mg, 0.3 mmol) and sodium carbonate (4 mg, 0.03 mmol) in 3 mL of water, 1-pentenone (42 mg, 0.5 mmol), 1-hexenone (49 mg, 0.5 mmol) and 1-octenone (63 mg, 0.5 mmol) were added, respectively. The mixture was heated at 100 °C for 16 h. Ethyl acetate was added to extract the mixture. The organic layers were combined and dried over anhydrous sodium sulfate. After concentration, purification on silica gel column (P:E = 4:1-2; 1) gave 17.2-17.4.

[0333] Compound 17.2 (i.e. NS-77): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.95 (t, J = 7.2 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H), 2.49 (q, J = 7.4 Hz, 2H), 1.74 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 387.06, 389.06, Found 387.0, 389.0.

[0334] Compound 17.3 (i.e. NS-200): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.95 (t, J = 7.2 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H), 2.49 (q, J = 7.4 Hz, 2H), 1.74 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 401.08, 403.08, Found 401.0, 403.0.

[0335] Compound 17.4 (i.e. NS-223): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.7, 1.8, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.94 (t, J = 7.1 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H), 2.45 (t, J = 7.1 Hz, 2H), 1.73 (s, 3H), 1.46 (h, J = 7.3 Hz, 2H), 1.21 (m, 4H), 0.84 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 429.11, 431.11, Found 429.0, 431.0.

[0336] Example 18. Synthesis of compounds 18.1-18.5

[0337] 5 mL of compound 9-1 (302 mg, 1 mmol), methyl 4-chlorobutyrate (150 mg, 1.1 mmol), a catalytic amount of tetrabutylammonium iodide and sodium carbonate (166 mg, 1.2 mmol) in DMF were heated to 70 °C for 16 h. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was combined. The combined organic layer was dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 2:1) to give compound 18.1 (i.e. NS-229) (312 mg, 77.6%, colorless transparent syrup,). 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.7, 1.8, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 3.94 (t, J = 7.1 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H), 2.45 (t, J = 7.1 Hz, 2H), 1.73 (s, 3H), 1.46 (h, J = 7.3 Hz, 2H), 1.21 (m, 4H), 0.84 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 403.06, 405.06, Found 403.0, 405.0.

[0338] Compound 18.1 (402 mg, 1 mmol) was dissolved in 5 mL of ethanol, 1 mL of aqueous sodium hydroxide (80 mg, 2 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. The pH was adjusted to 2-3, dichloromethane and dilute hydrochloric acid aqueous solution were added and separated. The organic phase was combined and washed with aqueous sodium bicarbonate and saturated brine. Anhydrous sodium sulfate was dried, concentrated to obtain compound 18-1, which was directly used in the next step.

[0339] Compound 18.2 and 18.3 were obtained by reacting compound 18-1 with ethyl iodide and 1-iodopropane respectively according to Example 16.

[0340] Compound 18.2 (i.e. NS-407): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 4.0 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (m, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.0, 4.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 3.79 (m, 2H), 2.41 (m, 2H), 1.89 (p, J = 7.0 Hz, 2H), 1.76 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 417.07, 419.07, Found 417.0, 419.0.

[0341] Compound 18.3 (i.e. NS-408): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 4.7, 0.8 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (m, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.1, 5.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 3.97 (t, J = 6.6 Hz, 2H), 3.79 (m, 2H), 2.44 (m, 2H), 1.90 (p, J = 7.2 Hz, 2H), 1.76 (s, 3H), 1.58 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 431.09, 433.09, Found 431.0, 433.0.

[0342] Compounds 18.4 and 18.5 were synthesized according to Example 6, using compound 18-1 as starting material, reacting with dimethylamine and dimethylhydroxylamine hydrochloride, respectively.

[0343] Compound 18.4 (i.e. NS-227): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 4.8, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.49 (m, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 3.77 (ddq, J = 20.5, 13.7, 6.9 Hz, 2H), 2.89 (s, 3H), 2.83 (s, 3H), 2.39 (m, 2H), 1.86 (p, J = 7.0 Hz, 2H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 416.09, 418.09, Found 416.0, 418.0.

[0344] Compound 18.5 (i.e. NS-228): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.7, 0.9 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.79 (m, 2H), 3.59 (s, 3H), 3.09 (s, 3H), 2.49 (m, 2H), 1.87 (m, 2H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 432.08, 434.08, Found 432.0, 434.0.

[0345] Example 19. Synthesis of compounds 19.1 and 19.2

[0346] Referring to Example 14, mono-p-toluene sulfonate intermediates 19-3 and 19-4 were synthesized using 1,4-pentanediol and 1,4-hexanediol as starting material, respectively, which were then reacted with compound 9-1 in the presence of potassium carbonate to give compounds 19-3 and 19-4, which were further oxidized to give compounds 19.1 and 19.2.

[0347] Compound 19.1 (i.e. NS-224): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 3.8 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.3, 2.2 Hz, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 6.8, 4.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.72 (m, 2H), 2.56 (m, 2H), 2.05 (s, 3H), 1.82 (m, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 387.06, 389.06, Found 387.0, 389.0.

[0348] Compound 19.2 (i.e. NS-225): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 3.8 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.3, 2.2 Hz, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 6.8, 4.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.72 (m, 2H), 2.56 (m, 2H), 2.05 (s, 3H), 1.82 (m, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 401.08, 403.08, Found 401.0, 403.0.

[0349] Example 20. Synthesis of compounds 20.1-20.4

[0350] Reference Example 13 Synthesis of compound 13-1, using compound 9-1 as starting material, reaction with bromoethanol to give compound 20-1.

[0351] Compound 20-1 (70 mg, 0.2 mmol) and pyridine (79 mg, 1 mmol) in dichloromethane were cooled to -30 °C under nitrogen protection, acetyl chloride (40 mg, 0.5 mmol) was added dropwise, the reaction was slowly warmed to room temperature, and ethyl acetate and water were added. The organic phase was combined, washed with dilute hydrochloric acid, sodium bicarbonate aqueous solution and saturated brine in turn. Dry over anhydrous sodium sulfate, concentrate, and purify on silica gel column (P:E = 3:1) to give compound 20.1 (i.e. NS-230) (62 mg, 80.0%, colorless transparent syrup). 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (t, J = 5.4 Hz, 2H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.30 (t, J = 5.0 Hz, 2H), 4.04 (t, J = 5.3 Hz, 2H), 1.89 (s, 3H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 389.04, 391.04, Found 389.0, 391.0.

[0352] Following the above procedure, compound 20-1 was reacted with propionyl chloride and isobutyryl chloride to give compounds 20.2 and 20.3, respectively.

[0353] Compound 20.2 (i.e. NS-231): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (t, J = 5.4 Hz, 2H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.30 (t, J = 5.0 Hz, 2H), 4.04 (t, J = 5.3 Hz, 2H), 1.89 (s, 3H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 403.06, 405.06, Found 403.0, 405.0.

[0354] Compound 20.3 (i.e. NS-232): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 1.0 Hz, 1H), 7.80 (td, J = 7.7, 1.9 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 5.2 Hz, 2H), 4.05 (m, 2H), 2.38 (dt, J = 13.9, 7.0 Hz, 1H), 1.74 (s, 3H), 0.95 (t, J = 7.0 Hz, 6H). LC-MS: [M+H] + Calcd 417.07, 419.07, Found 417.0, 419.0.

[0355] A solution of compound 20-1 (70 mg, 0.2 mmol) and pyridine (79 mg, 1 mmol) in dichloromethane was cooled to -30 °C under nitrogen protection, p-nitrophenyl chloroformate (44 mg, 0.22 mmol) was added, and 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, and 1 mL of dimethylamine in tetrahydrofuran (2 M) was added. The mixture was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (P:E = 2:1) to give compound 20.4 (i.e. NS-233) (68 mg, 81.3%, colorless transparent syrup). 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 1.0 Hz, 1H), 7.80 (td, J = 7.7, 1.9 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 5.2 Hz, 2H), 4.05 (m, 2H), 2.38 (dt, J = 13.9, 7.0 Hz, 1H), 1.74 (s, 3H), 0.95 (t, J = 7.0 Hz, 6H). LC-MS: [M+H] +Calcd 418.07, 420.07, Found 418.0, 420.0.

[0356] Example 21. Synthesis of compounds 21.1-21.28

[0357] Synthesis of compounds 21.1-21.24

[0358] Compound 9-1 (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 package) was added under ice water bath, after stirring at room temperature for 1 hour, methyl iodide (64 mg, 0.45 mmol), bromoacetaldehyde dimethyl acetal (76 mg, 0.45 mmol), 2-bromoethyl methyl ether (63 mg, 0.45 mmol), 1-iodobutane (84 mg, 0.45 mmol), 1-iodoisopentane (90 mg, 0.45 mmol), benzyl bromide (77 mg, 0.45 mmol), iodomethylcyclopropane (82 mg, 0.45 mmol), benzyl 2-bromoethyl ether (97 mg, 0.45 mmol), 2-iodobutane (84 mg, 0.45 mmol), iodoethane (70 mg, 0.45 mmol), iodopropane (76 mg, 0.45 mmol), 2-iodopropane (76 mg, 0.45 mmol), 1-iodopentane (89 mg, 0.45 mmol), 2-bromoethyl isopropyl ether (75 mg, 0.45 mmol), 2-bromoethyl ethyl ether (69 mg, 0.45 mmol), 1-bromopropyl methyl ether (69 mg, 0.45 mmol), iodoisobutane (84 mg, 0.45 mmol), allyl bromide (55 mg, 0.45 mmol), 1-bromo-3-methyl-2-butene (68 mg, 0.45 mmol), 1-bromo-2-butene (62 mg, 0.45 mmol), methyl allyl iodide (83 mg, 0.45 mmol), bromopropargyl (54 mg, 0.45 mmol), 1-bromo-3-fluoropropane (63 mg, 0.45 mmol), 1-iodo-2-fluoroethane (95 mg, 0.45 mmol) were added successively under ice water bath, and stirred at room temperature for 2 hours, and then quenched by saturated aqueous ammonium chloride solution. Ethyl acetate and water were added for liquid-liquid extraction, and the organic layer was combined. After drying over anhydrous sodium sulfate, concentration and purification on a silica gel column (P:E=3:1-2:1), compounds 21.1-21.24 (68.0-80.0%) were obtained.

[0359] Compound 21.1 (i.e. NS-460): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 3.23 (s, 3H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 317.02, 319.02, Found 317.0, 319.0.

[0360] Compound 21.2 (i.e. NS-586): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 4.66 (t, J = 5.5 Hz, 1H), 3.89 (dd, J = 14.7, 5.7 Hz, 1H), 3.84 (dd, J = 14.6, 5.8 Hz, 1H), 3.33 (s, 6H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 391.06, 393.06, Found 391.0, 393.0.

[0361] Compound 21.3 (i.e. NS-587): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (dd, J = 8.4, 2.1 Hz, 1H), 7.38 (t, J = 5.5 Hz, 2H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.95 (td, J = 5.5, 1.9 Hz, 2H), 3.61 (t, J = 5.6 Hz, 2H), 3.27 (s, 3H), 1.76 (s, 3H). LC-MS: [M+H] +Calcd 361.05, 363.05, Found 361.0, 363.0.

[0362] Compound 21.4 (i.e. NS-588): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.76 (m, 2H), 1.74 (s, 3H), 1.63 (m, 1H), 1.52 (dd, J = 14.4, 7.0 Hz, 2H), 0.96 (d, J = 2.7 Hz, 3H), 0.94 (d, J = 2.7 Hz, 3H). LC-MS: [M+H] + Calcd 359.07, 361.07, Found 359.1, 361.1.

[0363] Compound 21.5 (i.e. NS-589): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.76 (m, 2H), 1.74 (s, 3H), 1.63 (m, 1H), 1.52 (dd, J = 14.4, 7.0 Hz, 2H), 0.96 (d, J = 2.7 Hz, 3H), 0.94 (d, J = 2.7 Hz, 3H). LC-MS: [M+H] + Calcd 373.08, 375.08, Found 373.1, 375.1.

[0364] Compound 21.6 (i.e. NS-590): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.86 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.35 (m, 8H), 6.90 (d, J = 8.1 Hz, 1H), 5.05 (d, J = 16.0 Hz, 1H), 4.96 (d, J = 16.0 Hz, 1H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 393.05, 395.05, Found 393.0, 395.0.

[0365] Compound 21.7 (i.e. NS-591): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.70 (td, J = 7.7, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (m, 4H), 7.22 (dd, J = 7.4, 1.9 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 4.51 (s, 2H), 4.01 (m, 2H), 3.73 (t, J = 5.4 Hz, 2H), 1.74 (s, 3H). LC-MS: [M+H] + Calcd 357.05, 359.05, Found 357.0, 359.0.

[0366] Compound 21.8 (i.e. NS-592): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.70 (td, J = 7.7, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (m, 4H), 7.22 (dd, J = 7.4, 1.9 Hz, 2H), 7.18 (d, J = 8.4 Hz, 1H), 4.51 (s, 2H), 4.01 (m, 2H), 3.73 (t, J = 5.4 Hz, 2H), 1.74 (s, 3H). LC-MS: [M+H] +Calcd 437.08, 439.08, Found 437.1, 439.1.

[0367] Compound 21.9 (i.e. NS-593): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 3.57 (m, 1H), 1.75 (s, 3H), 1.45 (m, 2H), 1.32 (m, 3H), 0.85 (m, 3H). LC-MS: [M+H] + Calcd 359.07, 361.07, Found 359.1, 361.1.

[0368] Compound 21.10 (i.e. NS-594): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 3.79 (q, J = 7.1 Hz, 2H), 1.75 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 331.04, 333.04, Found 331.0, 333.0.

[0369] Compound 21.11 (i.e. NS-595) colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (dd, J = 8.3, 2.1 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 3.73 (td, J = 6.8, 1.1 Hz, 2H), 1.76 (s, 3H), 1.67 (dd, J = 14.5, 7.2 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 345.05, 347.05, Found 345.0, 347.0.

[0370] Compound 21.12 (i.e. NS-596): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.44 (dd, J = 8.4, 2.1 Hz, 1H), 7.36 (dd, J = 5.0, 2.8 Hz, 2H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.58 (m, 1H), 1.73 (s, 3H), 1.46 (d, J = 7.0 Hz, 6H). LC-MS: [M+H] + Calcd 345.05, 347.05, Found 345.0, 347.0.

[0371] Compound 21.13 (i.e. NS-597): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.75 (td, J = 6.9, 2.7 Hz, 2H), 1.75 (s, 3H), 1.65 (dd, J = 14.2, 7.1 Hz, 2H), 1.31 (m, 4H), 0.87 (t, J = 6.8 Hz, 3H). LC-MS: [M+H] + Calcd 373.08, 375.08, Found 373.1, 375.1.

[0372] Compound 21.14 (i.e. NS-561): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.90 (m, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.55 (dt, J = 12.1, 6.1 Hz, 1H), 1.75 (s, 3H), 1.01 (dd, J = 6.0, 3.1 Hz, 6H). LC-MS: [M+H] + Calcd 389.08, 391.08, Found 389.1, 391.1.

[0373] Compound 21.15 (i.e. NS-600): off-white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.1 Hz, 1H), 7.37 (t, J = 5.6 Hz, 2H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 3.94 (m, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.45 (q, J = 7.0 Hz, 2H), 1.75 (s, 3H), 1.04 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 375.06, 377.06, Found 375.1, 377.1.

[0374] Compound 21.16 (i.e. NS-562): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.7 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.80 (m, 2H), 3.37 (t, J = 6.2 Hz, 2H), 3.21 (s, 3H), 1.86 (p, J = 6.4 Hz, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 375.06, 377.06, Found 375.1, 377.1.

[0375] Compound 21.17 (i.e. NS-568): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (m, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 3.57 (m, 2H), 2.12 (dp, J = 14.0, 7.0 Hz, 1H), 1.76 (s, 3H), 0.94 (d, J = 2.3 Hz, 3H), 0.92 (d, J = 2.3 Hz, 3H). LC-MS: [M+H] +Calcd 359.07, 361.07, Found 359.1, 361.1.

[0376] Compound 21.18 (i.e. NS-560): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.7, 1.8, 0.8 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (m, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 5.90 (dtd, J = 15.1, 10.1, 4.8 Hz, 1H), 5.22 (ddd, J = 13.8, 11.8, 1.4 Hz, 2H), 4.40 (m, 2H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 343.04, 345.03, Found 342.7, 344.7.

[0377] Compound 21.19 (i.e. NS-1231): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.81 (dd, J = 7.8, 1.8 Hz, 1H), 7.47 (dd, J = 8.3, 2.1 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 5.20 (t, J = 6.6 Hz, 1H), 4.36 (d, J = 6.6 Hz, 2H), 1.81 (s, 3H), 1.76 (s, 3H), 1.73 (s, 3H).

[0378] Compound 21.20 (i.e. NS-1233): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.8 Hz, 1H), 7.82 (m, 1H), 7.45 (m, 2H), 7.38 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 7.2, 5.1 Hz, 1H), 7.01 (d, J = 8.3 Hz, 0.7H), 6.96 (d, J = 8.3 Hz, 0.3H), 5.73 (m, 1H), 5.47 (m, 1H), 4.42 (d, J = 6.6 Hz, 0.6H), 4.31 (d, J = 4.0 Hz, 1.4H), 1.80 (dd, J = 7.0, 0.9 Hz, 0.9H), 1.76 (s, 2.1H), 1.76 (s, 0.9H), 1.66 (dd, J = 6.4, 1.3 Hz, 2.1H). LC-MS: [M+H] + Calcd 357.05, 359.05, Found 356.8, 358.8.

[0379] Compound 21.21 (i.e. NS-1234): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.8 Hz, 1H), 7.82 (m, 1H), 7.45 (m, 2H), 7.38 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 7.2, 5.1 Hz, 1H), 7.01 (d, J = 8.3 Hz, 0.7H), 6.96 (d, J = 8.3 Hz, 0.3H), 5.73 (m, 1H), 5.47 (m, 1H), 4.42 (d, J = 6.6 Hz, 0.6H), 4.31 (d, J = 4.0 Hz, 1.4H), 1.80 (dd, J = 7.0, 0.9 Hz, 0.9H), 1.76 (s, 2.1H), 1.76 (s, 0.9H), 1.66 (dd, J = 6.4, 1.3 Hz, 2.1H). LC-MS: [M+H] + Calcd 357.05, 359.05, Found 356.8, 358.8.

[0380] Compound 21.22 (i.e. NS-1235): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 4.8, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.5, 2.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.25 (t, J = 6.7 Hz, 1H), 5.79 (d, J = 6.3 Hz, 2H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 341.02, 343.02, Found 340.8, 342.8.

[0381] Compound 21.23 (i.e. NS-1703): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 3.8 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 13.3, 5.0 Hz, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.4, 4.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.59 (t, J = 5.8 Hz, 1H), 4.47 (t, J = 5.8 Hz, 1H), 3.87 (m, 2H), 2.03 (m, 2H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 363.04, 365.04, Found 362.8, 364.8.

[0382] Compound 21.24 (i.e. NS-1704): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.41 (dd, J = 8.1, 5.0 Hz, 2H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.75 (t, J = 4.8 Hz, 1H), 4.63 (t, J = 4.8 Hz, 1H), 4.15 (t, J = 4.8 Hz, 1H), 4.08 (t, J = 4.8 Hz, 1H), 1.77 (s, 3H). LC-MS: [M+H] +Calcd 349.03, 351.03, Found 348.8, 350.8.

[0383] Synthesis of compounds 21.25 and 21.26

[0384] Compound 9-1 (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 package) was added under ice water bath, after stirring at room temperature for 1 hour, 2-iodo-1,1,1-trifluoroethane (95 mg, 0.45 mmol) was added under ice water bath, stirred at room temperature for 2 hours, heated and stirred at 70°C overnight, saturated aqueous ammonium chloride solution was added to quench the reaction. Extracted with ethyl acetate and water, the organic layer was combined. Dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 3:1 ~ 2:1) to obtain compounds 21.25 and 21.26 (68.0 ~ 80.0%).

[0385] Compound 21.25 (i.e. NS-1679): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.54 (dd, J = 8.4, 2.1 Hz, 1H), 7.45 (m, 2H), 7.33 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.75 (m, 2H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 385.01, 387.01, Found 384.8, 386.8.

[0386] Compound 21.26 (i.e. NS-1706): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 4.0 Hz, 0.45H), 8.50 (dd, J = 4.8, 1.0 Hz, 0.55H), 7.87 (td, J = 7.8, 1.8 Hz, 1H), 7.56 (m, 3H), 7.35 (ddd, J = 12.3, 6.4, 0.9 Hz, 1H), 7.11 (d, J = 5.9 Hz, 0.45H), 7.07 (d, J = 7.6 Hz, 0.55H), 7.03 (d, J = 8.2 Hz, 0.45H), 6.56 (d, J = 30.9 Hz, 0.55H), 1.88 (s, 1.35H), 1.87 (s, 1.65H). LC-MS: [M+H]+ Calcd 472.91, 474.91, Found 472.7, 474.7.

[0387] Synthesis of compounds 21.27 and 21.28

[0388] Compound 9-1 (96 mg, 0.3 mmol, 1 eq) and triphenylphosphine (118 mg, 0.45 mmol, 1.5 eq) were dissolved in 1 ml of 4,4,4-trifluorobutanol, the temperature was lowered to -5 °C, and diethyl azodicarboxylate (78 mg, 0.45 mmol, 1.5 eq) was added dropwise. The reaction was slowly brought to room temperature and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the target compound 21.27 (i.e. NS-1681) was obtained after purification on a silica gel column (P:E = 3:1):

[0389] Compound 21.27 (i.e. NS-1681): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (dd, J = 4.7, 1.0 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.86 (m, 2H), 2.38 (qdd, J = 22.8, 15.0, 9.8 Hz, 2H), 1.86 (m, 2H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 413.04, 415.04, Found 412.8, 414.8.

[0390] Following the procedure described above, compound 9-1 was reacted with trifluoropropanol to produce compound 21.28.

[0391] Compound 21.28 (i.e. NS-1680): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.51 (dd, J = 8.4, 2.1 Hz, 1H), 7.42 (m, 2H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.04 (m, 2H), 2.72 (m, 2H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 399.02, 401.02, Found 398.8, 400.8.

[0392] Example 22. Synthesis of compounds 22.1-22.4

[0393] Compound 10.5 (360 mg, 1 mmol) was dissolved in dry methanol under nitrogen protection, temperature was dropped to 0 °C, sodium borohydride (76 mg, 2 mmol) was added in portions, slowly raised to room temperature, after stirring for 1 hour, the reaction was quenched with dilute hydrochloric acid. Added ethyl acetate and water to separate liquid, combined the organic phase, washed with sodium bicarbonate aqueous solution and saturated brine in turn. Dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 2:1-1:1) to obtain compound 22-1 (338 mg, 93.6%).

[0394] Compound 22-1 (108 mg, 0.3 mmol) and iodomethane (64 mg, 0.45 mmol) were dissolved in dry DMF under nitrogen protection, temperature was dropped to 0 °C, sodium hydride (13 mg, 0.33 mmol, 40% wrapped in mineral oil) was added in portions, slowly raised to room temperature, after stirring for 1 hour, the reaction was quenched with aqueous ammonium chloride solution. Added ethyl acetate and water to separate liquid, combined the organic phase, washed with saturated brine. Dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 3:1-2:1) to obtain compound 22.1 (i.e. NS-566) (84 mg, 74.7%, colorless transparent syrup). 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dddd, J = 8.5, 4.8, 1.8, 0.8 Hz, 1H), 7.82 (tdd, J = 7.8, 3.5, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (m, 1H), 7.36 (dd, J = 3.7, 2.1 Hz, 1H), 7.31 (dd, J = 7.4, 4.8 Hz, 1H), 7.15 (dd, J = 8.4, 3.3 Hz, 1H), 3.76 (m, 3H), 3.24 (d, J = 4.5 Hz, 3H), 1.76 (s, 3H), 1.14 (dd, J = 6.0, 1.6 Hz, 3H). LC-MS: [M+H] + Calcd 375.06, 377.06, Found 375.1, 377.1.

[0395] Following the procedure described above, compound 22-1 and iodoethane were reacted to give compound 22.2 (i.e. NS-567). Colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 10.2, 4.8, 0.9 Hz, 1H), 7.81 (m, 1H), 7.46 (dd, J = 8.4, 1.9 Hz, 1H), 7.42 (m, 1H), 7.37 (dd, J = 7.2, 2.0 Hz, 1H), 7.31 (m, 1H), 7.15 (dd, J = 8.4, 2.5 Hz, 1H), 3.76 (m, 3H), 3.52 (dqd, J = 13.9, 7.0, 4.0 Hz, 1H), 3.37 (m, 1H), 1.76 (d, J = 2.2 Hz, 3H), 1.14 (d, J = 5.9 Hz, 3H), 0.99 (dd, J = 14.9, 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 389.08, 391.08, Found 389.1, 391.1.

[0396] Referring to the synthesis of compound 22.1 above, compound 22.3 and 22.4 were obtained from compound 10.4 as starting material via reduction and hydroxyl alkylation.

[0397] Compound 22.3 (i.e. NS-563): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 8.9, 4.8 Hz, 1H), 7.81 (tdd, J = 7.7, 3.4, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.42 (dd, J = 11.3, 8.0 Hz, 1H), 7.37 (m, 1H), 7.30 (m, 1H), 7.12 (dd, J = 8.4, 1.7 Hz, 1H), 3.79 (m, 2H), 3.47 (m, 1H), 3.25 (d, J = 6.9 Hz, 3H), 1.75 (s, 3H), 1.51 (m, 2H), 0.93 (td, J = 7.4, 1.5 Hz, 3H). LC-MS: [M+H] + Calcd 389.08, 391.08, Found 389.1, 391.1.

[0398] Compound 22.4 (i.e. NS-564): 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 8.9, 4.8 Hz, 1H), 7.81 (tdd, J = 7.7, 3.4, 1.9 Hz, 1H), 7.46 (dd, J = 8.4, 1.2 Hz, 1H), 7.42 (dd, J = 11.3, 8.0 Hz, 1H), 7.37 (m, 1H), 7.30 (m, 1H), 7.12 (dd, J = 8.4, 1.7 Hz, 1H), 3.79 (m, 2H), 3.47 (m, 1H), 3.25 (d, J = 6.9 Hz, 3H), 1.75 (s, 3H), 1.51 (m, 2H), 0.93 (td, J = 7.4, 1.5 Hz, 3H). LC-MS: [M+H] + Calcd 403.09, 405.09, Found 403.1, 405.1.

[0399] Example 23. Synthesis of compounds 23.1-23.4

[0400] Compound 9-1 (303 mg, 1 mmol) and diisopropylethylamine (390 mg, 3 mmol) were dissolved in dry dichloromethane under nitrogen protection, the temperature was reduced to 0 °C, bromomethyl methyl ether (250 mg, 2 mmol) was added dropwise, slowly raised to room temperature, after stirring for 1 hour, ethyl acetate and water were separated, the organic phase was combined, washed with saturated brine. Dry with anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 3:1-2:1) to obtain compound 23.1 (i.e. NS-598) (68.1 mg, 19.6%, white solid). 1H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.8, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.19 (d, J = 10.9 Hz, 1H), 5.15 (d, J = 10.9 Hz, 1H), 3.29 (s, 3H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 347.03, 349.03, Found 347.0, 349.0.

[0401] Referring to the above synthesis, compound 9-1 was reacted with bromomethyl ether to give compounds 23.2 and 23.3.

[0402] Compound 23.2 (i.e. NS-599): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.8, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.4, 2.1 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.19 (d, J = 10.9 Hz, 1H), 5.15 (d, J = 10.9 Hz, 1H), 3.29 (s, 3H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 361.05, 363.05, Found 361.0, 363.0.

[0403] Compound 23.3 (i.e. NS-541): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 3.9 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.50 (m, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.1, 5.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.32 (d, J = 11.1 Hz, 1H), 5.28 (d, J = 11.0 Hz, 1H), 4.74 (dd, J = 15.1, 6.9 Hz, 2H), 3.49 (m, 2H), 1.78 (s, 3H), 1.04 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 391.06, 393.06, Found 391.1, 393.1.

[0404] Referring to the above synthesis, compound 9-1 was reacted with bromomethyl isopropyl ether to give compound compound 23.4.

[0405] Compound 23.4 (i.e. NS-565): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (m, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (m, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 5.23 (d, J = 11.1 Hz, 1H), 5.19 (d, J = 11.1 Hz, 1H), 3.78 (hept, J = 6.1 Hz, 1H), 1.79 (s, 3H), 1.12 (d, J = 3.9 Hz, 3H), 1.11 (d, J = 3.9 Hz, 3H). LC-MS: [M+H] + Calcd 375.06, 377.06, Found 375.1, 377.1.

[0406] Example 24 Synthesis of compounds 24.1-24.5

[0407] Compound 21.2 (195 mg, 0.5 mmol) was dissolved in dichloromethane, trifluoroacetic acid was added, and the reaction was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure, and the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to give compound 24-1. Compound 24-1 was redissolved in 5 mL of 1,2-dichloroethane, and acetic acid (132 mg, 2.2 mmol) and 1 mL of dimethylamine in tetrahydrofuran (2 M) were added. The reaction was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (424 mg, 2 mmol) was added, and the reaction was refluxed under nitrogen for 8 hours. The reaction was quenched with dilute hydrochloric acid, and the pH was adjusted to 9-10 with sodium bicarbonate. The mixture was extracted with dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated. Purification on a silica gel column (100% EA - DCM / MeOH = 3:1) gave compound 24.1 (i.e., NS-584) (39 mg, 20.9%, yellowish solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (dd, J = 8.3, 2.1 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 3.85 (m, 2H), 2.50 (s, 2H), 2.21 (s, 6H), 1.75 (s, 3H). LC-MS: [M+H] + Calcd 374.08, 376.08, Found 374.1, 376.1.

[0408] Referring to the above reaction, compound 24-1 was reductive aminated with N-methyl isopropylamine, N-methyl isobutylamine, N-methyl-2-butylamine, and N-methyl propylamine to give compounds 24.2-24.5.

[0409] Compound 24.2 (i.e., NS-1548): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.3 Hz, 1H), 7.78 (t, J = 7.5 Hz, 1H), 7.44 (dd, J = 19.5, 7.7 Hz, 2H), 7.36 (s, 1H), 7.30 (dd, J = 6.7, 4.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 3.82 (br s, 2H), 2.75 (br s, 1H), 2.60 (br s, 2H), 2.22 (s, 3H), 0.85 (s, 6H). LC-MS: [M+H] +Calcd 402.11, 404.11, Found 401.8, 403.8.

[0410] Compound 24.3 (i.e. NS-1549): yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.8 Hz, 1H), 7.47 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.85 (m, 2H), 2.60 (m, 2H), 2.23 (s, 3H), 2.08 (d, J = 7.6 Hz, 2H), 1.74 (s, 3H), 1.61 (dp, J = 13.4, 6.7 Hz, 1H), 0.72 (d, J = 1.9 Hz, 3H), 0.70 (d, J = 1.9 Hz, 3H). LC-MS: [M+H] + Calcd 416.13, 418.13, Found 415.9, 417.9.

[0411] Compound 24.4 (i.e. NS-1550): yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.0, 0.8 Hz, 1H), 7.78 (td, J = 7.7, 1.6 Hz, 1H), 7.46 (dd, J = 8.3, 2.0 Hz, 1H), 7.41 (dd, J = 8.0, 2.9 Hz, 1H), 7.36 (t, J = 1.8 Hz, 1H), 7.30 (dd, J = 7.2, 5.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.81 (t, J = 6.3 Hz, 2H), 2.67 (dt, J = 12.1, 5.9 Hz, 1H), 2.58 (dt, J = 12.1, 5.9 Hz, 1H), 2.44 (m, 1H), 2.22 (s, 3H), 1.29 (m, 1H), 1.13 (m, 1H), 0.82 (dd, J = 6.5, 3.4 Hz, 3H), 0.68 (td, J = 7.3, 1.4 Hz, 3H). LC-MS: [M+H] + Calcd 416.13, 418.13, Found 415.9, 417.9.

[0412] Compound 24.5 (i.e. NS-1551): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 3.9, 0.7 Hz, 1H), 7.78 (td, J = 7.7, 1.6 Hz, 1H), 7.47 (dd, J = 8.4, 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 7.3, 4.9 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.85 (m, 2H), 2.59 (t, J = 6.4 Hz, 2H), 2.29 (m, 2H), 2.24 (d, J = 6.9 Hz, 3H), 1.74 (s, 3H), 1.32 (m, 2H), 0.74 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 402.11, 404.11, Found 401.8, 403.8.

[0413] Referring to the above synthesis, compound 10.5 was used as the starting material to give compound 24.6 (i.e. NS-585) (37 mg, 19.1%, yellowish solid) by reductive amination with dimethylamine. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 3.9, 0.7 Hz, 1H), 7.78 (td, J = 7.7, 1.6 Hz, 1H), 7.47 (dd, J = 8.4, 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 7.3, 4.9 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 3.85 (m, 2H), 2.59 (t, J = 6.4 Hz, 2H), 2.29 (m, 2H), 2.24 (d, J = 6.9 Hz, 3H), 1.74 (s, 3H), 1.32 (m, 2H), 0.74 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] +Calcd 388.09, 390.09, Found 388.1, 390.1.

[0414] Example 25. Synthesis of compounds 25.1-25.3

[0415] A mixture of compound 9-1 (288 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, then cuprous iodide (190 mg, 1 mmol) was added and the reaction was stirred at 100 °C for 6 h. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was combined. The combined organic layer was dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 1 : 1 to 100% EA to 10% DCM / MeOH) to give compounds 25.1 (48 mg, 24.5%) and 25.2 (50 mg, 24.9%).

[0416] Compound 25.1 (i.e. NS-516): light yellow solid, 1 H NMR (400 MHz, Acetone-d6) δ 8.74 (d, J = 5.2 Hz, 1H), 8.59 (d, J = 4.7 Hz, 1H), 7.86 (td, J = 7.7, 1.6 Hz, 1H), 7.81 (t, J = 1.0 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.61 (m, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 7.6, 4.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 3.36 (s, 3H). LC-MS: [M+H] + Calcd 405.03, 407.03, Found 405.0, 407.0.

[0417] Compound 25.2 (i.e. NS-505): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 5.2 Hz, 1H), 8.56 (d, J = 3.9 Hz, 1H), 8.16 (s, 1H), 7.86 (td, J = 7.8, 1.9 Hz, 1H), 7.83 (d, J = 1.5 Hz, 1H), 7.72 (s, 1H), 7.63 (m, 2H), 7.38 (m, 3H), 7.21 (d, J = 8.3 Hz, 1H), 3.27 (s, 3H). LC-MS: [M+H] + Calcd 423.04, 425.04, Found 423.0, 425.0.

[0418] Referring to the above synthesis, compound 9-1 and 2-chloro-5-iodopyridine were reacted to produce compound 25.3.

[0419] Compound 25.3 (i.e., NS-1266): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.6 Hz, 1H), 8.54 (dd, J = 4.8, 0.9 Hz, 1H), 8.11 (dd, J = 8.5, 2.7 Hz, 1H), 7.86 (dd, J = 7.8, 1.8 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 1.92 (s, 3H). LC-MS: [M+H] + Calcd 413.99, 415.99, Found 413.8, 415.8.

[0420] Example 26. Synthesis of compounds 26.1-26.4

[0421] Compound 9-1 (604 mg, 2 mmol) was dissolved in dry DMF under nitrogen protection, sodium hydride (88 mg, 2.2 mmol) was added in portions under ice water bath, after stirring at room temperature for 30 minutes, diphenyl phosphine hydroxylamine (513 mg, 2.2 mmol) was added, and stirred at 80 °C for 16 hours. Ethyl acetate and water were added, and the organic phase was separated, and the aqueous phase was washed with saturated brine. After drying over anhydrous sodium sulfate, concentration and purification on a silica gel column (P:E = 1:1-1:4), compound 26.1 (547 mg, 86.0%) was obtained.

[0422] Compound 26.1 (i.e., NS-1571): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 5.29 (s, 2H), 1.75 (s, 2H). LC-MS: [M+H]+ Calcd 318.02, 320.02, Found 317.8, 319.8.

[0423] Compound 26.1 (318 mg, 1 mmol, 1 eq) was dissolved in 5 mL dry dichloromethane, pyridine (780 mg, 10 mmol, 10 eq) and catalytic amount of DMAP were added, isobutyryl chloride (160 mg, 1.5 mmol, 1.5 eq) was added dropwise under ice bath condition, the reaction was slowly warmed to room temperature, the solvent was removed, ethyl acetate and water were used to extract the mixture three times, the organic layers were 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 give compound 26.2 (342 mg, 88.1%).

[0424] Compound 26.2 (i.e. NS-764): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.52 (s, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.49 (brs, 1H), 7.48 (dd, J = 8.3, 1.8 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.34 (dd, J = 7.1, 5.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 2.65 (dt, J = 13.7, 6.8 Hz, 1H), 1.82 (s, 3H), 1.17 (dd, J = 6.7, 4.0 Hz, 6H). LC-MS: [M+H] + Calcd 388.06, 390.06, Found 387.8, 389.8.

[0425] Compound 26.2 (194 mg, 0.5 mmol) was dissolved in dry tetrahydrofuran under nitrogen protection, sodium hydride (24 mg, 0.6 mol, 1.2 eq, 40% mineral oil package) was added under ice water bath, stirred at room temperature for 1 hour, then iodomethane (86 mg, 0.6 mmol) was added under ice water bath, stirred at room temperature for 2 hours, saturated aqueous ammonium chloride solution was added to quench the reaction. Ethyl acetate and water were used to extract the mixture, the organic layers were combined. Dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 3:1~2:1) to give compound 26.3 (99.0 mg, 49.3%).

[0426] Compound 26.3 (i.e. NS-769): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.7 Hz, 0.3 H), 8.42 (d, J = 3.8 Hz, 0.7 H), 7.90 (m, 1 H), 7.69 (d, J = 8.0 Hz, 0.7 H), 7.60 (d, J = 8.0 Hz, 0.3 H), 7.557 (m, 1.3 H), 7.53 (dd, J = 2.0, 3.2 Hz, 0.7 H), 7.33 (m, 1 H), 7.07 (d, J = 8.3 Hz, 0..3 H), 7.02 (d, J = 8.2 Hz, 0.7 H), 3.21 (s, 0.9 H), 3.19 (s, 2.1 H), 3.12 (m, 3 H), 3.00 (dt, J = 13.4, 6.6 Hz, 0.7 H), 1.88 (s, 3 H), 0.98 (m, 6 H). LC-MS: [M+H] + Calcd 402.07, 404.07, Found 401.8, 403.8.

[0427] Referring to the above synthesis, compound 26.1 was reacted with isopropyl chloroformate to produce compound 26.4 (i.e., NS-800): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 0.8 H), 9.88 (s, 0.2 H), 8.61 (s, 0.2 H), 8.49 (s, 0.8 H), 7.88 (s, 0.8 H), 7.80 (s, 0.2 H), 7.51 (m, 2.8 H), 7.34 (dd, J = 7.1, 5.1 Hz, 1.2 H), 6.90 (s, 1 H), 4.89 (s, 1 H), 1.80 (s, 3 H), 1.29 (d, J = 5.3 Hz, 4.8 H), 1.07 (d, J = 16.4 Hz, 1.2 H). LC-MS: [M+H] + Calcd 404.05, 406.05, Found 403.8, 405.8.

[0428] Example 27. Synthesis of compounds 27.1-27.4

[0429] Compound 26.1 (90 mg, 0.3 mmol) and triethylamine (4 mg, 0.03 mmol) were added to 3 mL of methanol, and 1-octenone (63 mg, 0.5 mmol) was added to the tube and heated at 100 °C for 16 hours. Ethyl acetate was added to extract, and the organic layers were combined. Anhydrous sodium sulfate was added to dry, concentrated, and purified by silica gel column (P:E = 4:1-2; 1) to obtain compound 27.1.

[0430] Compound 27.1 (i.e., NS-766): colorless transparent syrup,1 H NMR (400 MHz, DMSO-d6) δ 8.48 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (dd, J = 8.3, 2.1 Hz, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.10 (t, J = 5.2 Hz, 1H), 3.20 (dd, J = 11.9, 6.5 Hz, 2H), 2.66 (t, J = 6.6 Hz, 2H), 2.39 (t, J = 7.3 Hz, 2H), 1.77 (s, 3H), 1.44 (m, 2H), 1.21 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 444.12, 446.12, Found 443.9, 445.9.

[0431] Compound 27.1 (89 mg, 0.2 mmol) was dissolved in dry tetrahydrofuran under nitrogen protection, sodium hydride (9.6 mg, 0.24 mol, 1.2 eq, 40% mineral oil package) was added under ice water bath, stirred at room temperature for 1 hour, then iodomethane (43 mg, 0.3 mmol) was added under ice water bath, stirred at room temperature for 2 hours, then saturated aqueous ammonium chloride solution was added to quench the reaction. Extracted with ethyl acetate and water, combined the organic layers. Dried over anhydrous sodium sulfate, concentrated, purified by silica gel column (P:E = 3:1~2:1) to give compound 27.2 (99.0 mg, 41.0%).

[0432] Compound 27.2 (i.e. NS-770): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (t, J = 4.2 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.47 (m, 2H), 7.36 (dd, J = 6.1, 1.9 Hz, 1H), 7.31 (m, 1H), 6.94 (dd, J = 8.2, 6.3 Hz, 1H), 6.14 (dt, J = 13.0, 5.4 Hz, 1H), 3.25 (dt, J = 12.2, 5.6 Hz, 1H), 2.94 (m, 1H), 2.80 (m, 1H), 2.48 (m, 1H), 1.76 (d, J = 5.0 Hz, 3H), 1.44 (m, 2H), 1.23 (m, 4H), 1.06 (t, J = 7.2 Hz, 3H), 0.86 (td, J = 7.1, 1.7 Hz, 3H). LC-MS: [M+H] +Calcd 458.14, 460.14, Found 457.9, 459.9.

[0433] Following the above procedure, compound 26.1 (90 mg, 0.3 mmol) was reacted with 1-hexenone (49 mg, 0.5 mmol) and 1-pentenone (42 mg, 0.5 mmol) to give compounds 27.3 and 27.4, respectively.

[0434] Compound 27.3 (i.e. NS-1061): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (m, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.10 (t, J = 5.2 Hz, 1H), 3.21 (dd, J = 12.0, 6.5 Hz, 2H), 2.66 (t, J = 6.3 Hz, 2H), 2.40 (t, J = 7.2 Hz, 2H), 1.77 (s, 3H), 1.48 (h, J = 7.3 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 416.09, 418.09, Found 415.8, 417.8.

[0435] Compound 27.4 (i.e. NS-1062): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.7, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.2, 1.9 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.10 (br s, 1H), 3.21 (t, J = 6.6 Hz, 2H), 2.66 (td, J = 6.5, 2.4 Hz, 2H), 2.43 (q, J = 7.3 Hz, 2H), 1.77 (s, 3H), 0.92 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 402.07, 404.07, Found 401.8, 403.8.

[0436] Example 28. Synthesis of compounds 28.1-28.10

[0437] Compound 26.1 (318 mg, 1 mmol) and isobutyraldehyde (108 mg, 1.5 mmol) were dissolved in dichloroethane, and a catalytic amount of acetic acid was added, and stirred at room temperature overnight. Compound 28.1 (i.e., NS-768) (249 mg, 67.0%) was obtained after concentration under reduced pressure and purification by silica gel column (P:E = 4:1 ~ 3:1).

[0438] Compound 28.1 (i.e., NS-768): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 4.8 Hz, 1H), 8.49 (d, J = 3.5 Hz, 1H), 7.86 (td, J = 7.7, 1.7 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 7.5, 4.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 2.71 (dtd, J = 13.7, 6.8, 4.9 Hz, 1H), 1.84 (s, 3H), 1.19 (d, J = 6.9 Hz, 6H). LC-MS: [M+H] + Calcd 372.06, 374.06, Found 371.8, 373.8.

[0439] Referring to the above synthesis, compound 26-1 was reacted with cyclopropylcarboxaldehyde, isovaleraldehyde, propionaldehyde, butyraldehyde, glyoxal-1,1-dimethyl acetal, ethyl glyoxylate, 3-methoxythiophene-2-carboxaldehyde, and methylglyoxal, respectively, to obtain compounds 28.2 ~ 28.9

[0440] Compound 28.2 (i.e., NS-1041): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 0.9 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.12 (d, J = 8.3 Hz, 1H), 1.85 (m, 4H), 1.07 (m, 2H), 0.91 (d, J = 2.9 Hz, 2H). LC-MS: [M+H] +Calcd 370.05, 372.05, Found 369.8, 371.8.

[0441] Compound 28.3 (i.e. NS-1042): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (t, J = 5.8 Hz, 1H), 8.49 (dd, J = 4.8, 1.0 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 2.35 (m, 2H), 2.01 (dp, J = 13.5, 6.7 Hz, 1H), 1.83 (s, 3H), 1.01 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 386.08, 388.08, Found 385.8, 387.8.

[0442] Compound 28.4 (i.e. NS-1044): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 4.8 Hz, 1H), 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.33 (m, 1H), 7.13 (d, J = 8.3 Hz, 1H), 2.48 (m, 2H), 1.83 (s, 3H), 1.18 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 358.05, 360.05, Found 357.8, 359.8.

[0443] Compound 28.5 (i.e. NS-1045): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.87 (t, J = 5.3 Hz, 1H), 8.49 (dd, J = 4.8, 1.0 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.33 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H), 2.45 (dd, J = 13.0, 6.5 Hz, 2H), 1.83 (s, 3H), 1.65 (h, J = 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 372.06, 374.06, Found 371.8, 373.8.

[0444] Compound 28.6 (i.e. NS-1057): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 5.4 Hz, 1H), 8.48 (dd, J = 4.8, 1.0 Hz, 1H), 7.87 (td, J = 7.8, 1.9 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.34 (m, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 5.4 Hz, 1H), 3.43 (s, 3H), 3.43 (s, 3H), 1.86 (s, 3H). LC-MS: [M+H] + Calcd 404.05, 406.05, Found 403.8, 405.8.

[0445] Compound 28.7 (i.e. NS-1059): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.47 (dd, J = 4.8, 1.0 Hz, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 6.8, 4.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.90 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] +Calcd 402.04, 404.04, Found 401.8, 403.8.

[0446] Compound 28.8 (i.e. NS-1695): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (m, 0.9H), 8.73 (s, 0.1H), 8.54 (d, J = 4.0 Hz, 0.1H), 8.50 (dd, J = 4.7, 0.9 Hz, 0.9H), 7.86 (td, J = 8.0, 2.0 Hz, 1H), 7.83 (d, J = 6.2 Hz, 1H), 7.60 (d, J = 8.0 Hz, 0.9H), 7.54 (dd, J = 8.3, 2.0 Hz, 0.9H), 7.51 (d, J = 8.0 Hz, 0.2H), 7.47 (d, J = 1.9 Hz, 0.1H), 7.46 (d, J = 1.9 Hz, 0.9H), 7.34 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.18 (d, J = 5.6 Hz, 0.9H), 7.14 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 0.1H), 4.00 (s, 0.3H), 3.97 (s, 2.7H), 1.92 (s, 0.3H), 1.86 (s, 2.7H). LC-MS: [M+H] + Calcd 442.01, 444.01, Found 441.8, 443.8.

[0447] Compound 28.9 (i.e. NS-1050): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.46 (dd, J = 4.7, 0.9 Hz, 1H), 7.88 (td, J = 7.8, 1.8 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.4, 1.9 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 6.8, 4.8 Hz, 1H), 2.48 (s, 3H), 1.90 (s, 3H). LC-MS: [M+H] + Calcd 372.03, 374.03, Found 371.8, 373.8.

[0448] Example 29. Synthesis of compounds 29.1-29.5

[0449] Compound cyclopropaneethanol (318 mg, 1 mmol) and Dess-Martin reagent (509 mg, 1.2 mmol) were stirred overnight in 5 mL of dry dichloromethane. After adding 20 mL of methyl ether, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to give ketone compound 29-1. Compound 29-1 and compound 26.1 (318 mg, 1 mmol) were dissolved in 1,2-dichloroethane, and a catalytic amount of acetic acid was added. The mixture was stirred overnight at room temperature. After purification by silica gel column chromatography under reduced pressure (P:E = 4:1 to 3:1), compound 29.1 (i.e., NS-1043) was obtained.

[0450] Compound 29.1 (i.e., NS-1043): a pale yellow transparent syrup. 1 H NMR(400MHz,DMSO-d6)δ8.95(t,J=5.4Hz,1H),8.49(dd,J=4.7,0.9Hz,1H),7. 86(td,J=7.8,1.8Hz,1H),7.57(d,J=8.0Hz,1H),7.52(dd,J=8.3,2.0Hz,1H),7 .44(d,J=1.9Hz,1H),7.33(ddd,J=7.4,4.8,0.7Hz,1H),7.13(d,J=8.3Hz,1H), 2.37(m,2H),1.84(s,3H),1.01(m,1H),0.55(m,2H),0.25(m,2H).LC-MS:[M+H] + Calcd 384.06,386.06, Found 383.8,385.8.

[0451] Following the above procedure, isopropoxyethanol, 3,3,3-trifluoropropanol, 4,4,4-trifluorobutanol, and 1-hydroxy-2-butanone were oxidized to the corresponding aldehydes, and then reacted with compound 26.1 to obtain compounds 29.2 to 29.5.

[0452] Compound 29.2 (i.e., NS-1047): a colorless, transparent syrup. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (t, J = 4.8 Hz, 1H), 8.48 (dd, J = 4.8, 0.9 Hz, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.9, 0.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.28 (d, J = 5.4 Hz, 2H), 3.74 (dt, J = 12.2, 6.1 Hz, 1H), 1.85 (s, 3H), 1.18 (d, J = 6.1 Hz, 6H). LC-MS: [M+H] + Calcd 402.07, 404.07, Found 401.8, 403.8.

[0453] Compound 29.3 (i.e. NS-1682): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (t, J = 5.4 Hz, 1H), 8.48 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.88 (td, J = 7.8, 1.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 7.4, 4.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 3.66 (m, 2H), 1.87 (s, 3H). LC-MS: [M+H] + Calcd 412.02, 414.02, Found 411.8, 413.8.

[0454] Compound 29.4 (i.e. NS-1683): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (t, J = 5.4 Hz, 1H), 8.48 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.88 (td, J = 7.8, 1.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 8.4, 2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 7.4, 4.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 3.66 (m, 2H), 1.87 (s, 3H). LC-MS: [M+H] +Calcd 426.04, 428.04, Found 425.8, 427.8.

[0455] Compound 29.5 (i.e. NS-1099): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.47 (dd, J = 4.8, 0.9 Hz, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 3.00 (q, J = 7.3 Hz, 2H), 1.90 (s, 3H), 1.10 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 386.04, 388.04, Found 385.8, 387.8.

[0456] Example 30. Synthesis of compounds 30.1-30.2

[0457] Methyl isopropyl ketone (86 mg, 1 mmol) and selenium dioxide (222 mg, 2 mmol) were dissolved in a mixed solvent of epoxyhexane: water (10:1), and the tube was heated to 80 °C with stirring overnight. The reaction solution was filtered through diatomite, the filter cake was washed with DCE, and the filtrate was dried over anhydrous sodium sulfate to obtain a dichloromethane solution of 30-1. Compound 26.1 (96 mg, 0.3 mmol) and a catalytic amount of acetic acid were added to the above solution, and stirred at room temperature overnight. After concentration under reduced pressure, silica gel column purification (P:E = 4:1-3:1) gave compound 30.1 (i.e. NS-1051) (78 mg, 65.0%): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.47 (dd, J = 4.8, 0.9 Hz, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 3.00 (q, J = 7.3 Hz, 2H), 1.90 (s, 3H), 1.10 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 400.06, 402.06, Found 399.8, 401.8.

[0458] With reference to the above procedure, compound 30.2 was synthesized by oxidation of cyclopropyl methyl ketone to the corresponding diketone followed by reaction with compound 26.1.

[0459] Compound 30.2 (i.e. NS-1052): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.48 (dd, J = 4.8, 0.9 Hz, 1H), 7.89 (td, J = 7.8, 1.9 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.35 (m, 1H), 3.13 (m, 1H), 1.92 (s, 3H), 1.09 (m, 4H). LC-MS: [M+H] + Calcd 398.04, 400.04, Found 397.8, 399.8.

[0460] Example 31. Synthesis of compounds 31.1-31.3

[0461] Sodium hydride (220 mg, 5.5 mmol) was suspended in dry tetrahydrofuran under nitrogen protection, and a solution of acetone (290 mg, 5 mmol) and ethyl formate (400 mg, 5.5 mmol) was added dropwise under ice water bath. After 1 h, the mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride solution, and extracted with methyl tert-butyl ether three times. The combined organic phase was concentrated to give the aldehyde ketone compound 31-1. Compound 31-1, compound 26.1 (160 mg, 0.5 mmol) and catalytic amount of acetic acid were dissolved in dry dichloromethane and stirred at room temperature overnight. Compound 31.1 (i.e. NS-1051) (78 mg, 65.0%) was obtained after concentration under reduced pressure and purification on silica gel column (P:E = 3:1-2:1).

[0462] Compound 31.1 (i.e. NS-1053): yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (br s, 1H), 8.49 (d, J = 4.7 Hz, 1H), 7.90 (td, J = 7.8, 1.5 Hz, 1H), 7.64 (m, 2H), 7.50 (m, 2H), 7.35 (dd, J = 7.0, 5.1 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.29 (br s, 1H), 2.05 (s, 3H), 1.86 (s, 3H). LC-MS: [M+H] +Calcd 386.03, 388.03, Found 385.8, 387.8.

[0463] According to the above procedure, ethyl formate was reacted with compound 3-methyl-2-butanone and cyclopropyl methyl ketone, respectively, to give the corresponding aldehyde ketone compounds, which were further reacted with compound 26-1 to give compounds 31.2 and 31.3.

[0464] Compound 31.2 (i.e. NS-1054): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (br s, 1H), 8.48 (d, J = 4.7 Hz, 1H), 7.90 (td, J = 7.8, 1.8 Hz, 1H), 7.62 (m, 2H), 7.49 (m, 2H), 7.35 (dd, J = 6.9, 4.8 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 5.44 (br s, 1H), 2.61 (dt, J = 13.6, 6.8 Hz, 1H), 1.86 (s, 3H), 0.94 (d, J = 6.8 Hz, 6H). LC-MS: [M+H] + Calcd 414.07, 416.07, Found 413.8, 415.8.

[0465] Compound 31.3 (i.e. NS-1055): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.90 (td, J = 7.7, 1.8 Hz, 1H), 7.69 (d, J = 13.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.50 (m, 2H), 7.35 (dd, J = 7.0, 5.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.52 (br s, 1H), 2.00 (br s, 1H), 1.87 (s, 3H), 0.75 (m, 4H). LC-MS: [M+H] + Calcd 412.06, 414.06, Found 411.8, 413.8.

[0466] Example 32. Synthesis of compounds 32.1-32.2

[0467] Compound 26.1 (96 mg, 0.3 mmol) was dissolved in 1.5 mL of triethyl orthoformate and heated to 100 °C overnight. Compound 32.1 (i.e. NS-1048) (89 mg, 79.3%) was obtained after concentration under reduced pressure and purification on a silica gel column (P:E = 4:1 ~ 3:1).

[0468] Compound 32.1 (i.e. NS-1048): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.51 (d, J = 3.9 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.50 (dd, J = 11.8, 5.3 Hz, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 7.3, 4.9 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 1.82 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 374.04, 376.04, Found 373.8, 375.8.

[0469] Referring to the above procedure, compound 26-1 and triisopropyl orthoformate were reacted to produce compound 32.2 (i.e. NS-1049).

[0470] Compound 32.2 (i.e. NS-1049): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.51 (m, 2H), 7.43 (d, J = 2.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 5.11 (hept, J = 6.2 Hz, 1H), 1.83 (s, 3H), 1.39 (d, J = 6.2 Hz, 6H). LC-MS: [M+H] + Calcd 388.06, 390.06, Found 387.8, 389.8.

[0471] Example 33. Synthesis of compound 33.1

[0472] Compound 26.1 (96 mg, 0.3 mmol) was dissolved in acetonitrile, N,N- dimethylformamide dimethyl acetal (119 mg, 1 mmol) was added, heated to 50 °C overnight reaction. Compound 33.1 (i.e. NS-1056) (71 mg, 63.4%) was obtained after concentration under reduced pressure and purification by silica gel column (P:E = 2:1 ~ 1:1).

[0473] Compound 33.1 (i.e. NS-1056): pale yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 3.9 Hz, 1H), 8.24 (s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (dd, J = 8.3, 1.6 Hz, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 6.9, 4.8 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 2.99 (s, 6H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 373.06, 375.06, Found 372.9, 374.9.

[0474] Example 34. Synthesis of compounds 34.1-34.38

[0475] Each of compounds 26.1 (169 mg, 0.5 mmol), triethyl orthoformate (318 mg, 3 mmol), and acetic acid (180 mg, 3 mmol) was dissolved in 2.5 mL of 1,2-dichloroethane, and N-methyl furfurylamine (167 mg, 1.5 mmol), N,N,N'-trimethylethylenediamine (153 mg, 1.5 mmol), N-propylbutylamine (169 mg, 1.5 mmol), N-tert-butylethylamine (152 mg, 1.5 mmol), N-methylcyclohexylamine (170 mg, 1.5 mmol), isobutylamine (110 mg, 1.5 mmol), 2-methylpyrrolidine (128 mg, 1.5 mmol), N-isopropylmethylamine (110 mg, 1.5 mmol), N-isobutylmethylamine (131 mg, 1.5 mmol), N-methyl-2-butylamine (131 mg, 1.5 mmol), N-methyl-n-propylamine (110 mg, 1.5 mmol), N-ethyl-n-propylamine (131 mg, 1.5 mmol), N-methylbutylamine (131 mg, 1.5 mmol), N-methylpentylamine (152 mg, 1.5 mmol), 2-methylaminopyridine (162 mg, 1.5 mmol), cyclopentylmethylamine (149 mg, 1.5 mmol), N-methyl-cyclopentylmethylamine (170 mg, 1.5 mmol), N-methyl-allylamine (107 mg, 1.5 mmol), N-methyl-propargylamine (104 mg, 1.5 mmol), N-methyl-2-thiazolamine (171 mg, 1.5 mmol), N-ethylmethylamine (89 mg, 1.5 mmol), tetrahydropyrrole (107 mg, 1.5 mmol), morpholine (131 mg, 1.5 mmol), N-methylpiperazine (105 mg, 1.5 mmol), (cyclopropylmethyl)methylamine (128 mg, 1.5 mmol), N-ethylisopropylamine (131 mg, 1.5 mmol), pyrrolidine-2-carboxylate methyl ester (194 mg, 1.5 mmol), azetidine (114 mg, 2 mmol), N-ethyl-n-butylamine (152 mg, 1.5 mmol), N-isopropylbutan-1-amine (173 mg, 1.5 mmol), cyclobutylamine (107 mg, 1.5 mmol), isopropylamine (62 mg, 1.5 mmol), n-propylamine (62 mg, 1.5 mmol), 2-aminothiazole (150 mg, 1.5 mmol), 3,3-dimethylazetidine hydrochloride (161 mg, 1.5 mmol), 2-phenylpyrrolidine (221 mg, 1.5 mmol), indoline (179 mg, 1.5 mmol), isoindoline (179 mg, 1.5 mmol), were added, and the reaction was heated to 70 °C overnight.Triethylamine was added to terminate the reaction and the mixture was concentrated under reduced pressure. Purification on a silica gel column (P:E = 3:1 ~ 1:1) gave compound 34.1-34.38.

[0476] Compound 34.1 (i.e. NS-1541): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 8.49 (brs, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.68 (dd, J = 1.6, 0.7 Hz, 1H), 7.46 (m, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.47 (m, 2H), 4.54 (s, 2H), 2.93 (s, 3H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 425.05, 427.05, Found 424.8, 426.8.

[0477] Compound 34.2 (i.e. NS-1542): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.7, 0.9 Hz, 1H), 8.26 (s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 7.4, 4.8 Hz, 1H), 6.89 (d, J = 7.0 Hz, 1H), 3.44 (brs, 2H), 2.99 (s, 3H), 2.43 (brs, 2H), 2.21 (s, 6H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 430.12, 432.12, Found 429.9, 431.9.

[0478] Compound 34.3 (i.e. NS-1543): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 3.9 Hz, 1H), 8.22 (s, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.47 (m, 1H), 7.44 (d, J = 4.6 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 7.3, 4.9 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.22 (m, 4H), 1.78 (s, 3H), 1.62 (brs, 4H), 1.35 (brs, 2H), 0.95 (brs, 6H). LC-MS: [M+H] + Calcd 443.14, 445.14, Found 442.9, 444.9.

[0479] Compound 34.4 (i.e. NS-1544): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.52 (d, J = 6.4 Hz, 1H), 7.82 (td, J = 7.8, 1.7 Hz, 1H), 7.46 (dd, J = 8.4 1.2 Hz, 2H), 7.36 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 7.3, 4.9 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 3.53 (dd, J = 13.9, 7.0 Hz, 2H), 1.80 (s, 3H), 1.34 (s, 9H), 1.26 (t, J = 6.9 Hz, 3H). LC-MS: [M+H] + Calcd 429.12, 431.12, Found 428.9, 430.9.

[0480] Compound 34.5 (i.e. NS-1546): off-white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.7, 0.9 Hz, 1H), 8.37 (br s, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (dd, J = 8.2, 1.6 Hz, 2H), 7.35 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.9, 0.8 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 3.28 (br s, 1H), 2.91 (s, 3H), 1.78 (m, 7H), 1.62 (d, J = 11.8 Hz, 1H), 1.53 (qd, J = 12.0, 2.8 Hz, 2H), 1.32 (dd, J = 26.0, 13.6 Hz, 2H), 1.13 (dd, J = 24.8, 12.4 Hz, 1H). LC-MS: [M+H] + Calcd 441.12, 443.12, Found 440.9, 442.9.

[0481] Compound 34.6 (i.e. NS-1556): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 4.7 Hz, 0.7H), 8.41 (d, J = 4.7 Hz, 0.3H), 8.16 (d, J = 5.0 Hz, 0.7H), 7.92 (td, J = 7.6, 1.4 Hz, 0.3H), 7.80 (m, 1H), 7.37 (m, 4.7H), 7.04 (dt, J = 13.3, 6.7 Hz, 0.3H), 6.85 (d, J = 8.2 Hz, 0.7H), 6.76 (d, J = 8.3 Hz, 0.3H), 3.08 (dd, J = 13.0, 6.4 Hz, 2H), 1.99 (br s, 0.7H), 1.83 (s, 0.9H), 1.78 (s, 2.1H), 1.66 (m, 0.3H), 0.97 (d, J = 6.6 Hz, 4.2H), 0.85 (d, J = 6.7 Hz, 1.8H). LC-MS: [M+H] + Calcd 401.09, 403.09, Found 400.8, 402.8.

[0482] Compound 34.7 (i.e. NS-1560): pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.4 Hz, 1H), 8.42 (s, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.44 (dd, J = 8.0, 1.2 Hz, 2H), 7.35 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 7.4, 4.9 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 3.88 (br s, 1H), 3.45 (t, J = 6.6 Hz, 2H), 2.09 (dt, J = 14.0, 7.2 Hz, 1H), 1.99 (m, 1H), 1.89 (m, 1H), 1.78 (d, J = 1.9 Hz, 3H), 1.59 (m, 1H), 1.24 (d, J = 5.4 Hz, 3H). LC-MS: [M+H] + Calcd 413.09, 415.09, Found 412.8, 414.8.

[0483] Compound 34.8 (i.e. NS-1564): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 8.35 (s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (m, 2H), 7.35 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 7.5, 4.8 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 3.74 (s, 1H), 2.87 (s, 3H), 1.78 (s, 3H), 1.21 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 401.09, 403.09, Found 400.8, 402.8.

[0484] Compound 34.9 (i.e. NS-1565): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 8.24 (s, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 6.88 (br s, 1H), 3.09 (br s, 2H), 2.97 (s, 3H), 1.95 (br s, 1H), 1.78 (s, 3H), 0.89 (br s, 6H). LC-MS: [M+H] +Calcd 415.11, 417.11, Found 414.9, 416.9.

[0485] Compound 34.10 (i.e. NS-1566): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 4.0 Hz, 1H), 8.32 (br s, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (dd, J = 8.2, 1.9 Hz, 2H), 7.36 (d, J = 1.4 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 3.43 (br s, 1H), 2.84 (s, 3H), 1.78 (s, 3H), 1.53 (m, 2H), 1.19 (d, J = 6.7 Hz, 3H), 0.85 (br s, 3H). LC-MS: [M+H] + Calcd 415.11, 417.11, Found 414.9, 416.9.

[0486] Compound 34.11 (i.e. NS-1567): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.7, 0.8 Hz, 1H), 8.26 (s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (dd, J = 8.3, 2.1 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.31 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 3.27 (br s, 2H), 2.96 (s, 3H), 1.78 (s, 3H), 1.60 (br s, 2H), 0.89 (br s, 3H). LC-MS: [M+H] + Calcd 401.09, 403.09, Found 400.9, 402.9.

[0487] Compound 34.12 (i.e. NS-1569): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.53 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 8.22 (s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 3.37 (brs, 4H), 1.78 (s, 3H), 1.62 (brs, 2H), 1.20 (brs, 3H), 0.91 (brs, 3H). LC-MS: [M+H] + Calcd 415.11, 417.11, Found 414.9, 416.9.

[0488] Compound 34.13 (i.e. NS-1572): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.7, 0.7 Hz, 1H), 8.26 (brs, 1H), 7.81 (td, J = 7.8, 1.7 Hz, 1H), 7.45 (dd, J = 7.7, 2.8 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 7.4, 4.8 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 2.96 (s, 3H), 1.78 (s, 3H), 1.56 (brs, 2H), 1.32 (brs, 2H), 0.94 (brs, 3H). LC-MS: [M+H] + Calcd 415.11, 417.11, Found 414.9, 416.9.

[0489] Compound 34.14 (i.e. NS-1573, DA-1091): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 8.25 (s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (dd, J = 8.1, 2.4 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 6.88 (d, J = 7.4 Hz, 1H), 3.29 (brs, 2H), 2.96 (s, 3H), 1.78 (s, 3H), 1.57 (brs, 2H), 1.30 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H). LC-MS: [M+H] +Calcd 429.12, 431.12, Found 428.9, 430.9.

[0490] Compound 34.15 (i.e. NS-1575): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.52 (d, J = 4.7 Hz, 1H), 8.35 (d, J = 4.7 Hz, 1H), 7.86 (qd, J = 8.0, 1.2 Hz, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 8.3, 1.9 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 7.33 (dd, J = 7.5, 4.8 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.13 (dd, J = 7.1, 4.8 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 3.52 (s, 3H), 1.85 (s, 3H). LC-MS: [M+H] + Calcd 436.07, 438.07, Found 435.8, 437.8.

[0491] Compound 34.16 (i.e. NS-1576): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (m, 1H), 8.35 (br s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (dd, J = 8.0, 1.2 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 6.8, 4.8 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 3.99 (br s, 1H), 2.90 (s, 3H), 1.83 (m, 2H), 1.78 (s, 3H), 1.64 (m, 6H). LC-MS: [M+H] + Calcd 427.11, 429.11, Found 426.9, 428.9.

[0492] Compound 34.17 (i.e. NS-1577): off-white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.7, 0.8 Hz, 1H), 8.27 (s, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 7.1, 5.1 Hz, 1H), 6.89 (d, J = 6.5 Hz, 1H), 3.21 (brs, 2H), 2.98 (s, 3H), 2.23 (brs, 1H), 1.79 (s, 3H), 1.63 (m, 6H), 1.20 (brs, 2H). LC-MS: [M+H] + Calcd 441.12, 443.12, Found 440.9, 442.9.

[0493] Compound 34.18 (i.e. NS-1578): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.7, 0.8 Hz, 1H), 8.33 (s, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 7.5, 4.8 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 5.88 (m, 1H), 5.28 (d, J = 11.4 Hz, 1H), 5.25 (d, J = 3.5 Hz, 1H), 3.95 (s, 2H), 2.95 (s, 3H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 399.07, 401.07, Found 398.8, 400.8.

[0494] Compound 34.19 (i.e. NS-1579): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 8.41 (s, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.46 (m, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 4.24 (d, J = 2.0 Hz, 2H), 3.38 (s, 1H), 3.01 (s, 3H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 397.06, 399.06, Found 396.8, 398.8.

[0495] Compound 34.20 (i.e. NS-1580): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 7.86 (td, J = 7.8, 1.9 Hz, 1H), 7.55 (m, 3H), 7.45 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 3.5 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 3.63 (s, 3H), 1.86 (s, 3H). LC-MS: [M+H] + Calcd 442.03, 444.03, Found 441.8, 443.8.

[0496] Compound 34.21 (i.e. NS-1582): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.8, 0.9 Hz, 0H), 8.27 (s, 0H), 7.81 (td, J = 7.8, 1.8 Hz, 0H), 7.45 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 1.9 Hz, 0H), 7.32 (dd, J = 6.7, 4.8 Hz, 0H), 6.90 (d, J = 8.3 Hz, 0H), 3.38 (br s, 1H), 2.97 (s, 3H), 1.79 (s, 3H), 1.17 (t, J = 6.7 Hz, 1H). LC-MS: [M+H] + Calcd 387.07, 389.07, Found 386.8, 388.8.

[0497] Compound 34.22 (i.e. NS-1585): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 8.43 (s, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.44 (dd, J = 8.1, 1.5 Hz, 2H), 7.35 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 3.43 (br s, 4H), 1.92 (br s, 4H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 399.07, 401.07, Found 398.8, 400.8.

[0498] Compound 34.23 (i.e. NS-1586): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 8.37 (s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (dd, J = 8.3, 2.1 Hz, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 3.68 (m, 4H), 3.48 (br s, 4H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 415.07, 417.07, Found 414.8, 416.8.

[0499] Compound 34.24 (i.e. NS-1591): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 8.31 (s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (dd, J = 8.2, 1.9 Hz, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.46 (br s, 4H), 2.39 (m, 4H), 2.25 (s, 3H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 428.10, 430.10, Found 427.9, 429.9.

[0500] Compound 34.25 (i.e. NS-1595): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 1.0 Hz, 1H), 8.29 (s, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 3.17 (br s, 2H), 3.03 (s, 3H), 1.78 (s, 3H), 1.06 (br s, 1H), 0.53 (d, J = 7.8 Hz, 2H), 0.28 (br s, 2H). LC-MS: [M+H] +Calcd 413.09, 415.09, Found 412.8, 414.8.

[0501] Compound 34.26 (i.e. NS-1599): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.8, 0.9 Hz, 1H), 8.26 (s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 3.72 (brs, 1H), 3.39 (brs, 2H), 1.79 (s, 3H), 1.24 (d, J = 6.4 Hz, 9H). LC-MS: [M+H] + Calcd 415.11, 417.11, Found 414.9, 416.9.

[0502] Compound 34.27 (i.e. NS-1639): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.52 (t, J = 4.4 Hz, 1H), 7.82 (td, J = 7.8, 1.7 Hz, 1H), 7.48 (dd, J = 11.9, 5.2 Hz, 2H), 7.37 (m, 1H), 7.32 (ddd, J = 7.2, 4.7, 2.4 Hz, 1H), 6.78 (brs, 1H), 4.41 (brs, 1H), 3.73 (s, 3H), 3.59 (brs, 2H), 2.35 (brs, 1H), 1.96 (brs, 3H), 1.79 (d, J = 5.6 Hz, 3H). LC-MS: [M+H] + Calcd 457.08, 459.08, Found 456.8, 458.8.

[0503] Compound 34.28 (i.e. NS-1645): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 8.24 (s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 4.09 (t, J = 7.6 Hz, 4H), 2.41 (m, 2H), 1.77 (s, 3H). LC-MS: [M+H] + Calcd 385.06, 387.06, Found 384.8, 386.8.

[0504] Compound 34.29 (i.e. NS-1649): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 2.0, 0.8 Hz, 1H), 8.21 (br s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (m, 1H), 7.45 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 3.40 (br s, 2H), 3.28 (br s, 2H), 1.58 (m, 2H), 1.33 (br s, 2H), 1.20 (br s, 3H), 0.94 (br s, 3H). LC-MS: [M+H] + Calcd 429.12, 431.12, Found 428.9, 430.9.

[0505] Compound 34.30 (i.e. NS-1650): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 2.0, 0.8 Hz, 1H), 8.29 (br s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (m, 1H), 7.45 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.67 (br s, 0.5H), 3.31 (br s, 2.5H), 1.67 (br s, 2H), 1.36 (dd, J = 13.5, 6.7 Hz, 2H), 1.23 (d, J = 4.7 Hz, 6H), 0.96 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 443.14, 445.14, Found 442.9, 444.9.

[0506] Compound 34.31 (i.e. NS-1651): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 2.0, 0.8 Hz, 1H), 8.29 (br s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (m, 1H), 7.45 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.67 (br s, 0.5H), 3.31 (br s, 2.5H), 1.67 (br s, 2H), 1.36 (dd, J = 13.5, 6.7 Hz, 2H), 1.23 (d, J = 4.7 Hz, 6H), 0.96 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 399.07, 401.07, Found 498.8, 400.8.

[0507] Compound 34.32 (i.e. NS-1652): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 8.41 (dd, J = 4.9, 1.0 Hz, 0.15H), 8.06 (d, J = 4.6 Hz, 1H), 7.93 (td, J = 7.8, 1.8 Hz, 0.15H), 7.81 (m, 1.15H), 7.54 (d, J = 12.7 Hz, 0.15H), 7.46 (m, 2.15H), 7.39 (dd, J = 8.2, 2.0 Hz, 0.15H), 7.36 (m, 1.15H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.17 (brs, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.75 (d, J = 8.2 Hz, 0.15H), 6.67 (dd, J = 12.6, 7.8 Hz, 0.15H), 3.96 (s, 0.75H), 3.67 (m, 0.1H), 3.12 (m, 0.15H), 1.83 (s, 0.45H), 1.78 (s, 3H), 1.23 (d, J = 6.5 Hz, 6H), 1.17 (d, J = 6.5 Hz, 0.9H). LC-MS: [M+H] + Calcd 387.07, 389.07, Found 386.9, 388.9.

[0508] Compound 34.33 (i.e. NS-1654): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.7, 1.7, 0.7 Hz, 1H), 8.42 (dd, J = 4.8, 0.9 Hz, 0.5H), 8.15 (d, J = 5.4 Hz, 1H), 7.92 (td, J = 7.8, 1.8 Hz, 0.5H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.45 (ddd, J = 6.4, 5.6, 4.1 Hz, 3H), 7.40 (dd, J = 8.2, 2.0 Hz, 0.5H), 7.32 (m, 2.5H), 7.26 (br s, 0.5H), 7.03 (m, 0.5H), 6.87 (d, J = 8.3 Hz, 1H), 6.74 (d, J = 8.2 Hz, 0.5H), 3.20 (dd, J = 12.8, 6.5 Hz, 3H), 1.83 (s, 1.5H), 1.78 (s, 3H), 1.63 (dd, J = 13.5, 6.3 Hz, 2H), 1.46 (h, J = 7.1 Hz, 1H), 0.97 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.4 Hz, 1.5H). LC-MS: [M+H] + Calcd 387.07, 389.07, Found 386.9, 388.9.

[0509] Compound 34.34 (i.e. NS-1655): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (br s, 1H), 8.51 (dd, J = 4.7, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.55 (dd, J = 8.3, 1.9 Hz, 2H), 7.51 (d, J = 3.6 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.34 (t, J = 5.0 Hz, 3H), 7.20 (d, J = 8.3 Hz, 1H), 1.85 (s, 3H). LC-MS: [M+H] + Calcd 428.01, 430.01, Found 427.8, 429.8.

[0510] Compound 34.35 (i.e. NS-1656): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.7, 0.9 Hz, 1H), 8.31 (s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (dd, J = 8.2, 1.5 Hz, 2H), 7.35 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 7.5, 4.8 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 3.76 (s, 4H), 1.77 (s, 3H), 1.31 (s, 6H). LC-MS: [M+H] + Calcd 413.09, 415.09, Found 412.8, 414.8.

[0511] Compound 34.36 (i.e. NS-1689): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (t, J = 4.8 Hz, 1H), 8.39 (br s, 1H), 7.78 (ddd, J = 9.2, 3.0, 1.5 Hz, 1H), 7.40 (m, 4H), 7.30 (m, 5H), 4.96 (m, 1H), 3.67 (m, 2H), 2.39 (br s, 1H), 1.98 (m, 2H), 1.85 (dt, J = 17.8, 6.0 Hz, 1H), 1.73 (d, J = 2.9 Hz, 3H). LC-MS: [M+H] + Calcd 475.11, 477.11, Found 474.9, 476.9.

[0512] Compound 34.37 (i.e. NS-1690): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.54 (dd, J = 4.7, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.33 (m, 3H), 7.19 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 4.10 (t, J = 8.6 Hz, 2H), 3.24 (t, J = 8.5 Hz, 2H), 1.84 (s, 3H). LC-MS: [M+H] + Calcd 447.07, 449.07, Found 446.9, 448.9.

[0513] Compound 34.38 (i.e. NS-1698): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.53 (dd, J = 4.8, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (m, 2H), 7.43 (br s, 2H), 7.38 (d, J = 1.9 Hz, 1H), 7.35 (m, 2H), 7.32 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 4.82 (br s, 4H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 447.07, 449.07, Found 446.8, 448.8.

[0514] Example 35. Synthesis of compounds 35.1-35.9

[0515] Compound 26.1 (169 mg, 0.5 mmol), triethyl orthoformate (318 mg, 3 mmol) and acetic acid (180 mg, 3 mmol) were dissolved in 2.5 ml 1,2-dichloroethane, sec-butylamine (110 mg, 1.5 mmol) was added and heated to 70 °C overnight. The reaction was terminated with triethylamine and concentrated under reduced pressure. Purification on silica gel column (P:E = 3:1-1:1) gave compound 35-1 (171 mg, 85.3%).

[0516] Compound 35-1 (171 mg, 0.43 mmol) and iodo-propane (87 mg, 0.51 mmol) were dissolved in 2 mL dry DMF under nitrogen protection. Sodium hydride (21 mg, 0.51 mmol) was added portionwise under ice-water bath. The mixture was incubated for 1 hour and slowly warmed to room temperature. The reaction was terminated with saturated aqueous ammonium chloride solution and extracted with methyl tert-butyl ether three times. The organic phase was combined and concentrated under reduced pressure. Purification on silica gel column (P:E = 4:1-3:1) gave compound 35.1 (i.e. NS-1545) (78 mg, 65.0%).

[0517] Compound 35.1 (i.e. NS-1545): pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.7 Hz, 1H), 8.24 (d, J = 2.6 Hz, 1H), 7.81 (td, J = 7.7, 1.7 Hz, 1H), 7.46 (m, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 7.4, 4.9 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 3.26 (br s, 3H), 1.79 (s, 3H), 1.62 (m, 4H), 1.22 (m, 3H), 0.92 (m, 6H). LC-MS: [M+H] + Calcd 443.14, 445.14, Found 442.9, 444.9.

[0518] Referring to the above reaction, compound 26.1 is reacted with (R)-sec-butylamine, followed by methylation to obtain compound 35.2.

[0519] Compound 35.2 (i.e., NS-1553): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.6 Hz, 1H), 8.32 (d, J = 4.6 Hz, 0.8H), 8.20 (br s, 0.2H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (dd, J = 8.3, 1.9 Hz, 2H), 7.36 (d, J = 1.8 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.90 (d, J = 8.0 Hz, 0.8H), 6.83 (br s, 0.2H), 3.44 (br s, 1H), 2.84 (s, 3H), 1.78 (s, 3H), 1.54 (m, 2H), 1.19 (d, J = 6.7 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 415.11, 417.11, Found 414.9, 416.9.

[0520] Referring to the above reaction, compound 26.1 is reacted with (R)-sec-butylamine, followed by methylation to obtain compound 35.2.

[0521] Compound 35.3 (i.e., NS-1570): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 1.0 Hz, 1H), 8.28 (s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (m, 1H), 7.45 (m, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 3.68 (s, 1H), 3.27 (s, 2H), 1.79 (s, 3H), 1.70 (s, 2H), 1.23 (d, J = 5.7 Hz, 6H), 0.94 (t, J = 7.0 Hz, 3H). LC-MS: [M+H] + Calcd 429.12, 431.12, Found 428.9, 430.9.

[0522] Compound 35.4 (i.e. NS-1574): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 8.28 (br s, 0.75H), 8.19 (br s, 0.25H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.87 (br s, 1H), 3.41 (br s, 0.5H), 3.30 (br s, 1.5H), 2.95 (s, 3H), 1.77 (s, 3H), 1.51 m, 3H), 0.92 (s, 6H). LC-MS: [M+H] + Calcd 429.12, 431.12, Found 428.9, 430.9.

[0523] Compound 35.5 (i.e. NS-1592): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 ddd, J = 4.8, 2.0, 0.8 Hz, 1H), 8.43 (s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 2.98 (s, 3H), 2.82 (m, 1H), 1.79 (s, 3H), 0.74 (m, 4H). LC-MS: [M+H] +Calcd 399.07, 401.07, Found 398.8, 400.8.

[0524] Compound 35.6 (i.e. NS-1593): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.7 Hz, 1H), 8.34 (s, 1H), 7.81 (td, J = 7.8, 1.6 Hz, 1H), 7.44 (m, 2H), 7.36 (d, J = 1.7 Hz, 1H), 7.31 (dd, J = 7.5, 4.8 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 4.13 (s, 1H), 3.35 (s, 3H), 2.23 (m, 2H), 2.12 (dd, J = 16.1, 7.9 Hz, 2H), 1.78 (s, 3H), 1.65 (m, 2H). LC-MS: [M+H] + Calcd 413.09, 415.09, Found 412.8, 414.8.

[0525] Compound 35.7 (i.e. NS-1596): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.7, 0.9 Hz, 1H), 8.30 (s, 0.75H), 8.21 (br s, 0.25H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 ((ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.88 (d, J = 7.9 Hz, 1H), 3.48 (br s, 0.5H), 3.30 (br s, 1.5H), 2.94 (s, 3H), 2.61 (s, 1H), 2.02 (s, 2H), 1.84 (m, 7H). LC-MS: [M+H] + Calcd 427.11, 429.11, Found 426.9, 428.9.

[0526] Compound 35.8 (i.e. NS-1684): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 8.34 (br s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (m, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 3.62 (br s, 2H), 3.01 (br s, 3H), 2.69 (br s, 2H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 455.06, 457.06, Found 454.8, 456.8.

[0527] Compound 35.9 (i.e. NS-1685): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 8.29 (s, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (dd, J = 8.2, 2.0 Hz, 2H), 7.36 (d, J = 2.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.90 (d, J = 5.9 Hz, 1H), 3.40 (br s, 2H), 2.98 (br s, 3H), 2.30 (br s, 2H), 1.82 (br s, 2H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 469.08, 471.08, Found 468.8, 470.8.

[0528] Example 36. Synthesis of compound 36.1

[0529] Compound 26.1 (96 mg, 0.3 mmol) and 1-octen-3-one (76 mg, 0.6 mmol) were dissolved in dichloromethane, potassium carbonate (124 mg, 0.9 mmol), iodobenzene diacetate (145 mg, 0.45 mmol) were added, stirred at room temperature overnight. Compound 36.1 (i.e. NS-767) (68 mg, 51.3%) was obtained after silica gel column purification (P:E = 4:1 ~ 3:1) under reduced pressure.

[0530] Compound 36.1 (i.e. NS-767): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.5 Hz, 1H), 7.82 (td, J = 7.8, 1.6 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 1H), 7.46 (dd, J = 7.8, 5.1 Hz, 1H), 7.41 (dd, J = 11.6, 2.0 Hz, 1H), 7.32 (dd, J = 7.4, 4.8 Hz, 1H), 7.03 (dd, J = 8.3, 3.1 Hz, 1H), 3.47 (m, 1H), 3.00 (dd, J = 13.3, 7.2 Hz, 1H), 2.88 (d, J = 5.4 Hz, 1H), 2.66 (t, J = 7.1 Hz, 2H), 1.76 (s, 3H), 1.56 (m, 2H), 1.29 (m, 4H), 0.88 (td, J = 6.9, 3.1 Hz, 3H). LC-MS: [M+H] + Calcd 442.11, 444.11, Found 441.9, 443.9.

[0531] Example 37. Synthesis of compounds 37.1-37.3

[0532] Compound 26.1 (159 mg, 0.5 mmol) and glyoxylic acid (37 mg, 0.5 mmol) were dissolved in dichloroethane, and a catalytic amount of acetic acid was added, and stirred at room temperature overnight. After concentration under reduced pressure, it was dried under vacuum overnight to obtain the crude product of compound 37-1. Compound 37-1 was dissolved in dry dichloromethane under nitrogen protection, and dichlorosulfoxide (300 mg, 5 mmol) and a catalytic amount of DMF were added under ice water bath, and after incubation for 4 hours, the solvent was removed under reduced pressure to obtain the crude product of acyl chloride.

[0533] The crude product was redissolved in dry dichloromethane, and the redissolved acyl chloride solution was slowly added dropwise into a dimethylamine (0.5 mL, 4M) solution in tetrahydrofuran under ice water bath under nitrogen protection. The solvent was removed under reduced pressure, and compound 37.1 (i.e. NS-1060) was obtained after purification by silica gel column (P:E = 2:1)

[0534] Compound 37.1 (i.e. NS-1060): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.49 (dd, J = 4.8, 0.9 Hz, 1H), 7.88 (td, J = 7.8, 1.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 3.20 (s, 3H), 2.99 (s, 3H), 1.89 (s, 3H). LC-MS: [M+H] + Calcd 401.05, 403.05, Found 400.8, 402.8.

[0535] Referring to the above example, the acyl chloride solution was reacted with methylpropylamine and N-methylcyclopropylamine respectively to give compounds 37.2 and 37.3.

[0536] Compound 37.2 (i.e. NS-1096): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 0.55H), 9.38 (s, 0.45H), 8.49 (d, J = 3.9 Hz, 1H), 7.88 (td, J = 7.9, 1.7 Hz, 1H), 7.63 (br s, 0.55H), 7.62 (br s, 0.45H), 7.57 (m, 1H), 7.51 (br s, 1H), 7.35 (dd, J = 7.5, 4.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 0.45H), 7.15 (d, J = 8.4 Hz, 0.55H), 3.48 (m, 1H), 3.40 (m, 1H), 3.18 (s, 1.35H), 2.98 (s, 1.65H), 1.89 (s, 3H), 1.63 (m, 2H), 0.89 (m, 3H). LC-MS: [M+H] + Calcd 429.08, 431.08, Found 428.9, 430.9.

[0537] Compound 37.3 (i.e. NS-1097): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 0.55H), 9.39 (s, 0.45H), 8.49 (m, 1H), 7.88 (td, J = 7.8, 1.8 Hz, 1H), 7.64 (br s, 0.55H), 7.62 (br s, 0.45H), 7.57 (t, J = 2.0 Hz, 0.45H), 7.55 (t, J = 2.0 Hz, 0.55H), 7.51 (d, J = 1.9 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.21 (d, J = 8.4 Hz, 0.45H), 7.17 (d, J = 8.4 Hz, 0.55H), 3.43 (dd, J = 6.8, 1.5 Hz, 1H), 3.34 (d, J = 5.5 Hz, 1H), 3.26 (s, 1.35H), 3.05 (s, 1.65H), 1.09 (m, 1H), 0.54 (m, 2H), 0.30 (m, 2H). LC-MS: [M+H] + Calcd 441.08, 443.08, Found 440.9, 442.9.

[0538] Example 38. Synthesis of compounds 38.1-38.8

[0539] Compound 28.1 (112 mg, 0.3 mmol) was dissolved in anhydrous methanol, cooled to 0 °C under nitrogen protection, sodium borohydride (23 mg, 0.6 mmol) was added in portions, 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 for three times, and the organic phases were combined. Compound 38.1 (78 mg, 69.5%) was obtained after concentration under reduced pressure and purification by silica gel column (P:E = 2:1-1:1).

[0540] Compound 38.1 (i.e. NS-763): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.49 (dd, J = 8.3, 2.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.04 (t, J = 5.5 Hz, 1H), 2.80 (m, 2H), 1.76 (s, 3H), 1.70 (m, 1H), 0.98 (d, J = 4.6 Hz, 3H), 0.96 (d, J = 4.6 Hz, 3H). LC-MS: [M+H] + Calcd 374.08,376.08,Found 373.8,375.8.

[0541] Compound 37.1 (i.e. NS-1060), compound 28.2 (i.e. NS-1041), compound 29.2 (i.e. NS-1047), compound 37.2 (i.e. NS-1096), compound 37.3 (i.e. NS-1097) were reduced by sodium borohydride to give compounds 38.2-38.6, respectively, according to the above described Example.

[0542] Compound 38.2 (i.e. NS-785): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (m, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.16 (t, J = 4.8 Hz, 1H), 3.87 (d, J = 4.8 Hz, 2H), 2.99 (s, 3H), 2.84 (s, 3H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 403.07,405.07,Found 402.8,404.8.

[0543] Compound 38.3 (i.e. NS-1069): light yellow transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (m, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.16 (t, J = 4.5 Hz, 1H), 2.86 (dd, J = 6.9, 4.5 Hz, 2H), 1.76 (s, 3H), 0.91 (m, 1H), 0.36 (m, 2H), 0.11 (m, 2H). LC-MS: [M+H] + Calcd 372.06, 374.06, Found 371.8, 373.8.

[0544] Compound 38.4 (i.e. NS-1072): pale yellow clear syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.47 (dd, J = 8.3, 2.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.31 (ddd, J = 7.5, 4.9, 0.7 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.11 (t, J = 4.4 Hz, 1H), 3.46 (dt, J = 12.2, 5.8 Hz, 3H), 3.14 (m, 2H), 1.76 (s, 3H), 0.99 (dd, J = 8.1, 6.1 Hz, 6H). LC-MS: [M+H] + Calcd 404.09, 406.09, Found 403.8, 405.8.

[0545] Compound 38.5 (i.e. NS-1094): pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.6 Hz, 1H), 7.80 (m, 1H), 7.47 (dt, J = 8.3, 1.7 Hz, 1H), 7.43 (dd, J = 8.0, 0.9 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.15 (t, J = 4.8 Hz, 1H), 3.88 (d, J = 4.8 Hz, 2H), 3.24 (dd, J = 8.1, 6.6 Hz, 2H), 2.96 (s, 1.67H), 2.82 (s, 1.33H), 1.76 (s, 3H), 1.55 (m, 0.89H), 1.45 (dt, J = 14.7, 7.3 Hz, 1.11H), 0.85 (t, J = 7.4 Hz, 1.33H), 0.82 (t, J = 8.7 Hz, 1.67H). LC-MS: [M+H] + Calcd 431.10, 433.10, Found 430.9, 432.9.

[0546] Compound 38.6 (i.e. NS-1095): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (t, J = 4.4 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.47 (dd, J = 8.3, 1.7 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.32 (dd, J = 7.3, 5.0 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.16 (q, J = 4.5 Hz, 1H), 3.89 (d, J = 4.6 Hz, 2H), 3.21 (d, J = 6.3 Hz, 0.8H), 3.18 (d, J = 6.9 Hz, 1.2H), 3.04 (s, 1.8H), 2.90 (s, 1.2H), 1.77 (s, 3H), 0.95 (m, 1H), 0.50 (m, 0.8H), 0.43 (m, 1.2H), 0.26 (m, J = 5.1 Hz, 0.8H), 0.21 (m, J = 5.2 Hz, 1.2H). LC-MS: [M+H] + Calcd 429.08, 431.08, Found 428.9, 430.9.

[0547] Compound 38-2 was prepared by the reaction of ethylene glycol methyl ether, which was oxidized by Dess-Martin reagent to give compound 38-1, with compound 26.1 in the presence of catalytic acetic acid according to the procedure described in Reference Example 29;

[0548] Compound 38.7 was prepared by the reduction of compound 38-2 with sodium borohydride according to the procedure described in Reference Example 29.

[0549] Compound 38.7 (i.e. NS-1073): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.31 (m, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.12 (t, J = 4.7 Hz, 1H), 3.45 (t, J = 5.5 Hz, 2H), 3.20 (s, 3H), 3.15 (td, J = 5.3, 1.5 Hz, 2H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 376.06, 378.06, Found 375.8, 377.8.

[0550] Compound 38.8 was prepared by the reaction of the aldehyde, which was prepared by the oxidation of epoxypropanol, with compound 26.1 to give imine, followed by reduction with sodium borohydride according to the procedure described in Reference Example 29.

[0551] Compound 38.8 (i.e. NS-1074): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.31 (m, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.12 (t, J = 4.7 Hz, 1H), 3.45 (t, J = 5.5 Hz, 2H), 3.20 (s, 3H), 3.15 (td, J = 5.3, 1.5 Hz, 2H), 1.76 (s, 3H). LC-MS: [M+H] +Calcd 374.04,376.04,Found 373.8,375.8.

[0552] Example 39. Synthesis of compound 39.1

[0553] Compound 31.3 (i.e. NS-1055) (206 mg, 0.5 mmol) was dissolved in anhydrous methanol, cooled to 0 °C under nitrogen protection, sodium borohydride (76 mg, 2 mmol) was added in portions, 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 for three times, and the organic phases were combined. The crude hydroxyl compound 39-1 was obtained by concentration under reduced pressure. The crude compound 39-1 was stirred with Dess-martin (509 mg, 1.2 mmol) reagent in 5 mL of dry dichloromethane overnight, filtered through celite after the addition of 20 mL of ethyl acetate, and the filtrate was concentrated under reduced pressure. Compound 39.1 (103 mg, 49.8%) was obtained by silica gel column purification (P:E = 1:1 ~ 1:2).

[0554] Compound 39.1 (i.e. NS-1063): yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (dd, J = 8.2, 1.5 Hz, 2H), 7.37 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 7.1, 5.2 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.13 (t, J = 5.2 Hz, 1H), 3.23 (dd, J = 11.9, 6.4 Hz, 2H), 2.80 (t, J = 6.6 Hz, 2H), 2.02 (m, 1H), 1.77 (s, 3H), 0.85 (m, 4H). LC-MS: [M+H] + Calcd 414.07,416.07,Found 413.8,415.8.

[0555] Example 40. Synthesis of compound 40.1

[0556] Under nitrogen protection, sodium hydride (220 mg, 5.5 mmol) was suspended in a dry tetrahydrofuran solution in an ice-water bath. A mixture of ethyl acetate (440 mg, 5 mmol) and ethyl formate (400 mg, 5.5 mmol) was added dropwise. The mixture was kept at this temperature for 1 hour, then slowly raised to room temperature and stirred overnight. The reaction was terminated with a saturated ammonium chloride aqueous solution. The mixture was extracted three times with methyl ether, and the organic phases were combined and concentrated to obtain crude ketone ester compound 40-1. Compound 40-1, 26.1 (160 mg, 0.5 mmol), and a catalytic amount of acetic acid were stirred overnight at room temperature. The mixture was purified by silica gel column chromatography under reduced pressure (P:E = 3:1–2:1) to obtain compound 40-2 (141 mg, 67.8%). Compound 40-2 was dissolved in dry tetrahydrofuran, cooled to 0°C under nitrogen protection, and sodium borohydride (76 mg, 2 mmol) was added in portions. The mixture was slowly raised to room temperature and stirred continuously for 16 hours. Under ice-water bath conditions, an aqueous solution of ammonium chloride was added. The aqueous phase was washed three times with dichloromethane, and the organic phases were combined. After purification by silica gel column chromatography under reduced pressure (P:E = 1:1 to 1:2), compound 40.1 (87 mg, 61.4%) was obtained.

[0557] Compound 40.1 (i.e., NS-1064): pale yellow syrup. 1 H NMR (400MHz, DMSO-d6) δ8.47 (dd, J=4.8, 0.9Hz, 1H), 7.83 (td, J=7.8, 1.9Hz, 1H ),7.47(m,2H),7.36(d,J=1.9Hz,1H),7.31(ddd,J=7.5,4.8,0.9Hz,1H),7.01(d ,J=8.3Hz,1H),6.23(t,J=5.0Hz,1H),4.05(m,2H),3.25(dd,J=11.7,6.5Hz,2H) ,2.55(dd,J=11.7,6.5Hz,2H),1.77(s,3H),1.18(t,J=7.1Hz,3H).LC-MS:[M+H] + Calcd 418.07,420.07,Found 417.8,419.8.

[0558] Example 41. Synthesis of compound 41.1

[0559] Compound 26.1 (580 mg, 1.83 mmol), 1,5-dibromopentane (1.684 g, 7.32 mmol), tetrabutylammonium iodide (738 mg, 2 mmol) and potassium carbonate (1.01 g, 7.32 mmol) in dry DMF were stirred at room temperature for 70 h, saturated solution of ammonium chloride was added and the mixture was extracted with ethyl acetate, the organic phase was combined and concentrated under reduced pressure, compound 41.1 (36 mg, 5.1%) was obtained after purification on silica gel column (P:E = 3:1 to 2:1).

[0560] Compound 41.1 (i.e. NS-1075): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 4.6 Hz, 1H), 7.81 (td, J = 7.7, 1.4 Hz, 1H), 7.48 (dd, J = 8.3, 1.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 (m, 2H), 7.03 (d, J = 8.3 Hz, 1H), 3.54 (m, 2H), 3.07 (br s, 2H), 1.67 (m, 8H), 1.23 (m, 1H). LC-MS: [M+H] + Calcd 386.08, 388.08, Found 385.8, 387.8.

[0561] Example 42. Synthesis of compounds 42.1-42.24

[0562] Compounds 42.1-42.24 were synthesized according to Examples 1, 2, 4 and 7.

[0563] Compound 42.1 (i.e. NS-706): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.2 Hz, 1H), 7.79 (td, J = 7.8, 1.7 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.1, 5.2 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.06 (s, 1H), 6.91 (d, J = 7.9 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 2.24 (d, J = 10.3 Hz, 3H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 326.14, Found 326.1.

[0564] Compound 42.2 (i.e. NS-707): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 7.1, 5.2 Hz, 1H), 7.13 (m, 2H), 7.02 (s, 1H), 4.94 (s, 2H), 3.03 (s, 3H), 2.86 (s, 3H), 2.24 (s, 3H), 1.77 (s, 3H). LC-MS: [M+H] + Calcd 340.16, Found 340.2.

[0565] Compound 42.3 (i.e. NS-708): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.0 Hz, 1H), 7.78 (td, J = 7.8, 1.8 Hz, 1H), 7.33 (m, 2H), 7.14 (m, 1H), 6.62 (dd, J = 6.7, 2.2 Hz, 2H), 3.78 (s, 3H), 3.15 (s, 3H), 2.99 (s, 3H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 342.14, Found 342.1.

[0566] Compound 42.4 (i.e. NS-709): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 7.1, 5.2 Hz, 1H), 7.13 (m, 2H), 7.02 (s, 1H), 4.94 (s, 2H), 3.03 (s, 3H), 2.86 (s, 3H), 2.24 (s, 3H), 1.77 (s, 3H). LC-MS: [M+H] + Calcd 356.15, Found 356.1.

[0567] Compound 42.5 (i.e. NS-710): off-white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.0 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.33 (m, 2H), 7.26 (d, J = 7.0 Hz, 1H), 7.09 (td, J = 7.6, 0.9 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 3.16 (s, 3H), 2.99 (s, 3H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 312.13, Found 312.1.

[0568] Compound 42.6 (i.e. NS-711): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.7, 0.9 Hz, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (m, 2H), 7.22 (dd, J = 11.6, 7.3 Hz, 2H), 7.06 (td, J = 7.5, 0.9 Hz, 1H), 4.97 (s, 2H), 3.03 (s, 3H), 2.86 (s, 3H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 326.14, Found 326.1.

[0569] Compound 42.7 (i.e. NS-712): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.2 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.23 (dd, J = 8.3, 2.5 Hz, 1H), 7.17 (m, 1H), 7.07 (dd, J = 8.5, 4.3 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 1.83 (s, 3H). LC-MS: [M+H] + Calcd 330.12, Found 330.1.

[0570] Compound 42.8 (i.e. NS-713): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.29 (ddd, J = 7.5, 4.5, 1.2 Hz, 1H), 7.19 (m, 2H), 4.97 (s, 2H), 3.00 (s, 3H), 2.86 (s, 3H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 344.13, Found 344.1.

[0571] Compound 42.9 (i.e. NS-714, NS-382): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 4.0 Hz, 1H), 7.86 (td, J = 7.8, 1.7 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J = 6.4 Hz, 1H), 7.36 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 3.16 (s, 3H), 2.99 (s, 3H), 1.88 (s, 3H). LC-MS: [M+H] + Calcd 380.11, Found 380.1.

[0572] Compound 42.10 (i.e. NS-715): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 5.03 (s, 2H), 3.00 (s, 3H), 2.86 (s, 3H), 1.85 (s, 3H). LC-MS: [M+H] + Calcd 394.13, Found 394.1.

[0573] Compound 42.11 (i.e. NS-717): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.91 (dd, J = 8.5, 2.5 Hz, 1H), 6.85 (d, J = 2.5 Hz, 1H), 4.94 (s, 2H), 3.70 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 356.15, Found 356.1.

[0574] Compound 42.12 (i.e. NS-718): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.2 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.39 (td, J = 4.4, 2.1 Hz, 2H), 7.35 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 1.84 (s, 3H). LC-MS: [M+H] + Calcd 346.09, Found 346.1.

[0575] Compound 42.13 (i.e. NS-719): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.7, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.1 Hz, 1H), 7.34 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 4.98 (s, 2H), 3.00 (s, 3H), 2.86 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 360.10, Found 360.1.

[0576] Compound 42.14 (i.e. NS-945): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.7, 0.9 Hz, 1H), 7.87 (td, J = 7.8, 1.8 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.34 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 4.04 (d, J = 9.5 Hz, 1H), 4.01 (d, J = 9.4 Hz, 1H), 2.09 (hept, J = 0.7 Hz, 1H), 1.84 (s, 3H), 1.06 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 365.14, Found 364.9.

[0577] Compound 42.15 (i.e. NS-1276): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.6 Hz, 1H), 7.86 (t, J = 7.1 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.56 (brs, 1H), 7.36 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.21 (dd, J = 29.1, 8.2 Hz, 1H), 3.46 (t, J = 7.1 Hz, 1H), 3.30 (t, J = 7.1 Hz, 1H), 3.14 (s, 1.5H), 2.98 (s, 1.5H), 1.88 (s, 3H), 1.73 (m, 1H), 1.60 (m, 1H), 0.98 (t, J = 7.4 Hz, 1.5H), 0.88 (t, J = 7.4 Hz, 1.5H). LC-MS: [M+H] + Calcd 408.15, Found 407.9.

[0578] Compound 42.16 (i.e. NS-953): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 1.0 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.1 Hz, 1H), 7.33 (m, 2H), 7.09 (d, J = 8.3 Hz, 1H), 4.01 (d, J = 8.8 Hz, 1H), 3.97 (d, J = 9.2 Hz, 1H), 2.07 (dp, J = 13.3, 6.6 Hz, 1H), 1.80 (s, 3H), 1.04 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 331.11, Found 330.9.

[0579] Compound 42.17 (i.e. NS-1278): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.9 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.50 (br s, 1H), 7.38 (m, 3H), 7.07 (d, J = 8.8 Hz, 0.5H), 7.00 (d, J = 8.7 Hz, 0.5H), 3.44 (t, J = 7.2 Hz, 1H), 3.29 (t, J = 7.1 Hz, 1H), 3.12 (s, 1.5H), 2.97 (s, 1.5H), 1.84 (s, 3H), 1.72 (dq, J = 14.1, 7.0 Hz, 1H), 1.59 (m, 1H), 0.98 (t, J = 7.3 Hz, 2H), 0.88 (t, J = 7.3 Hz, 2H). LC-MS: [M+H] + Calcd 374.12, Found 373.9.

[0580] Compound 42.18 (i.e. NS-921): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.7, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 4.01 (d, J = 8.9 Hz, 1H), 3.97 (d, J = 8.8 Hz, 1H), 2.25 (s, 3H), 2.08 (dp, J = 13.3, 6.7 Hz, 1H), 1.77 (s, 3H), 1.06 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 311.17, Found 312.9.

[0581] Compound 42.19 (i.e. NS-937): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.7, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.04 (s, 1H), 6.97 (d, J = 7.9 Hz, 1H), 4.01 (d, J = 8.9 Hz, 1H), 3.97 (d, J = 8.8 Hz, 1H), 2.25 (s, 3H), 2.08 (dp, J = 13.3, 6.7 Hz, 1H), 1.77 (s, 3H), 1.06 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 315.14, Found 314.9.

[0582] Compound 42.20 (i.e. NS-1272): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 3.8 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 6.8 Hz, 1H), 7.28 (dd, J = 7.4, 4.9 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 7.02 (s, 1H), 6.82 (dd, J = 20.6, 7.8 Hz, 1H), 3.40 (t, J = 6.9 Hz, 1H), 3.25 (t, J = 6.9 Hz, 1H), 3.09 (s, 1.5H), 2.93 (s, 1.5H), 2.21 (s, 3H), 1.77 (s, 3H), 1.68 (m, 1H), 1.55 (m, 1H), 0.94 (t, J = 7.2 Hz, 1.5H), 0.84 (t, J = 7.2 Hz, 1.5H). LC-MS: [M+H] + Calcd 354.17, Found 353.9.

[0583] Compound 42.21 (i.e. NS-1274): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 3.9 Hz, 1H), 7.83 (td, J = 7.8, 1.3 Hz, 1H), 7.47 (d, J = 6.2 Hz, 1H), 7.35 (dd, J = 7.1, 5.2 Hz, 1H), 7.23 (dd, J = 8.3, 2.4 Hz, 1H), 7.18 (td, J = 9.2, 2.5 Hz, 1H), 7.04 (dd, J = 8.4, 4.1 Hz, 0.5H), 6.97 (dd, J = 8.3, 3.8 Hz, 0.5H), 3.44 (t, J = 7.2 Hz, 1H), 3.29 (t, J = 7.0 Hz, 1H), 3.13 (s, 1.5H), 2.97 (s, 1.5H), 1.84 (s, 3H), 1.72 (m, 1H), 1.59 (m, 1H), 0.98 (t, J = 7.3 Hz, 1.5H), 0.88 (t, J = 7.3 Hz, 1.5H). LC-MS: [M+H] + Calcd 358.15, Found 357.9.

[0584] Compound 42.22 (i.e. NS-929): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.33 (m, 2H), 7.22 (d, J = 7.0 Hz, 1H), 7.06 (m, 2H), 4.00 (d, J = 6.5 Hz, 2H), 2.08 (dp, J = 13.2, 6.6 Hz, 1H), 1.78 (s, 3H), 1.06 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 297.15, Found 296.9.

[0585] Compound 42.23 (i.e. NS-977): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.90 (dd, J = 8.4, 2.5 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H), 3.99 (d, J = 9.1 Hz, 1H), 3.95 (d, J = 9.0 Hz, 1H), 3.69 (s, 3H), 2.06 (m, 1H), 1.77 (s, 3H), 1.04 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 327.16, Found 326.9.

[0586] Compound 42.24 (i.e. NS-1270): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 3.4 Hz, 1H), 7.81 (td, J = 7.7, 1.1 Hz, 1H), 7.42 (br s, 1H), 7.33 (m, 2H), 7.26 (d, J = 7.0 Hz, 1H), 7.08 (td, J = 7.6, 0.8 Hz, 1H), 6.98 (dd, J = 22.6, 7.7 Hz, 1H), 3.45 (t, J = 7.2 Hz, 1H), 3.30 (t, J = 7.0 Hz, 1H), 3.14 (s, 1.5H), 2.98 (s, 1.5H), 1.83 (s, 3H), 1.73 (m, 1H), 1.59 (m, 1H), 0.99 (t, J = 7.3 Hz, 1.5H), 0.88 (t, J = 7.3 Hz, 1.5H). LC-MS: [M+H] + Calcd 340.16, Found 339.9.

[0587] Compound 42.25 (i.e. NS-2034): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.7, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.1 Hz, 1H), 7.34 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 5.12 (s, 1H), 5.08 (t, J = 1.6 Hz, 1H), 4.63 (s, 2H), 1.93 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 329.10, Found 329.0.

[0588] Compound 42.26 (i.e. NS-2038): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 7.6, 4.7, 0.9 Hz, 1H), 7.86 (td, J = 7.8, 1.8 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.63 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.34 (ddd, J = 4.8, 0.7 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 5.14 (s, 1H), 5.09 (t, J = 1.2 Hz, 1H), 4.67 (s, 2H), 1.95 (s, 3H), 1.84 (s, 3H). LC-MS: [M+H] +Calcd 363.12, Found 363.1.

[0589] Compound 42.27 (i.e. NS-2035): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (m, 1H), 7.83 (m, 1H), 7.49 (d, J = 8.0 Hz, 0.25H), 7.45 (d, J = 8.0 Hz, 0.75H), 7.39 (dd, J = 8.3, 2.1 Hz, 1H), 7.33 (m, 2H), 7.13 (d, J = 8.3 Hz, 0.25H), 7.10 (d, J = 8.3 Hz, 0.75H), 5.86 (m, 1H), 5.74 (m, 1H), 4.80 (d, J = 7.4 Hz, 0.5H), 4.64 (d, J = 6.9 Hz, 1.5H), 1.78 (s, 0.75H), 1.78 (s, 2.25H), 1.63 (m, 3H). LC-MS: [M+H] + Calcd 329.10, Found 329.0.

[0590] Compound 42.28 (i.e. NS-2039): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (m, 1H), 7.85 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.60 (br s, 1H), 7.55 (d, J = 8.0 Hz, 0.25H), 7.52 (d, J = 8.0 Hz, 0.75H), 7.33 (ddd, J = 7.6, 4.8, 0.9 Hz, 1H), 7.31 (d, J = 8.2 Hz, 0.25H), 7.27 (d, J = 8.2 Hz, 0.75H), 5.86 (m, 1H), 5.76 (m, 1H), 4.83 (d, J = 7.3 Hz, 0.5H), 4.67 (d, J = 6.9 Hz, 1.5H), 1.83 (s, 0.75H), 1.82 (s, 2.25H), 1.63 (d, J = 5.7 Hz, 3H). LC-MS: [M+H] + Calcd 363.12, Found 363.1.

[0591] Example 43. Synthesis of compounds 43.1-43.13

[0592] Reference Example 9 Synthesis of indolinone intermediates 43-1 with various substituents on the benzene ring.

[0593] Reference Examples 9, 10, 17 and 21 Synthesis of N-substituted indolinones 43.1-43.13.

[0594] Compound 43.1 (i.e. NS-446): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.8, 0.9 Hz, 1H), 7.77 (td, J = 7.8, 1.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.29 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H), 4.72 (s, 2H), 2.65 (q, J = 7.3 Hz, 2H), 2.22 (s, 3H), 1.76 (s, 3H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 309.15, Found 309.2.

[0595] Compound 43.2 (i.e. NS-447): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.8, 0.9 Hz, 1H), 7.77 (td, J = 7.8, 1.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.29 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.98 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H), 4.72 (s, 2H), 2.65 (q, J = 7.3 Hz, 2H), 2.22 (s, 3H), 1.76 (s, 3H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 295.14, Found 295.1.

[0596] Compound 43.3 (i.e. NS-448): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.53 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.76 (td, J = 7.8, 1.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.28 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 2.3 Hz, 1H), 6.54 (dd, J = 8.2, 2.3 Hz, 1H), 4.74 (s, 2H), 3.74 (s, 3H), 2.65 (q, J = 7.2 Hz, 2H), 1.75 (s, 3H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 325.15, Found 325.2.

[0597] Compound 43.4 (i.e. NS-449): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.10 (m, 2H), 7.02 (dd, J = 8.4, 4.4 Hz, 1H), 4.76 (s, 2H), 2.65 (q, J = 7.3 Hz, 2H), 1.79 (s, 3H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 313.13, Found 313.1.

[0598] Compound 43.5 (i.e. NS-450): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (ddd, J = 4.8, 1.6, 0.7 Hz, 1H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.64 (dd, J = 8.3, 0.9 Hz, 1H), 7.55 (d, J = 1.3 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.84 (s, 2H), 2.67 (q, J = 7.3 Hz, 2H), 1.83 (s, 3H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 363.12, Found 363.1.

[0599] Compound 43.6 (i.e. NS-451): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.78 (td, J = 7.8, 1.9 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.30 (m, 1H), 6.91 (m, 1H), 6.81 (dd, J = 6.7, 2.5 Hz, 2H), 4.71 (s, 2H), 3.68 (s, 3H), 2.64 (q, J = 7.3 Hz, 2H), 1.77 (s, 3H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 325.15, Found 325.2.

[0600] Compound 43.7 (i.e. NS-452): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.31 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 2.65 (q, J = 7.3 Hz, 2H), 1.79 (s, 3H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 329.10, Found 329.1.

[0601] Compound 43.8 (i.e. NS-919): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.7, 0.8 Hz, 1H), 7.74 (td, J = 7.7, 1.9 Hz, 1H), 7.27 (m, 2H), 7.07 (m, 2H), 6.97 (s, 1H), 3.89 (m, 2H), 3.64 (m, 2H), 3.57 (dt, J = 12.1, 6.1 Hz, 1H), 2.23 (s, 3H), 1.72 (s, 3H), 1.04 (d, J = 3.9 Hz, 3H), 1.02 (d, J = 3.9 Hz, 3H). LC-MS: [M+H] + Calcd 325.18, Found 324.9.

[0602] Compound 43.9 (i.e. NS-927): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (m, 1H), 7.74 (td, J = 7.7, 1.9 Hz, 1H), 7.27 (m, 3H), 7.16 (d, J = 7.9 Hz, 2H), 6.98 (td, J = 7.5, 0.9 Hz, 1H), 3.92 (m, 2H), 3.65 (t, J = 5.8 Hz, 2H), 3.57 (hept, J = 6.1 Hz, 1H), 1.74 (s, 3H), 1.04 (d, J = 3.4 Hz, 3H), 1.02 (d, J = 3.4 Hz, 3H). LC-MS: [M+H] + Calcd 311.17, Found 310.9.

[0603] Compound 43.10 (i.e. NS-935): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 4.7 Hz, 1H), 7.77 (td, J = 7.8, 1.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 7.1, 5.2 Hz, 1H), 7.18 (dd, J = 8.4, 4.4 Hz, 1H), 7.10 (ddd, J = 11.0, 8.8, 2.5 Hz, 2H), 3.90 (m, 2H), 3.63 (t, J = 5.7 Hz, 2H), 3.55 (m, 1H), 1.75 (s, 3H), 1.02 (d, J = 3.1 Hz, 3H), 1.01 (d, J = 3.1 Hz, 3H). LC-MS: [M+H] + Calcd 329.16, Found 328.9.

[0604] Compound 43.11 (i.e. NS-943): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.67 (dd, J = 8.2, 0.8 Hz, 1H), 7.53 (d, J = 1.3 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 3.97 (m, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.56 (m, 1H), 1.79 (s, 3H), 1.02 (d, J = 2.6 Hz, 3H), 1.01 (d, J = 2.5 Hz, 3H). LC-MS: [M+H] +Calcd 379.16, Found 378.9.

[0605] Compound 43.12 (i.e. NS-951): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 7.78 (td, J = 7.8, 1.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.4, 2.2 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 3.91 (m, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.55 (hept, J = 6.1 Hz, 1H), 1.75 (s, 3H), 1.02 (d, J = 3.1 Hz, 3H), 1.00 (d, J = 3.1 Hz, 3H). LC-MS: [M+H] + Calcd 345.13, Found 344.9.

[0606] Compound 43.13 (i.e. NS-975): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (m, 1H), 7.74 (td, J = 7.8, 1.9 Hz, 1H), 7.28 (m, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.84 (dd, J = 8.5, 2.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 3.88 (qt, J = 14.2, 5.6 Hz, 2H), 3.68 (s, 3H), 3.63 (t, J = 5.8 Hz, 2H), 3.57 (dt, J = 12.1, 6.1 Hz, 1H), 1.73 (s, 3H), 1.04 (d, J = 3.6 Hz, 3H), 1.02 (d, J = 3.6 Hz, 3H). LC-MS: [M+H] + Calcd 341.18, Found 340.9.

[0607] Example 44. Synthesis of compounds 44.1-44.5

[0608] Compound 43-1 (R = H) ((448 mg, 2 mmol) as starting material, and iron nitrate nonahydrate, mixed in hexafluoroisopropanol (HFIP), sealed tube heated to 100 °C, reaction overnight. The organic solvent was removed under reduced pressure, dichloromethane was added, suction filtered, the filtrate was concentrated, and compound 44-1 (513 mg, 95.4%) was obtained after silica gel column purification (P:E = 1 : 1).

[0609] Compounds 44.1-44.5 were synthesized according to the procedures described in Examples 10, 17 and 21.

[0610] Compound 44.1 (i.e. NS-454): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.8, 0.9 Hz, 1H), 8.24 (dd, J = 8.7, 2.4 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.85 (td, J = 7.8, 1.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.35 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 4.90 (s, 2H), 2.69 (q, J = 7.3 Hz, 2H), 1.86 (s, 3H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 340.12, Found 340.1.

[0611] Compound 44.2 (i.e. NS-537): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 4.8, 0.9 Hz, 1H), 8.24 (dd, J = 8.7, 2.4 Hz, 1H), 8.15 (m, 3H), 7.88 (td, J = 7.8, 1.9 Hz, 1H), 7.78 (t, J = 7.4 Hz, 1H), 7.65 (t, J = 7.7 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.36 (m, 2H), 5.61 (s, 2H), 1.91 (s, 3H). LC-MS: [M+H] + Calcd 388.12, Found 388.1.

[0612] Compound 44.3 (i.e. NS-538): light yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.8, 1.0 Hz, 1H), 8.27 (dd, J = 8.7, 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 4.04 (t, J = 7.0 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.81 (s, 3H), 1.48 (h, J = 7.3 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 368.15, Found 368.2.

[0613] Compound 44.4 (i.e. NS-539): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.8, 1.0 Hz, 1H), 8.27 (dd, J = 8.7, 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 4.04 (t, J = 7.0 Hz, 2H), 2.88 (t, J = 7.1 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.81 (s, 3H), 1.48 (h, J = 7.3 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 396.18, Found 396.2.

[0614] Compound 44.5 (i.e. NS-959): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 0.9 Hz, 1H), 8.26 (dd, J = 8.8, 2.4 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 4.01 (m, 2H), 3.66 (t, J = 5.4 Hz, 2H), 3.54 (dq, J = 12.0, 6.0 Hz, 1H), 1.83 (s, 3H), 1.00 (d, J = 1.8 Hz, 3H), 0.99 (d, J = 1.8 Hz, 3H). LC-MS: [M+H] + Calcd 356.15, Found 355.9.

[0615] Example 45. Synthesis of compounds 45.1-45.4

[0616] Compound 42-3 (R = OMe) (270 mg, 1 mmol) was dissolved in 5 mL dry DMF. Potassium bicarbonate (150 mg, 1.5 mmol) and chloroformic dimethylamine (161 mg, 1.5 mmol) were added successively and stirred at room temperature for two hours. The 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 and concentrated. Purification on a silica gel column (P:E = 3:1-2:1) gave compound 45-1 (113 mg, 27.5%) and 45-2 (132 mg, 32.1%).

[0617] Compounds 45.1 and 45.2 were obtained by reacting 45-1 and 45-2 respectively with bromobutanone according to Example 10.

[0618] Compound 45.1 (i.e. NS-463): pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.65 (s, 2H), 3.66 (s, 3H), 3.02 (s, 3H), 2.93 (s, 3H), 2.55 (q, J = 7.2 Hz, 2H), 1.80 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H). LC-MS: [M+H] + Calcd 412.18, Found 412.2.

[0619] Compound 45.2 (i.e. NS-464): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 4.7, 0.8 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.00 (s, 1H), 6.91 (s, 1H), 4.70 (s, 2H), 3.67 (s, 3H), 3.04 (s, 3H), 2.90 (s, 3H), 2.64 (q, J = 7.2 Hz, 2H), 1.80 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H). LC-MS: [M+H] + Calcd 412.18, Found 412.2.

[0620] Following the procedure described above, compound 42-3 (R = OMe) was reacted with chloroformyl methyl propyl amine to give compounds 45-3 and 45-4.

[0621] Following the procedure described above, compound 42-3 (R = OMe) was reacted with chloroformyl methyl propyl amine to give compounds 45-3 and 45-4.

[0622] Compound 45.3 (i.e. NS-1291): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 1.2 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.30 (ddd, J = 7.4, 4.8, 0.7 Hz, 1H), 6.70 (m, 1H), 6.58 (d, J = 2.5 Hz, 0.6H), 6.51 (d, J = 2.4 Hz, 0.4H), 3.66 (s, 3H), 3.55 (dd, J = 7.3, 3.9 Hz, 2H), 3.42 (m, 0.8H), 3.29 (m, 1.2H), 3.10 (s, 1.8H), 2.96 (s, 1.2H), 2.01 (m, 1H), 1.75 (s, 3H), 1.68 (m, 0.8H), 1.59 (m, 1.2H), 0.90 (m, 9H). LC-MS: [M+H] + Calcd 426.23, Found 425.9.

[0623] Compound 45.4 (i.e. NS-1292): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.29 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.98 (d, J = 11.4 Hz, 2H), 3.65 (s, 3H), 3.52 (m, 2H), 3.33 (t, J = 7.2 Hz,), 3.24 (t, J = 7.2 Hz, 1H), 3.03 (s, 1.5H), 2.90 (s, 1.5H), 2.08 (s, 1H), 1.76 (s, 3H), 1.66 (dd, J = 14.8, 7.3 Hz, 1H), 1.56 (dd, J = 14.7, 7.3 Hz, 1H), 0.90 (m, 9H). LC-MS: [M+H] + Calcd 426.23, Found 425.9.

[0624] Example 46. Synthesis of compounds 46.1-46.3

[0625] Compound 43.8 (176 mg, 0.5 mmol) was dissolved in 5 mL of ethanol, 1 mL of aqueous sodium hydroxide (40 mg, 1 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 hours. The pH was adjusted to 2-3, and ethyl acetate and dilute aqueous hydrochloric acid were added to separate the layers. The organic layers were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated to obtain a crude carboxylic acid. The crude product was dissolved in 5 mL of thionyl chloride, and a catalytic amount of DMF was added dropwise. The reaction was allowed to proceed under reflux for 2 hours under nitrogen protection. After the solvent was removed under reduced pressure, the reaction mixture was added to an ammonia / methanol solution cooled to -40 °C. After 10 minutes, the solvent was removed under reduced pressure. Purification by silica gel column chromatography (P:E = 1:1) afforded compound 46.1 (i.e., NS-521) (154 mg, 91.7%, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (dd, J = 4.7, 0.8 Hz, 1H), 7.81 (ddd, J = 10.0, 6.2, 1.8 Hz, 3H), 7.70 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 6.8, 4.9 Hz, 1H), 7.19 (s, 1H), 7.07 (d, J = 8.3 Hz, 1H), 4.81 (s, 2H), 2.67 (q, J = 7.3 Hz, 2H), 1.81 (s, 3H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 338.14, Found 338.1.

[0626] Compound 46.1 (100 mg, 0.3 mmol) was dissolved in dry acetonitrile, and phosphorus oxychloride (115 mg, 0.75 mmol) was added dropwise under nitrogen protection. The reaction was allowed to proceed at 80 °C for 2 hours. After the reaction mixture was cooled to room temperature, it was quenched by dropwise addition to water. The pH was adjusted to 8-9 by adding aqueous sodium bicarbonate solution. Ethyl acetate was added to separate the layers, and the organic layers were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography (P:E = 3:1) afforded compound 46.2 (i.e., NS-522) (64 mg, 66.9%, white solid). 1H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.8, 0.8 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.77 (dd, J = 8.2, 1.6 Hz, 1H), 7.69 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 6.7, 4.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 4.84 (s, 2H), 2.67 (q, J = 7.2 Hz, 2H), 1.81 (s, 3H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 320.13 Found 320.1.

[0627] Reference Example 21, synthesis of compound 46-4;

[0628] Reference the above example, with compound 46-4 as raw material, through ester aminolysis and dehydration to generate compound 46.3.

[0629] Compound 46.3 (i.e. NS-983): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 0.9 Hz, 1H), 7.80 (ddd, J = 14.9, 8.1, 1.8 Hz, 2H), 7.66 (d, J = 1.6 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 3.96 (m, 2H), 3.63 (t, J = 5.5 Hz, 2H), 3.54 (hept, J = 6.1 Hz, 1H), 1.77 (s, 3H), 0.99 (dd, J = 6.1, 1.6 Hz, 6H). LC-MS: [M+H] + Calcd 336.16 Found 335.9.

[0630] Example 47. Synthesis of compounds 47.1 and 47.2

[0631] Reference Example 1, compound 46-1 is reduced with zinc powder to close ring to obtain compound 47-1;

[0632] Compound 47-1 (298 mg, 1 mmol, 1 eq) was dissolved in dry DCM, diisopropylethylamine (194 mg, 1.5 mmol, 1.5 eq) was added. The reaction was cooled to -40 °C under nitrogen protection. Bromomethyl methyl ether (150 mg, 1.2 mmol, 1.2 eq) was added dropwise. After 1 hour of reaction at -40 °C, the reaction was quenched with water. The reaction was partitioned with ethyl acetate and water, the organic phase was washed with saturated brine, concentrated, and purified on silica gel column (P:E = 3:1) to give compound 47-2 (312 mg, 91.2%).

[0633] Referring to Example 46 above, compound 47-2 was subjected to amineolysis of ester group and dehydration to give compound 47-3 (251 mg, 89.1%).

[0634] The compound was dissolved in 10 ml dry dichloromethane, 2 ml trifluoroacetic acid was added, stirred at room temperature for 16 hours, the solvent was removed under reduced pressure, saturated sodium carbonate solution and ethyl acetate were partitioned, the organic phase was combined, concentrated under reduced pressure to give the crude compound 47-4.

[0635] The crude compound 47-4, potassium bicarbonate (100 mg, 1 mmol) and N-methyl-N-propylcarboxamide in DMF were stirred at room temperature for 2 hours. Water and ethyl acetate were partitioned. The organic phase was combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on silica gel column (P:E = 3:1) to give compound 47.1 (i.e. NS-1286) (113 mg, 32.8%).

[0636] Compound 47.1 (i.e. NS-1286): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.5 Hz, 1H), 7.85 (m, 3H), 7.54 (br s, 1H), 7.36 (dd, J = 7.4, 4.9 Hz, 1H), 7.25 (d, J = 8.1 Hz, 0.5H), 7.16 (d, J = 8.1 Hz, 0.5H), 3.44 (t, J = 6.8 Hz, 1H), 3.29 (t, J = 7.1 Hz, 1H), 3.13 (s, 1.5H), 2.97 (s, 1.5H), 1.85 (s, 3H), 1.72 (m, 1H), 1.59 (m, 1H), 0.97 (t, J = 7.4 Hz, 1.5H), 0.87 (t, J = 7.4 Hz, 1.5H). LC-MS: [M+H] + Calcd 365.15 Found 364.9.、

[0637] Referring to the above synthesis, compound 47-4 crude was reacted with isobutyl iodide under potassium bicarbonate condition to produce compound 47.2.

[0638] Compound 47.2 (i.e. NS-985): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (dd, J = 4.8, 1.0 Hz, 1H), 7.87 (m, 2H), 7.76 (d, J = 1.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.01 (m, 2H), 2.08 (dp, J = 13.3, 6.7 Hz, 1H), 1.82 (s, 3H), 1.04 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 322.15 Found 321.9.

[0639] Example 48. Synthesis of compounds 48.1-48.3

[0640] Compound 43.2 (588 mg, 2 mmol) was dissolved in dry dichloromethane, chlorosulfonic acid (1.16 g, 10 mmol) was added dropwise under ice bath. After 1 hour, it was slowly warmed to room temperature, saturated NaHC03 aqueous solution was added slowly under ice bath to adjust pH to 8-9. The solvent was removed under reduced pressure. C18 reverse phase silica gel column purification (ACN:H20 = 1:3-1:1) gave product 48.1 (i.e. NS-525) (612 mg, 72.3%, yellow solid). 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.1, 1.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 1.5 Hz, 1H), 7.31 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 4.77 (s, 2H), 2.66 (q, J = 7.2 Hz, 2H), 1.79 (s, 3H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 375.09 Found 375.1.

[0641] Sodium sulfonate 48.1 (198 mg, 0.5 mmol) was dissolved in water and the pH was adjusted to 2-3. The product was purified by reverse phase and lyophilized to give the sulfonic acid. The sulfonic acid was dissolved in anhydrous dichloromethane, 2 mL of thionyl chloride was added, and a catalytic amount of DMF was added. The mixture was refluxed at 55 °C for half an hour. The organic solvent was removed by vacuum evaporation. The crude sulfuryl chloride was dissolved in dry dichloromethane and slowly added to 5 mL of ammonia in dioxane (1 M) at -40 °C. The organic solvent was removed by vacuum evaporation. The product 48.2 (i.e., NS-523) was purified by C18 reverse phase silica gel column (ACN:H2O = 1:3-2:1) to give a white solid (612 mg, 72.3%). 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 4.7, 0.7 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.73 (dd, J = 8.3, 1.8 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 6.8, 4.9 Hz, 1H), 7.21 (s, 2H), 7.18 (d, J = 8.3 Hz, 1H), 4.84 (s, 2H), 2.68 (q, J = 7.3 Hz, 2H), 1.82 (s, 3H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 374.11 Found 374.1.

[0642] Following the procedure described above, the crude sulfuryl chloride was added to a tetrahydrofuran solution of dimethylamine to give compound 48.3 (i.e., NS-524): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.67 (dd, J = 8.3, 1.9 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.86 (s, 2H), 2.69 (q, J = 7.2 Hz, 2H), 2.54 (s, 6H), 1.86 (d, J = 17.5 Hz, 3H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 402.14 Found 402.1.

[0643] Example 49. Synthesis of compounds 49.1-49.8

[0644] Reference Example 26 reacted indolinone with different phenyl substituents with diphenylphosphoryl hydroxylamine to form intermediate 49-1.

[0645] Reference Example 34 reacted intermediate 49-1 with methylpropylamine, trimethyl orthoformate in the presence of acid to form compound 49.1.

[0646] Compound 49.1 (i.e. NS-1273): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (dd, J = 4.7, 0.9 Hz, 1H), 8.26 (s, 1H), 7.76 (td, J = 7.7, 1.9 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.29 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.83 (d, J = 7.6 Hz, 1H), 3.27 (brs, 2H), 2.97 (s, 3H), 2.23 (s, 3H), 1.75 (s, 3H), 1.59 (brs, 2H), 0.89 (brs, 3H). LC-MS: [M+H] + Calcd 337.20, Found 336.9.

[0647] Reference Example 34 reacted 49-1 with different amines to form compounds 49.2-49.8.

[0648] Compound 49.2 (i.e. NS-1271): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.7, 0.8 Hz, 1H), 8.26 (brs, 1H), 7.76 (td, J = 7.8, 1.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.27 (ddd, J = 8.6, 7.6, 2.9 Hz, 2H), 7.15 (d, J = 7.1 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 7.2 Hz, 1H), 3.26 (brs, 2H), 2.97 (s, 3H), 1.77 (s, 3H), 1.60 (brs, 2H), 0.89 (brs, 3H). LC-MS: [M+H] + Calcd 323.18, Found 322.9.

[0649] Compound 49.3 (i.e. NS-1275): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 4.6 Hz, 1H), 8.27 (br s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.4, 4.8 Hz, 1H), 7.10 (ddd, J = 8.9, 5.2, 2.2 Hz, 2H), 6.92 (br s, 1H), 3.27 (br s, 2H), 2.97 (s, 3H), 1.78 (s, 3H), 1.59 (br s, 2H), 0.89 (br s, 3H). LC-MS: [M+H] + Calcd 341.17, Found 340.9.

[0650] Compound 49.4 (i.e. NS-1279): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 4.6 Hz, 1H), 8.27 (br s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.4, 4.8 Hz, 1H), 7.10 (ddd, J = 8.9, 5.2, 2.2 Hz, 2H), 6.92 (br s, 1H), 3.27 (br s, 2H), 2.97 (s, 3H), 1.78 (s, 3H), 1.59 (br s, 2H), 0.89 (br s, 3H). LC-MS: [M+H] + Calcd 357.14, Found 356.9.

[0651] Compound 49.5 (i.e. NS-1285): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 4.6 Hz, 1H), 8.27 (br s, 1H), 7.80 (td, J = 7.8, 1.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.4, 4.8 Hz, 1H), 7.10 (ddd, J = 8.9, 5.2, 2.2 Hz, 2H), 6.92 (br s, 1H), 3.27 (br s, 2H), 2.97 (s, 3H), 1.78 (s, 3H), 1.59 (br s, 2H), 0.89 (br s, 3H). LC-MS: [M+H] + Calcd 353.19, Found 352.9.

[0652] Compound 49.6 (i.e. NS-1277): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 2.0, 0.8 Hz, 1H), 8.28 (brs, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.65 (dd, J = 8.2, 0.8 Hz, 1H), 7.51 (dd, J = 6.1, 5.0 Hz, 2H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 3.26 (brs, 4H), 2.97 (s, 3H), 1.82 (s, 3H), 1.59 (brs, 2H), 0.87 (brs, 3H). LC-MS: [M+H] + Calcd 391.17, Found 390.9.

[0653] Compound 49.7 (i.e. NS-1281): yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.7, 0.8 Hz, 1H), 8.30 (brs, 0.75H), 8.26 (dd, J = 8.7, 2.3 Hz, 1H), 8.23 (brs, 0.25H), 8.07 (d, J = 2.3 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.34 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 0.75H), 7.08 (brs, 0.25H), 3.40 (brs, 0.5H), 3.27 (t, J = 6.1 Hz, 1.5H), 2.98 (s, 3H), 1.70 (brs, 0.5H), 1.58 (m, 1.5H), 0.97 (brs, 1H), 0.87 (t, J = 6.6 Hz, 2H). LC-MS: [M+H] + Calcd 368.16, Found 367.9.

[0654] Compound 49.8 (i.e. NS-1287): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.51 (dd, J = 4.8, 1.0 Hz, 1H), 8.26 (br s, 0.66H), 8.21 (br s, 0.34H), 7.83 (td, J = 7.8, 1.9 Hz, 1H), 7.76 (dd, J = 8.1, 1.6 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 3.38 (br s, 0.5H), 3.26 (br s, 1.5H), 2.97 (s, 3H), 1.81 (s, 3H), 1.65 (br s, 0.5H), 1.58 (br s, 1.5H), 0.95 (br s, 1H), 0.87 (br s, 2H). LC-MS: [M+H] + Calcd 348.12 Found 347.9.

[0655] Example 50: Synthesis of compounds 50.1 and 50.2

[0656] Compound 1-1 (3.5 g, 10 mmol, 1 eq) was dissolved in 50 mL of ethanol, 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 condition. The reaction was slowly warmed to room temperature and stirred at room temperature overnight. 200 mL of tetrahydrofuran was added for stirring, and the mixture was filtered through diatomite. The filter cake was washed with tetrahydrofuran. After the filtrate was concentrated, water was added for slurry, and the mixture was filtered. The filter cake was dried to obtain compound 50-1 (2.87 g, yellow solid, 94.1%).

[0657] Compound 50-1 (153 mg, 0.5 mmol), potassium carbonate (138 mg, 1 mmol), and ethyl bromoacetate (125 mg, 0.75 mmol) were stirred in DMF for 6 hours. Ethyl acetate and water were added for liquid separation, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 3:1) to obtain compound 50.1 (i.e., NS-29) (89 mg, 37.2%), and compound 50.2 (i.e., NS-30) (64 mg, 32.7%) was obtained by further increasing the polarity of the mobile phase (100% EA ~ 10% MeOH / DCM).

[0658] Compound 50.1 (i.e., NS-29): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (ddd, J = 4.7, 1.8, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 8.3, 2.0 Hz, 1H), 7.32 (m, 2H), 7.22 (d, J = 8.3 Hz, 1H), 4.94 (d, J = 15.8 Hz, 1H), 4.89 (d, J = 15.8 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.90 (m, 2H), 3.79 (d, J = 17.0 Hz, 1H), 3.50 (d, J = 17.0 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 477.06, 479.06 Found 477.1, 479.1.

[0659] Compound 50.2 (i.e. NS-30): yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 14.25 (s, 1H), 8.20 (t, J = 5.6 Hz, 1H), 7.88 (ddd, J = 8.7, 7.0, 1.6 Hz, 1H), 7.76 (d, J = 9.1 Hz, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.13 (dd, J = 8.3, 1.7 Hz, 1H), 6.90 (t, J = 6.7 Hz, 1H), 4.98 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 391.02, 393.02 Found 391.0, 393.0.

[0660] Example 51. Synthesis of compounds 51.1-51.1

[0661] Reference to the synthesis of 1-3 in Reference Example 1, using iodoethane, allyl bromide and iodomethylcyclopropane as the alkylating reagents, the reaction gave compound 51-1. Reference to Reference Examples 1 and 10, the intermediates 51-2 and 51-3 were obtained by reduction of the ring closure, respectively.

[0662] Reference to Reference Examples 4 and 5, compounds 51.1-51.3 were synthesized using intermediate 51-2 as the starting material.

[0663] Compound 51.1 (i.e. NS-60): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (dd, J = 4.7, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.9 Hz, 1H), 7.57 (dd, J = 8.3, 2.0 Hz, 1H), 7.50 (t, J = 4.7 Hz, 2H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5.01 (d, J = 15.7 Hz, 1H), 4.96 (d, J = 15.8 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.46 (dq, J = 14.3, 7.1 Hz, 1H), 2.32 (dq, J = 14.3, 7.1 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H), 0.64 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 419.05, 421.05 Found 419.0, 421.0.

[0664] Compound 51.2 (i.e. NS-274): colorless clear syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J = 4.8, 0.9 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.55 (dd, J = 8.3, 1.9 Hz, 1H), 7.49 (dd, J = 4.9, 2.9 Hz, 2H), 7.33 (ddd, J = 7.5, 4.8, 0.7 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 4.99 (s, 2H), 3.01 (s, 3H), 2.85 (s, 3H), 2.46 (dq, J = 14.5, 7.3 Hz, 1H), 2.32 (dq, J = 14.5, 7.3 Hz, 1H), 0.66 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 418.07, 420.07 Found 418.1, 420.1.

[0665] Compound 51.3 (i.e. NS-275): colorless clear syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (t, J = 4.3 Hz, 1H), 7.83 (tt, J = 8.1, 1.8 Hz, 1H), 7.55 (dd, J = 8.2, 1.5 Hz, 1H), 7.48 (dd, J = 5.7, 2.0 Hz, 2H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.26 (dd, J = 8.3, 4.7 Hz, 1H), 5.00 (s, 2H), 3.25 (t, J = 7.5 Hz, 2H), 2.98 (s, 1.7H), 2.83 (s, 1.3H), 2.46 (dq, J = 14.5, 7.3 Hz, 1H), 2.32 (dq, J = 14.5, 7.3 Hz, 1H), 1.50 (m, 2H), 0.84 (t, J = 7.4 Hz, 1.3H), 0.81 (t, J = 7.4 Hz, 1.7H), 0.66 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 446.10, 448.10 Found 446.1, 448.1.

[0666] The important intermediate 51-2 can be synthesized from compound 50-1 using the method shown in the following scheme.

[0667] Compound 51-1 (3.05 g, 10 mmol, 1 eq) was dissolved in dry DMF, diisopropylethylamine (1.94 g, 15 mmol, 1.5 eq) was added. Under nitrogen protection, it was cooled to -40 °C. Bromomethyl methyl ether (1.5 g, 12 mmol, 1.2 eq) was added dropwise. After 1 hour of reaction at -40 °C, the reaction was quenched with water. Ethyl acetate and water were added to separate the layers, and the organic layers were combined. The organic phase was washed with saturated brine, concentrated, slurried with water, and filtered to obtain compound 51-4 (3.38 g, 96.8%) as a filter cake which was dried. Compound 51-4 was redissolved in dry DMF, and iodoalkane (1.2 mmol) and potassium carbonate (2.1 g, 15 mmol) were added. After stirring overnight at room temperature, ethyl acetate and water were added to separate the layers, and the organic layers were combined. The organic phase was washed with saturated brine, concentrated to obtain the crude compound 51-5.

[0668] The above crude compound was redissolved in 20 mL of ethanol, 2 mL of concentrated hydrochloric acid was added, and the reaction was carried out at 50 °C for 5 hours. After adjusting the pH to 7-8 by dropwise addition of sodium bicarbonate solution, ethyl acetate and water were added to separate the layers. The organic layers were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 1:1) to obtain compound 51-2.

[0669] Compounds 51.4 to 51.11 were synthesized by following the N-alkylation procedure of Reference Examples 10, 17 and 18.

[0670] Compound 51.4 (i.e. NS-67): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (dd, J = 4.8, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.45 (m, 3H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 4.82 (d, J = 18.3 Hz, 1H), 4.76 (d, J = 18.3 Hz, 1H), 2.66 (q, J = 7.3 Hz, 2H), 2.48 (dq, J = 14.4, 7.1 Hz, 1H), 2.32 (dq, J = 14.4, 7.1 Hz, 1H), 1.02 (t, J = 7.3 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 387.06, 389.06 Found 387.1, 389.1.

[0671] Compound 51.5 (i.e. NS-296): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.7, 1.8, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.48 (dd, J = 8.4, 2.1 Hz, 1H), 7.41 (t, J = 4.9 Hz, 2H), 7.30 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 3.95 (m, 2H), 2.82 (t, J = 6.9 Hz, 2H), 2.44 (m, 3H), 2.28 (dq, J = 14.4, 7.1 Hz, 1H), 1.45 (m, 2H), 1.21 (m, 4H), 0.84 (t, J = 7.1 Hz, 3H), 0.59 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 443.13, 445.13 Found 443.1, 445.1.

[0672] Compound 51.6 (i.e. NS-329): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 3.9 Hz, 1H), 8.14 (d, J = 7.3 Hz, 2H), 7.83 (td, J = 7.8, 1.8 Hz, 1H), 7.77 (t, J = 7.4 Hz, 1H), 7.64 (t, J = 7.7 Hz, 2H), 7.46 (m, 3H), 7.34 (dd, J = 7.1, 5.1 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 5.51 (d, J = 18.2 Hz, 1H), 5.45 (d, J = 18.3 Hz, 1H), 2.51 (m, 1H), 2.36 (dq, J = 14.3, 7.2 Hz, 1H), 0.76 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 435.06, 437.06 Found 435.1, 437.1.

[0673] Compound 51.7 (i.e. NS-413): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (dd, J = 4.8, 1.0 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 3.79 (td, J = 7.2, 2.0 Hz,), 3.61 (s, 3H), 2.45 (m, 3H), 2.30 (dq, J = 14.5, 7.3 Hz, 1H), 1.88 (p, J = 7.2 Hz, 2H), 0.61 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 417.07, 419.07 Found 417.1, 419.1.

[0674] Compound 51.8 (i.e. NS-414): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.80 (t, J = 7.7 Hz, 2H), 2.43 (m, 3H), 2.30 (dq, J = 14.5, 7.3 Hz, 1H), 1.88 (p, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H), 0.62 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 431.09, 433.09 Found 431.1, 433.1.

[0675] Compound 51.9 (i.e. NS-415): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (dd, J = 8.3, 2.1 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.30 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.80 (t, J = 7.7 Hz, 2H), 2.43 (m, 3H), 2.30 (dq, J = 14.5, 7.3 Hz, 1H), 1.88 (p, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H), 0.62 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 445.10, 447.10 Found 445.1, 447.1.

[0676] Compound 51.10 (i.e. NS-483): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.55 (dd, J = 4.7, 0.9 Hz, 1H), 7.79 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.3, 2.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.31 (dd, J = 6.7, 4.9 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 4.81 (d, J = 18.4 Hz, 1H), 4.76 (d, J = 18.4 Hz, 1H), 2.66 (q, J = 7.3 Hz, 2H), 2.57 (dd, J = 13.7, 6.3 Hz, 1H), 2.13 (dd, J = 13.7, 7.3 Hz, 1H), 1.01 (t, J = 7.3 Hz, 3H), 0.41 (m, 1H), 0.26 (m, 1H), 0.17 (m, 1H), 0.03 (m, 1H), -0.10 (td, J = 9.2, 5.0 Hz, 1H). LC-MS: [M+H] + Calcd 413.08, 415.08 Found 413.1, 415.1.

[0677] Compound 51.11 (i.e. NS-400): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 3.8 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.44 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.7 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 5.49 (ddt, J = 17.1, 9.9, 7.0 Hz, 1H), 5.00 (m, 2H), 4.75 (s, 2H), 3.29 (dd, J = 13.8, 6.8 Hz, 1H), 3.02 (dd, J = 13.8, 6.8 Hz, 1H), 2.63 (t, J = 7.2 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 399.06, 401.06 Found 399.1, 401.1.

[0678] Example 52. Synthesis of compound 52.1

[0679] DAST (161 mg, 1 mmol) was added dropwise to a solution of compound 51.4 (194 mg, 0.5 mmol) in dichloromethane at 0 °C under nitrogen. After 2 h, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with water at 0 °C and saturated NaHC03solution was added. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous Na2S04and concentrated. Purification on silica gel (P:E = 3:1 to 2:1) gave compound 52.1 (112 mg, 54.7%).

[0680] Compound 52.1 (i.e. NS-1699): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.82 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (t, J = 5.1 Hz, 2H), 7.31 (ddd, J = 7.6, 4.8, 0.9 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.30 (t, J = 14.8 Hz, 2H), 2.47 (m, 1H), 2.32 (m, 1H), 2.03 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H), 0.63 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 409.06, 411.06, Found 408.8, 410.8.

[0681] Example 53. Synthesis of compound 53.1

[0682] Compound 1-1 (351 mg, 1 mol, 1 eq), potassium carbonate (207 mg, 1.5 mol) and iodine isopropyl (204 mg, 1.2 mol) were stirred in DMF overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous Na2S04and concentrated. Purification on silica gel (P:E = 4:1 to 3:1) gave compound 53-1 (338 mg, 91.8%).

[0683] Compound 53-2 was obtained by reductive ring closure according to Example 8; compound 53.1 (i.e. NS-455) was obtained by alkylation according to Example 10. Pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 4.7 Hz, 1H), 7.90 (td, J = 7.6, 1.7 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.28 (m, 2H), 7.08 (d, J = 7.2 Hz, 1H), 7.02 (s, 1H), 6.96 (dd, J = 17.3, 7.7 Hz, 2H), 4.65 (s, 2H), 2.65 (qd, J = 7.2, 1.6 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 375.03, 377.03 Found 375.0, 377.0.

[0684] Example 54. Synthesis of compounds 54.1 and 54.2

[0685] A solution of 200 mL of compound 1-1 (35.0 g, 0.1 mol, 1 eq) and 4,4'-dipyridine (780.9 mg, 0.005 mol, 0.05 eq) in DMF was cooled to -40 °C, and tetrahydroxyboron (26.9 g, 0.3 mol, 3 eq) solid was added in batches. After stirring for 2 h, it was slowly raised to 0 °C and stirred overnight. After the reaction solution was added to 2 L of water in batches, it was filtered under suction, and the filter cake was washed with water, ethanol, and ethyl acetate in sequence to obtain compound 54-1 (26.1 g, orange red solid, 90.0%).

[0686] A solution of compound 54-1 (26.1 g, 0.09 mol, 1 eq) and pyridine (14.4 g, 0.18 mol, 2 eq) in 350 mL of dry dichloromethane was cooled to 0 °C under N2 protection, and a solution of acetyl chloride (10.6 g, 0.14 mmol, 1.5 eq) in dry dichloromethane was added dropwise slowly. The reaction was monitored by TLC until the raw material was completely reacted. The reaction solution was concentrated to 40 mL, filtered under suction, and the filter cake was washed with a small amount of ice dichloromethane and dried to obtain compound 54-2 (19.9 g, orange red solid, 67.0%).

[0687] Under N2protection, intermediate 54-2 (12.12 g, 0.04 mol, 1 eq) was dissolved in dry 100 mL DMF solution, iodine isopropyl (7.1 g, 0.05 mol, 1.25 eq) and potassium carbonate (6.6 g, 0.048 mol, 1.2 eq) were added, after stirring overnight, ethyl acetate and water were added, the organic phase was separated, the combined organic phase was washed with brine, concentrated, then methanol solution and catalytic amount of sodium methoxide were added to adjust the pH to 9-10, after TLC monitoring the reaction was complete, concentrated, purified by silica gel column (P:E = 2:1-1:1) to obtain compound 54-3 (11.8 g, white solid, 93.0%).

[0688] Intermediate 54-3 (165 mg, 0.5 mmol) was dissolved in dry DMF solution, bromo butanone (90 mg, 0.6 mmol) and potassium carbonate (83.0 mg, 0.6 mol, 1.2 eq) were added, after stirring for 4 hours, TLC monitoring the reaction was complete, ethyl acetate and water were added, the organic phase was separated, the combined organic phase was washed with brine, concentrated, then purified by silica gel column (P:E = 3:1-2:1) to obtain the target compound 54.1 (i.e. NS-68). White solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.45 (m, 2H), 7.32 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.79 (d, J = 18.2 Hz, 1H), 4.73 (d, J = 18.3 Hz, 1H), 3.01 (m, 1H), 2.65 (q, J = 7.3 Hz, 2H), 1.01 (t, J = 7.3 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H), 0.79 (d, J = 6.9 Hz, 3H). LC-MS: [M+H] + Calcd 401.08, 403.08, Found 400.8, 402.8.

[0689] According to the above synthesis, compound 54-2 was used as raw material, reacted with bromomethyl methyl ether, acetyl deprotection and N-alkylation to obtain compound 54.2 (i.e. NS-253). White solid, 1H NMR (400 MHz, DMSO-d6) δ 8.57 (ddd, J = 4.8, 1.8, 0.8 Hz, 1H), 7.81 (td, J = 7.8, 1.9 Hz, 1H), 7.47 (m, 2H), 7.35 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 4.74 (q, J = 18.2 Hz, 2H), 4.41 (d, J = 9.2 Hz, 1H), 4.10 (d, J = 9.2 Hz, 1H), 3.21 (s, 3H), 2.63 (q, J = 7.3 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 403.06, 405.06, Found 403.1, 405.1.

[0690] Example 55. Synthesis of compound 55.1

[0691] Compound 51.11 (400 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 by sodium thiosulfate solution. Ethyl acetate and water were added, and the organic phase was separated, washed with brine, and concentrated. Compound 55-1 (273 mg, 68.1%) was obtained after purification by silica gel column (P:E=2:1). Compound 55-1 (273 mg, 0.7 mmol) was dissolved in 1,2-dichloroethane, 0.4 mL of dimethylamine tetrahydrofuran solution (2M) and sodium triacetyl borohydride (297 mg, 1.4 mmol) were added, and stirred at room temperature for 4 hours. The reaction was quenched by adding dilute hydrochloric acid, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. Dichloromethane and water were added to separate the liquid. The organic phase was combined, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated, and purified by silica gel column (100% EA ~ DCM / MeOH=10:1) to obtain compound 55.1 (338 mg, 91.8%).

[0692] Compound 55.1 (i.e. NS-203): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 4.0 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.52 (m, 2H), 7.38 (m, 2H), 7.08 (d, J = 8.3 Hz, 1H), 4.84 (s, 2H), 2.89 (m, 4H), 2.78 (s, 6H), 2.69 (q, J = 7.3 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: [M+H] + Calcd 430.11, 432.11, Found 430.1, 432.1.

[0693] Example 56: Synthesis of compounds 56.1 and 56.2

[0694] A solution of compound 53-1 (351 mg, 1 mmol, 1 eq) and iodomethane (170 mg, 1.2 mmol, 1.2 eq) in 5 ml dry DMF was cooled to -10 °C under nitrogen protection, sodium hydride (44 mg, 1.1 mol, 1.1 eq, 40% mineral oil package) was added, and after slowly rising to room temperature, it was stirred for 1 hour, and then quenched with saturated aqueous ammonium chloride solution. Extracted with ethyl acetate and water three times, combined the organic layer, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column (P:E = 4:1) to give compound 56-1 (346 mg, 90.8%).

[0695] Reference Example 1: compound 56-1 was reduced to close ring to synthesize intermediate 56-2 by zinc powder / ammonium chloride system, and Reference Example 2: compound 56.1 was synthesized; Reference Example 9: compound 56-1 was reduced to close ring to synthesize intermediate 56-3, and Reference Example 10: compound 56.2 was synthesized.

[0696] Compound 56.1 (i.e. NS-248): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 4.0 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.52 (m, 2H), 7.38 (m, 2H), 7.08 (d, J = 8.3 Hz, 1H), 4.84 (s, 2H), 2.89 (m, 4H), 2.78 (s, 6H), 2.69 (q, J = 7.3 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: [M+H] +Calcd 406.03, 408.03, Found 406.0, 408.0.

[0697] Compound 56.2 (i.e. NS-249): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H), 7.92 (td, J = 7.7, 1.8 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.4, 2.1 Hz, 1H), 7.35 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.82 (d, J = 18.3 Hz, 1H), 4.75 (d, J = 18.3 Hz, 1H), 3.26 (s, 3H), 2.66 (q, J = 7.2 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 389.04, 391.04, Found 389.0, 391.0.

[0698] Example 57: Synthesis of compounds 57.1-57.5

[0699] Under nitrogen protection, sodium hydride (240 mg, 6 mmol, 40% mineral oil package) was washed with n-hexane and then suspended in 30 mL of dry tetrahydrofuran, 20 mL of dry tetrahydrofuran solution of compound 1-1 (1.76 g, 5 mmol) was added dropwise under ice water bath. After stirring at low temperature for 1 hour, N-fluorobenzenesulfonimide (1.74 g, 5.5 mmol) was added in batches. The reaction was slowly raised to room temperature. The reaction was quenched with methanol, and the reaction solution was filtered with celite. The filtrate was concentrated. Compound 57-1 (1.71 g, 92.7%) was obtained after silica gel column purification (P:E=3:1).

[0700] Reference Example 1 was used to synthesize intermediate 57-2;

[0701] Reference Example 9 was used to synthesize intermediate 57-3.

[0702] With 57-2 as raw material, Reference Examples 2 and 4 were used to synthesize compounds 57.1 and 57.2.

[0703] With 57-3 as raw material, Reference Examples 9 and 17 were used to synthesize compounds 57.3-57.5.

[0704] Compound 57.1 (i.e. NS-742): pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.54 (dt, J = 4.8, 1.2 Hz, 1H), 8.05 (td, J = 7.8, 1.7 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.72 (ddd, J = 7.7, 3.8, 1.8 Hz, 2H), 7.50 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.17 (dd, J = 8.2, 0.9 Hz, 1H), 3.13 (s, 3H), 2.98 (s, 3H). LC-MS: [M+H] + Calcd 394.01, 396.01, Found 394.0, 396.0.

[0705] Compound 57.2 (i.e. NS-744): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.50 (dt, J = 4.4, 0.8 Hz, 1H), 8.04 (td, J = 7.8, 1.7 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.77 (dt, J = 8.4, 1.8 Hz, 1H), 7.65 (t, J = 1.9 Hz, 1H), 7.49 (m, 1H), 7.38 (dd, J = 8.4, 1.2 Hz, 1H), 5.04 (d, J = 15.9 Hz, 1H), 4.94 (d, J = 15.9 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 409.01, 411.01, Found 409.0, 411.0.

[0706] Compound 57.3 (i.e. NS-465): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (dt, J = 4.6, 1.0 Hz, 1H), 8.03 (td, J = 7.8, 1.7 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.65 (dt, J = 8.4, 1.9 Hz, 1H), 7.54 (t, J = 2.0 Hz, 1H), 7.47 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.09 (dd, J = 8.4, 1.1 Hz, 1H), 4.79 (s, 2H), 2.65 (q, J = 7.2 Hz, 2H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 377.02, 379.02, Found 377.0, 379.0.

[0707] Compound 57.4 (i.e. NS-582): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (m, 1H), 8.02 (td, J = 7.8, 1.7 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.68 (dt, J = 8.4, 1.9 Hz, 1H), 7.50 (t, J = 2.0 Hz, 1H), 7.46 (ddd, J = 7.6, 4.8, 1.0 Hz, 1H), 7.26 (dd, J = 8.5, 0.9 Hz, 1H), 3.94 (t, J = 7.1 Hz, 2H), 2.85 (t, J = 7.1 Hz, 2H), 2.47 (t, J = 7.3 Hz, 2H), 1.46 (m, 2H), 1.23 (m, 1H), 0.84 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 433.08, 435.08, Found 433.1, 435.1.

[0708] Compound 57.5 (i.e. NS-583): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 4.8 Hz, 1H), 8.12 (m, 2H), 8.05 (td, J = 7.8, 1.7 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.4 Hz, 1H), 7.63 (m, 3H), 7.58 (t, J = 2.0 Hz, 1H), 7.49 (dd, J = 6.8, 4.8 Hz, 1H), 7.17 (dd, J = 8.5, 0.9 Hz, 1H), 5.51 (s, 2H). LC-MS: [M+H] + Calcd 425.02, 427.02, Found 425.0, 427.0.

[0709] Example 58. Synthesis of compound 58.1

[0710] Compound 54-1 (289 mg, 1 mmol) was suspended in 10 mL of acetonitrile, trimethylsilyl azide (230 mg, 2 mmol) and copper acetate (36 mg, 0.2 mmol) were added, stirred at 40 °C for 2 hours, the reaction was clarified, ethyl acetate was added, suction filtration, the filtrate was concentrated under reduced pressure, purified by silica gel column (P:E = 1:2) to obtain compound 58-1 (69 mg, 20.9%).

[0711] Reference Example 10 was used to synthesize compound 58.1 (i.e. NS-467) with 58-1 as raw material. Yellow solid,1 H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, J = 4.8, 0.8 Hz, 1H), 7.97 (td, J = 7.8, 1.8 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (m, 2H), 7.11 (d, J = 8.5 Hz, 1H), 4.85 (s, 2H), 2.68 (q, J = 7.3 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 400.03, 402.03, Found 400.0, 402.0.

[0712] Example 59. Synthesis of compound 59.1

[0713] Compound 54-1 (289 mg, 1 mmol) was suspended in 10 mL of acetonitrile, nitrile trimethylsilane (200 mg, 2 mmol) and copper acetate (36 mg, 0.2 mmol) were added, stirred at 40 °C for 6 hours, the reaction was clarified, ethyl acetate was added, suction filtration, the filtrate was concentrated under reduced pressure, and compound 59-1 (52 mg, 16.6%) was obtained after silica gel column purification (P:E = 1:4).

[0714] Reference Example 10 was synthesized with 59-1 as raw material to synthesize compound 59.1 (i.e. NS-468). White solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (dd, J = 4.8, 0.8 Hz, 1H), 7.97 (td, J = 7.8, 1.8 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (m, 2H), 7.11 (d, J = 8.5 Hz, 1H), 4.85 (s, 2H), 2.68 (q, J = 7.3 Hz, 2H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 384.03, 386.03, Found 384.0, 386.0.

[0715] Example 60. Synthesis of compounds 60.1-60.5

[0716] Compound 54-1 (144 mg, 0.5 mmol) was suspended in 10 mL of ethanol, azetidine (57 mg, 1 mmol) and iodine (28 mg, 0.1 mmol) were added, and hydrogen peroxide (113 μl, 1 mmol, 30 wt%) was added dropwise at room temperature. After stirring for 1 hour, the reaction was clear. The reaction was quenched by adding thiosulfate, and the reaction solution was filtered and partitioned with ethyl acetate. The organic layer was combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 1 : 1 to 1 : 4) to obtain compound 60-1 (52 mg, 16.6%).

[0717] Referring to Example 10, compound 60.1 (i.e., NS-527) was synthesized using 60-1 as a starting material. Yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 4.6 Hz, 1H), 7.89 (m, 2H), 7.42 (dd, J = 8.4, 2.0 Hz, 1H), 7.31 (ddd, J = 6.7, 4.8, 1.8 Hz, 1H), 7.20 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.87 (d, J = 18.2 Hz, 1H), 4.71 (d, J = 18.2 Hz, 1H), 3.59 (q, J = 7.0 Hz, 2H), 2.68 (q, J = 7.3 Hz, 2H), 1.98 (p, J = 7.1 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 414.07, 416.07, Found 414.1, 416.1.

[0718] Following the above procedure, 54-1 was reacted with dimethylamine to ultimately obtain compounds 60.2-60.4.

[0719] Compound 60.2 (i.e., NS-528): Yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (dd, J = 4.8, 0.7 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.90 (td, J = 7.7, 1.8 Hz, 1H), 7.44 (dd, J = 8.3, 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.33 (ddd, J = 7.2, 4.8, 1.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 4.78 (d, J = 18.2 Hz, 1H), 4.67 (d, J = 18.2 Hz, 1H), 2.65 (m, 2H), 2.30 (s, 6H), 1.00 (t, J = 7.3 Hz, 3H). LC-MS: [M+H]+ Calcd 402.07, 404.07, Found 402.1, 404.1.

[0720] Compound 60.3 (i.e. NS-573): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 4.7 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.89 (m, 1H), 7.47 (dd, J = 8.4, 2.1 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.32 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 4.00 (ddd, J = 14.4, 6.8, 5.0 Hz, 1H), 3.82 (dt, J = 14.5, 5.1 Hz, 1H), 3.58 (m, 2H), 3.24 (s, 3H), 2.25 (s, 6H). LC-MS: [M+H] + Calcd 390.07, 392.07, Found 390.1, 392.1.

[0721] Compound 60.4 (i.e. NS-574): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.90 (td, J = 7.7, 1.7 Hz, 1H), 7.48 (dd, J = 8.3, 2.0 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.32 (m, 1H), 7.07 (d, J = 8.4 Hz, 1H), 3.78 (dt, J = 14.1, 7.2 Hz, 1H), 3.68 (dt, J = 14.0, 7.0 Hz, 1H), 2.26 (s, 6H), 1.59 (m, 2H), 1.36 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 388.09, 390.09, Found 388.1, 390.1.

[0722] Compound 60.5 (i.e. NS-575): pale yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.89 (m, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.32 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 3.97 (dt, J = 14.4, 7.2 Hz, 1H), 3.87 (dt, J = 14.1, 6.9 Hz, 1H), 2.81 (td, J = 7.1, 2.0 Hz, 2H), 2.47 (t, J = 7.2 Hz, 2H), 2.24 (s, 6H), 1.48 (h, J = 7.3 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 430.11, 432.11, Found 430.1, 432.1.

[0723] Example 61. Synthesis of compounds 61.1-61.7

[0724] 2-Formylthiazole (1.13 g, 10 mmol) was dissolved in 30 mL of ethanol, sodium acetate (984 mg, 12 mmol) and hydroxylamine hydrochloride (732 mg, 12 mmol) were added, after refluxing for two hours, the solvent was removed under reduced pressure, the organic layer was separated with water, the organic layer was combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 2:1) to obtain compound 61-1 (1.26 mg, 98.4%). Compound 61-1 was dissolved in 20 mL of ethanol, acetic acid (3.6 g, 60 mmol) was added under ice bath condition, zinc powder (1.95 g, 30 mmol) was added in batches, slowly warmed to room temperature, stirred at room temperature overnight, saturated sodium bicarbonate solution was added to quench the reaction, the reaction solution was filtered through celite, the filter cake was washed with dichloromethane, and the filtrate was separated with ammonium chloride aqueous solution. The organic layer was combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (100% EA ~ DCM / MeOH = 10:1) to obtain compound 61-2 (214 mg, 18.9%).

[0725] Referring to Example 22, compound 61-2 was subjected to reductive amination with compound 24-1 to obtain compounds 61.1 and 61.2.

[0726] Compound 61.1 (i.e. NS-337): yellow gum, 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 3.8 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.70 (d, J = 3.3 Hz, 1H), 7.57 (d, J = 3.3 Hz, 1H), 7.47 (dd, J = 11.6, 5.1 Hz, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 7.5, 4.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.05 (s, 2H), 3.90 (m, 2H), 2.91 (s, 2H), 1.77 (s, 3H). LC-MS: [M+H] + Calcd 443.05, 445.05, Found 443.1, 445.1.

[0727] Compound 61.2 (i.e. NS-365): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 3.8 Hz, 1H), 7.79 (td, J = 7.8, 1.9 Hz, 1H), 7.70 (d, J = 3.3 Hz, 1H), 7.57 (d, J = 3.3 Hz, 1H), 7.47 (dd, J = 11.6, 5.1 Hz, 2H), 7.38 (d, J = 2.0 Hz, 1H), 7.29 (dd, J = 7.5, 4.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.05 (s, 2H), 3.90 (m, 2H), 2.91 (s, 2H), 1.77 (s, 3H). LC-MS: [M+H] + Calcd 540.04, 542.04, Found 540.0, 542.0.

[0728] Referring to the above synthesis method, the amino compound 61-3 was synthesized using 3-methoxythiophene-2-carboxaldehyde as the raw material, and further reductive amination with compound 24-1 to obtain compound 61.3 (i.e. NS-335): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.9 Hz, 1H), 7.78 (td, J = 7.8, 1.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.29 (t, J = 6.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 3.86 (m, 2H), 3.77 (s, 2H), 3.75 (s, 3H), 2.82 (t, J = 6.1 Hz, 2H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 472.06, 474.06, Found 472.1, 474.1.

[0729] 3-Hydroxythiophene-2-carboxaldehyde (2.56 g, 20 mmol) was dissolved in dry DMF with p-toluenesulfonic acid cyclopentyl ester (7.2 g, 30 mmol) and a catalytic amount of tetrabutylammonium iodide and potassium carbonate (4.14 g, 30 mmol) was added. Stirred at room temperature overnight, partitioned with ethyl acetate and water, combined the organic layers, dried over anhydrous sodium sulfate, concentrated, and purified on silica gel column (P:E = 4:1 to 3:1) to give compound 61-4 (879 mg, 22.4%).

[0730] Amino compound 61-5 was obtained by referring to the synthesis method of compound 61-2. Compound 61-5 was subjected to reductive amination with compound 24-1 to give compound 61.4 (i.e., NS-341): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.9 Hz, 1H), 7.78 (td, J = 7.8, 1.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 1.9 Hz, 1H), 7.29 (t, J = 6.0 Hz, 2H), 7.13 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 3.86 (m, 2H), 3.77 (s, 2H), 3.75 (s, 3H), 2.82 (t, J = 6.1 Hz, 2H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 526.11, 528.11, Found 526.1, 528.1.

[0731] Compound 61-6 was synthesized according to the alkylation procedure of Example 4. Compound 61-7 was obtained by reference to the synthesis of compound 24-1 of Example 24. Reduction amination of 61-7 with 61-2, 61-3 and 61-5 in sequence gave compounds 61.5, 61.6 and 61.7, respectively.

[0732] Compound 61.5 (i.e. NS-325): yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.7, 1.0 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.62 (d, J = 3.3 Hz, 1H), 7.53 (dd, J = 8.2, 1.9 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.30 (t, J = 4.9 Hz, 2H), 4.09 (br s, 2H), 2.98 (s, 3H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 459.04, 461.04, Found 459.0, 461.0.

[0733] Compound 61.6 (i.e. NS-321): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.7, 1.0 Hz, 1H), 7.85 (td, J = 7.8, 1.9 Hz, 1H), 7.73 (d, J = 3.3 Hz, 1H), 7.62 (d, J = 3.3 Hz, 1H), 7.53 (dd, J = 8.2, 1.9 Hz, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.33 (ddd, J = 7.5, 4.8, 0.8 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.30 (t, J = 4.9 Hz, 2H), 4.09 (br s, 2H), 2.98 (s, 3H), 1.81 (s, 3H). LC-MS: [M+H] + Calcd 487.06, 489.06, Found 487.1, 489.1.

[0734] Compound 61.7 (i.e. NS-316): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (dd, J = 4.8, 0.9 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.51 (dd, J = 8.2, 1.9 Hz, 2H), 7.45 (d, J = 1.9 Hz, 1H), 7.32 (m, 2H), 7.17 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 5.5 Hz, 1H), 4.69 (m, 1H), 4.26 (t, J = 5.3 Hz, 2H), 3.77 (s, 2H), 2.86 (br s, 2H), 1.79 (s, 3H), 1.71 (m, 6H), 1.54 (m, 2H). LC-MS: [M+H] + Calcd 542.10, 544.10, Found 542.1, 544.1.

[0735] Example 62. Synthesis of compounds 62.1-62.6

[0736] Referring to the synthesis of Example 15, after synthesis of the corresponding acyl chloride from 15-1, compounds 62.1, 62.2 and 62.3 were obtained by reacting with amino compounds 61-2, 61-3 and 61-6, respectively.

[0737] Compound 62.1 (i.e. NS-338): yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (t, J = 5.9 Hz, 1H), 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.81 (td, J = 7.8, 1.8 Hz, 1H), 7.75 (d, J = 3.3 Hz, 1H), 7.66 (d, J = 3.3 Hz, 1H), 7.47 (m, 2H), 7.40 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 7.0, 5.2 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.54 (s, 2H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 457.03, 459.03, Found 457.0, 459.0.

[0738] Compound 62.2 (i.e. NS-336): light yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.6 Hz, 1H), 8.47 (d, J = 3.9 Hz, 1H), 7.82 (td, J = 7.8, 1.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.3, 2.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 5.5 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 0.9 Hz, 1H), 6.97 (dd, J = 13.1, 6.9 Hz, 2H), 4.44 (d, J = 3.5 Hz, 2H), 4.35 (d, J = 5.7 Hz, 2H), 3.80 (s, 3H), 1.79 (s, 3H). LC-MS: [M+H] + Calcd 486.04, 488.04, Found 486.0, 488.0.

[0739] Compound 62.3 (i.e. NS-342): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 5.7 Hz, 1H), 8.45 (d, J = 3.8 Hz, 1H), 7.82 (td, J = 7.9, 1.7 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.3, 2.0 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 7.31 (m, 1H), 6.95 (dd, J = 6.9, 3.7 Hz, 2H), 4.73 (br s, 1H), 4.45 (d, J = 5.3 Hz, 2H), 4.33 (d, J = 5.5 Hz, 2H), 1.79 (s, 3H), 1.70 (m, 6H), 1.56 (m, 2H). LC-MS: [M+H] + Calcd 540.09, 542.09, Found 540.1, 542.1.

[0740] Reference Example 4 alkylation reaction to obtain compound 62-1, Reference Example 6 after hydrolysis of tert-butyl ester and condensation with amino compounds 61-2, 61-3 and 61-6 to obtain compounds to obtain compounds 62.4-62.6.

[0741] Compound 62.4 (i.e. NS-327): pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 9.18 (t, J = 5.2 Hz, 1H), 8.49 (dd, J = 4.7, 0.9 Hz, 1H), 7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.72 (d, J = 3.3 Hz, 1H), 7.61 (d, J = 3.3 Hz, 1H), 7.52 (dd, J = 8.3, 1.9 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 7.5, 4.8 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 4.82 (s, 2H), 4.63 (d, J = 6.0 Hz, 2H), 1.80 (s, 3H). LC-MS: [M+H] + Calcd 473.02, 475.02, Found 473.0, 475.0.

[0742] Compound 62.5 (i.e. NS-323): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (t, J = 5.4 Hz, 1H), 8.48 (d, J = 4.7 Hz, 1H), 7.81 (td, J = 7.7, 1.6 Hz, 1H), 7.52 (dd, J = 8.4, 1.8 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 7.33 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 5.5 Hz, 1H), 4.72 (s, 2H), 4.32 (d, J = 5.7 Hz, 2H), 3.77 (s, 3H), 1.78 (s, 3H). LC-MS: [M+H] + Calcd 502.04, 504.04, Found 502.0, 504.0.

[0743] Compound 62.6 (i.e. NS-318): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.72 (t, J = 5.6 Hz, 1H), 8.48 (d, J = 3.9 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz, 1H), 7.52 (dd, J = 8.3, 2.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.31 (m, 3H), 6.92 (d, J = 5.5 Hz, 1H), 4.71 (m, 3H), 4.30 (d, J = 5.7 Hz, 2H), 1.78 (s, 3H), 1.72 (t, J = 11.5 Hz, 6H), 1.55 (d, J = 4.9 Hz, 2H). LC-MS: [M+H] + Calcd 556.08, 558.08, Found 556.1, 558.1.

[0744] Example 63. Synthesis of compounds 63.1-63.11

[0745] Reference Example 1, methyl 2-fluorobenzoate was reacted with 2-fluoro-p-bromonitrobenzene to give 63-1, which was further methylated to give compound 63-2.

[0746] Reference Example 1, zinc powder reduction of the nitro group to give compound 63-3;

[0747] Reference Example 2 to synthesize compounds 63.1 (i.e. NS-795) and 63.2 (i.e. NS-1093);

[0748] Reference Example 4 to synthesize compound 63.3 (i.e. NS-796);

[0749] Reference Example 7 to synthesize compound 63.4 (i.e. NS-797).

[0750] Compound 63.1 (i.e. NS-795): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (td, J = 8.1, 1.4 Hz, 1H), 7.53 (dd, J = 8.3, 1.9 Hz, 1H), 7.45 (tdd, J = 7.3, 5.3, 1.6 Hz, 1H), 7.34 (td, J = 7.6, 1.1 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.14 (ddd, J = 11.6, 8.1, 1.1 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 3.13 (s, 3H), 2.98 (s, 3H), 1.80 (s, 3H). LC-MS: [M+H] +Calcd 407.03, 409.03, Found 407.0, 409.0.

[0751] Compound 63.2 (i.e. NS-1093): pale yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (t, J = 7.7 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.45 (dd, J = 13.4, 5.9 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.15 (ddd, J = 11.6, 8.1, 1.0 Hz, 1H), 6.96 (m, 1H), 4.18 (m, 0.4H), 3.98 (m, 0.6H), 2.96 (s, 1.8H), 2.82 (s, 1.2H), 1.53 (m, 2H), 1.23 (m, 4H), 0.95 (dt, J = 12.7, 6.5 Hz, 1.2H), 0.86 (t, J = 7.2 Hz, 1.8H). LC-MS: [M+H] + Calcd 449.08, 451.08, Found 448.8, 450.8.

[0752] Compound 63.3 (i.e. NS-796): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (td, J = 8.0, 1.6 Hz, 1H), 7.55 (dd, J = 8.3, 2.0 Hz, 1H), 7.44 (tdd, J = 7.3, 5.3, 1.6 Hz, 1H), 7.34 (td, J = 7.6, 1.2 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 7.13 (ddd, J = 11.6, 8.1, 1.0 Hz, 1H), 4.99 (d, J = 14.1 Hz, 1H), 4.96 (d, J = 14.1 Hz, 1H), 3.00 (s, 3H), 2.87 (s, 3H), 1.76 (s, 3H). LC-MS: [M+H] + Calcd 421.05, 423.05, Found 421.0, 423.0.

[0753] Compound 63.4 (i.e. NS-797): white solid, 1H NMR (400 MHz, DMSO-d6) δ 7.74 (td, J = 8.0, 1.4 Hz, 1H), 7.55 (dd, J = 8.3, 1.9 Hz, 1H), 7.43 (m, 1H), 7.33 (m, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.13 (dd, J = 11.7, 8.2 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 3.98 (m, 2H), 2.07 (dt, J = 13.4, 6.7 Hz, 1H), 1.76 (s, 3H), 1.05 (d, J = 6.7 Hz, 6H). LC-MS: [M+H] + Calcd 392.06, 394.06, Found 392.1, 394.1.

[0754] Reference Example 9 Zinc dust reduction of nitro group to give compound 63-4;

[0755] Reference Example 10 Synthesis of compound 63.4 (i.e. NS-569);

[0756] Reference Example 21 Synthesis of compound 63.5 (i.e. NS-570) and 63.6 (i.e. NS-571);

[0757] Reference Example 17 Synthesis of compound 63.7 (i.e. NS-572);

[0758] Reference Example 9 Synthesis of compound compound 63.8 (i.e. NS-1092).

[0759] Compound 63.4 (i.e. NS-569): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (td, J = 8.0, 1.6 Hz, 1H), 7.45 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (ddd, J = 7.1, 4.6, 1.9 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.11 (ddd, J = 11.6, 8.1, 1.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.78 (d, J = 18.2 Hz, 1H), 4.73 (d, J = 18.2 Hz, 1H), 2.64 (q, J = 7.2 Hz, 2H), 1.75 (s, 3H), 1.01 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 390.04, 392.04, Found 390.0, 3 92.0.

[0760] Compound 63.5 (i.e. NS-570): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (td, J = 8.0, 1.6 Hz, 1H), 7.47 (dd, J = 8.4, 2.1 Hz, 1H), 7.41 (tdd, J = 7.3, 5.3, 1.7 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.16 (m, 2H), 7.09 (ddd, J = 11.6, 8.1, 1.1 Hz, 1H), 3.93 (qt, J = 14.4, 5.4 Hz, 2H), 3.59 (m, 2H), 3.27 (d, J = 5.2 Hz, 3H), 1.69 (s, 3H). LC-MS: [M+H] + Calcd 378.04, 380.04, Found 378.0, 380.0.

[0761] Compound 63.6 (i.e. NS-571): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (td, J = 8.0, 1.7 Hz, 1H), 7.48 (dd, J = 8.3, 2.1 Hz, 1H), 7.40 (tdd, J = 7.3, 5.3, 1.7 Hz, 1H), 7.32 (td, J = 7.6, 1.3 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.09 (ddd, J = 11.7, 8.1, 1.2 Hz, 1H), 3.75 (tq, J = 14.2, 7.0 Hz, 2H), 1.69 (s, 3H), 1.62 (m, 2H), 1.37 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 376.06, 378.06, Found 376.1, 378.1.

[0762] Compound 63.7 (i.e. NS-572): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 7.72 (td, J = 8.0, 1.7 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (dt, J = 5.3, 3.7 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.08 (ddd, J = 11.7, 8.1, 1.1 Hz, 1H), 3.95 (t, J = 7.1 Hz, 2H), 2.82 (m, 2H), 2.48 (td, J = 7.2, 2.0 Hz, 2H), 1.68 (s, 3H), 1.47 (m, 2H), 1.23 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 446.11, 448.11, Found 445.9, 447.9.

[0763] Compound 63.8 (i.e. NS-1092): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.76 (t, J = 7.4 Hz, 1H), 7.52 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d, J = 5.4 Hz, 1H), 7.36 (t, J = 7.1 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.32 (dd, J = 13.4, 7.8 Hz, 0.6H), 3.77 (br s, 0.4H), 2.90 (s, 1.2H), 2.83 (s, 1.8H), 1.82 (s, 1.8H), 1.77 (s, 1.2H), 1.55 (br s, 2H), 1.23 (m, 3H), 0.92 (br s, 1.8H), 0.73 (br s, 1.2H). LC-MS: [M+H] + Calcd 433.08, 435.08, Found 432.8, 434.8.

[0764] Compound 63-5 was synthesized according to the procedure described in Reference Example 54 for the synthesis of compound 54-1;

[0765] Compound 63-6 was synthesized according to the procedure described in Reference Example 60;

[0766] Compounds 63.8-63.11 were synthesized according to the procedures described in Reference Examples 10, 17 and 21.

[0767] Compound 63.8 (i.e. NS-542): white solid,1 H NMR (400 MHz, DMSO-d6) δ 7.90 (td, J = 7.8, 1.9 Hz, 1H), 7.50 (dd, J = 8.4, 2.0 Hz, 1H), 7.40 (tdd, J = 7.2, 5.1, 1.9 Hz, 1H), 7.34 (td, J = 7.6, 1.4 Hz, 1H), 7.15 (m, 2H), 7.12 (m, 1H), 3.99 (ddd, J = 14.4, 6.6, 5.1 Hz, 1H), 3.89 (dt, J = 14.5, 5.1 Hz, 1H), 3.60 (m, 2H), 3.27 (s, 3H), 2.24 (s, 6H). LC-MS: [M+H] + Calcd 407.07, 409.07, Found 406.9, 408.9.

[0768] Compound 63.9 (i.e. NS-543): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (td, J = 7.8, 1.9 Hz, 1H), 7.51 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (tdd, J = 7.3, 5.1, 2.0 Hz, 1H), 7.34 (td, J = 7.5, 1.4 Hz, 1H), 7.12 (m, 3H), 3.74 (t, J = 7.3 Hz, 2H), 2.24 (s, 6H), 1.61 (m, 2H), 1.39 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 405.09, 407.09, Found 404.9, 406.9.

[0769] Compound 63.10 (i.e. NS-544): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (td, J = 7.9, 1.9 Hz, 1H), 7.52 (dd, J = 8.4, 2.1 Hz, 1H), 7.39 (m, 1H), 7.33 (td, J = 7.6, 1.4 Hz, 1H), 7.13 (m, 3H), 3.94 (td, J = 7.7, 2.0 Hz, 2H), 2.84 (t, J = 7.1 Hz, 2H), 2.49 (m, 2H), 2.22 (s, 6H), 1.48 (m, 2H), 1.24 (m, 4H), 0.86 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 475.13, 477.13, Found 474.9, 476.9.

[0770] Compound 63.11 (i.e. NS-545): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (td, J = 7.8, 1.7 Hz, 1H), 7.48 (dd, J = 8.4, 2.0 Hz, 1H), 7.41 (tdd, J = 7.3, 5.1, 1.8 Hz, 1H), 7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.14 (ddd, J = 12.1, 8.2, 1.1 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 4.81 (d, J = 18.2 Hz, 1H), 4.72 (d, J = 18.2 Hz, 1H), 2.67 (q, J = 7.3 Hz, 2H), 2.28 (s, 6H), 1.02 (t, J = 7.3 Hz, 3H). LC-MS: [M+H] + Calcd 419.07,421.07,Found 418.9,420.9.

[0771] Example 64. Synthesis of compounds 64.1-64.8

[0772] Potassium tert-butoxide (11.2 g, 100 mmol) was dissolved in dry DMF under nitrogen protection, and the temperature was reduced to -40 °C. A mixture of p-bromonitrobenzene (8.0 g, 40 mmol) and methyl 2-chloropropionate (5.4 g, 44 mmol) in DMF was added dropwise, keeping the reaction temperature below -15 °C during the process. After the dropwise addition was completed, the reaction was slowly raised to 0 °C and incubated at 0 °C for 1 h, and then quenched by the addition of dilute hydrochloric acid. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 3:1-2:1) to give compound 64-1 (4.96 g, 43.1%).

[0773] A mixture of compound 64-1 (1.44 g, 5 mmol), potassium carbonate (1.66 g, 12 mmol) and 2-(bromomethyl)pyridine hydrobromide (1.52 g, 6 mmol) in 15 mL of dry DMF was stirred at room temperature for 16 h under nitrogen protection, and then partitioned between ethyl acetate and water. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column (P:E = 4:1-3:1) to give compound 64-2 (1.45 g, 76.7%).

[0774] Compound 64-3 was obtained by reduction and ring closure according to Reference Example 1;

[0775] Compounds 64.1-64.3 were synthesized according to Reference Examples 1 and 2 using 64-3 as the starting material.

[0776] Compound 64.1 (i.e. NS-353): white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 4.5 Hz, 1H), 7.59 (td, J = 7.7, 1.4 Hz, 1H), 7.54 (s, 1H), 7.36 (dd, J = 8.2, 1.4 Hz, 1H), 7.11 (dd, J = 7.2, 5.2 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 3.43 (d, J = 14.2 Hz, 1H), 3.32 (d, J = 14.1 Hz, 1H), 3.09 (s, 3H), 2.94 (s, 3H), 1.46 (s, 3H). LC-MS: [M+H] + Calcd 404.05, 406.05, Found 404.1, 406.1.

[0777] Compound 64.2 (i.e. NS-354): light yellow syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (dd, J = 4.8, 0.8 Hz, 1H), 7.56 (td, J = 7.7, 1.8 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.36 (dd, J = 8.3, 2.0 Hz, 1H), 7.07 (dd, J = 7.1, 5.3 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 4.91 (d, J = 13.7 Hz, 1H), 4.73 (d, J = 13.7 Hz, 1H), 3.43 (d, J = 14.6 Hz, 1H), 3.34 (d, J = 14.2 Hz, 1H), 2.99 (s, 3H), 2.85 (s, 3H), 1.42 (s, 3H). LC-MS: [M+H] + Calcd 418.07, 420.07, Found 418.1, 420.1.

[0778] Compound 64.3 (i.e. NS-616): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.0 Hz, 1H), 7.56 (m, 2H), 7.37 (dd, J = 8.3, 2.0 Hz, 1H), 7.07 (dd, J = 7.3, 5.0 Hz, 1H), 7.02 (m, 2H), 4.89 (d, J = 16.0 Hz, 1H), 4.80 (d, J = 16.0 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.45 (d, J = 14.6 Hz, 1H), 3.35 (d, J = 14.9 Hz, 3H), 1.43 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 419.05, 421.05, Found 419.1, 421.1.

[0779] Referring to the above synthesis, compound 64-1 was reacted with 3-bromomethylpyridine hydrobromide to give compound 64-4, which was further reduced to close the ring to give compound 64-5.

[0780] Referring to Examples 1 and 2, compounds 64.4-64.6 were synthesized using 64-5 as the starting material.

[0781] Compound 64.4 (i.e., NS-694): light yellow solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J = 4.0 Hz, 1H), 7.56 (m, 2H), 7.37 (dd, J = 8.3, 2.0 Hz, 1H), 7.07 (dd, J = 7.3, 5.0 Hz, 1H), 7.02 (m, 2H), 4.89 (d, J = 16.0 Hz, 1H), 4.80 (d, J = 16.0 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.45 (d, J = 14.6 Hz, 1H), 3.35 (d, J = 14.9 Hz, 3H), 1.43 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 404.05, 406.05, Found 404.1, 406.1.

[0782] Compound 64.5 (i.e., NS-695): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.30 (dd, J = 4.7, 1.7 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.3, 2.0 Hz, 1H), 7.18 (dt, J = 7.8, 1.9 Hz, 1H), 7.13 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 4.70 (d, J = 14.1 Hz, 1H), 4.47 (d, J = 14.1 Hz, 1H), 3.24 (d, J = 13.3 Hz, 1H), 3.09 (d, J = 13.3 Hz, 1H), 2.89 (s, 3H), 2.79 (s, 3H), 1.47 (s, 3H). LC-MS: [M+H] + Calcd 418.07, 420.07, Found 418.1, 420.1.

[0783] Compound 64.6 (i.e. NS-740): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (dd, J = 4.7, 1.6 Hz, 0H), 8.00 (d, J = 1.7 Hz, 0H), 7.85 (d, J = 1.9 Hz, 0H), 7.47 (dd, J = 8.3, 1.9 Hz, 0H), 7.18 (dt, J = 7.7, 1.8 Hz, 0H), 7.11 (dd, J = 7.6, 4.7 Hz, 0H), 6.97 (d, J = 8.3 Hz, 0H), 4.72 (d, J = 16.0 Hz, 0H), 4.50 (d, J = 16.0 Hz, 0H), 4.07 (q, J = 7.1 Hz, 1H), 3.25 (d, J = 13.3 Hz, 0H), 3.09 (d, J = 13.3 Hz, 0H), 1.47 (s, 3H), 1.16 (t, J = 7.1 Hz, 1H). LC-MS: [M+H] + Calcd 419.05, 421.05, Found 419.1, 421.1.

[0784] Referring to the above method, compound 64-1 reacts with 4-bromomethylpyridine hydrobromide to generate 64-6, and then ring closure reduction to obtain compound 64-7, and finally to synthesize compounds 64.7 and 64.8.

[0785] Compound 64.7 (i.e. NS-730): light yellow syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J = 4.5, 1.5 Hz, 2H), 7.85 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 5.9 Hz, 2H), 4.75 (d, J = 16.1 Hz, 1H), 4.58 (d, J = 16.1 Hz, 1H), 4.04 (m, 2H), 3.26 (d, J = 12.9 Hz, 1H), 3.09 (d, J = 12.9 Hz, 1H), 1.47 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 419.05, 421.05, Found 419.1, 421.1.

[0786] Compound 64.8 (i.e. NS-731): off-white solid, 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (dd, J = 4.5, 1.5 Hz, 2H), 7.85 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 8.3, 1.9 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 5.9 Hz, 2H), 4.75 (d, J = 16.1 Hz, 1H), 4.58 (d, J = 16.1 Hz, 1H), 4.04 (m, 2H), 3.26 (d, J = 12.9 Hz, 1H), 3.09 (d, J = 12.9 Hz, 1H), 1.47 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). LC-MS: [M+H] + Calcd 404.05, 406.05, Found 404.1, 406.1.

[0787] Example 65: Synthesis of compounds 65.1-65.8

[0788] The indolinone intermediate 65-1 was obtained by reduction of the ring closure of compound 65-2 according to Example 9.

[0789] The reaction of compound 65-1 with 1-hexen-3-one and 1-octen-3-one was carried out according to Reference Example 17 to give compounds 65.1 and 65.2, respectively.

[0790] Compound 65.1 (i.e. NS-477): white solid, 1H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J = 4.8, 0.9 Hz, 1H), 7.56 (td, J = 7.7, 1.8 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.3, 2.1 Hz, 1H), 7.08 (dd, J = 7.0, 5.3 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.86 (dt, J = 8.1, 7.2 Hz, 1H), 3.71 (dt, J = 14.4, 7.2 Hz, 1H), 3.36 (d, J = 14.2 Hz, 1H), 3.28 (d, J = 14.1 Hz, 1H), 2.62 (m, 2H), 2.44 (m, 2H), 1.48 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 415.09, 417.09, Found 415.1, 417.1.

[0791] Compound 65.2 (i.e. NS-478): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (dd, J = 4.8, 0.9 Hz, 1H), 7.56 (td, J = 7.7, 1.8 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.30 (dd, J = 8.3, 2.1 Hz, 1H), 7.08 (dd, J = 7.0, 5.3 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 3.86 (dt, J = 8.1, 7.2 Hz, 1H), 3.71 (dt, J = 14.4, 7.2 Hz, 1H), 3.36 (d, J = 14.2 Hz, 1H), 3.28 (d, J = 14.1 Hz, 1H), 2.62 (m, 2H), 2.44 (m, 2H), 1.48 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 443.13, 445.13, Found 443.1, 445.1.

[0792] Referring to the above method, compound 64-4 and 64-6 were used as starting materials, respectively, and the ring closure was reduced according to Reference Example 9; and the indolone was derivatized according to Reference Examples 17 and 10 to obtain compounds 65.3-65.8.

[0793] Compound 65.3 (i.e. NS-491): colorless transparent syrup, 1H NMR (400 MHz, DMSO-d6) δ 8.29 (dd, J = 3.9, 2.5 Hz, 1H), 7.98 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.13 (d, J = 2.7 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 3.70 (ddd, J = 14.4, 8.3, 6.1 Hz, 1H), 3.57 (ddd, J = 14.4, 8.2, 6.6 Hz, 1H), 3.20 (d, J = 13.1 Hz, 1H), 3.05 (d, J = 13.1 Hz, 1H), 2.30 (m, 4H), 1.43 (m, 5H), 0.83 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 415.09, 417.09, Found 415.1, 417.1.

[0794] Compound 65.4 (i.e. NS-492): colorless transparent syrup, 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (dd, J = 3.9, 2.5 Hz, 1H), 7.98 (s, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.13 (d, J = 2.7 Hz, 2H), 6.85 (d, J = 8.4 Hz, 1H), 3.70 (ddd, J = 14.4, 8.3, 6.1 Hz, 1H), 3.57 (ddd, J = 14.4, 8.2, 6.6 Hz, 1H), 3.20 (d, J = 13.1 Hz, 1H), 3.05 (d, J = 13.1 Hz, 1H), 2.30 (m, 4H), 1.43 (m, 5H), 0.83 (t, J = 7.4 Hz, 3H). LC-MS: [M+H] + Calcd 443.13, 445.13, Found 443.1, 445.1.

[0795] Compound 65.5 (i.e. NS-493): pale yellow solid, 1H NMR (400 MHz, DMSO-d6) δ 8.32 (dd, J = 4.7, 1.6 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 8.05 (m, 2H), 7.76 (d, J = 2.0 Hz, 1H), 7.73 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 2H), 7.34 (d...

Claims

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: L0is selected from the group consisting of nothing, O, S, C 1-5 alkylene, L 01 -L 02 -L 03 ; L 01 is selected from the group consisting of nothing, C 1-5 alkylene, L 02 is selected from the group consisting of CONH, NHCO, NR a0 , CO, L 03 is selected from the group consisting of nothing, C 1-5 alkylene, R a0 is selected from the group consisting of hydrogen, C 1-8 alkyl; R0 is selected from those that are not substituted or are selected by one or more R0. q1 Substituted aryl group, unsubstituted or substituted with one or more R groups q1 Substituted heteroaryl groups, unsubstituted or substituted with one or more R groups q1 Substituted rings, unsubstituted rings, or rings with one or more R groups q2 Substituted saturated nitrogen-containing heterocyclic groups; R q1 each independently selected from -O, =O, halogen, C 1-8 alkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyl, halogen-substituted C 1-8 alkoxy, halogen-substituted C 1c R 1d , NR 1c R 1d , COR 1e ; R q2 each independently selected from -O, halogen, C 1-8 alkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkyl, halogen-substituted C 1-8 alkoxy, amino protecting group, NR 1c R 1d , COR 1e ; R 1c is selected from hydrogen, C 1-8 alkyl, amino protecting group, R 1d is selected from hydrogen, C 1-8 alkyl, amino protecting group, R 1e is selected from hydrogen, C 1-8 alkyl; 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, unsubstituted or substituted with one or more R 1-8 alkyl, unsubstituted or substituted with one or more R a1 alkyl, unsubstituted or substituted with one or more R 1-8 alkyl, unsubstituted or substituted with one or more R a1 alkyl, 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 a2 ; R b is selected from the group consisting of hydrogen, C 1-8 alkyl, R c is selected from the group consisting of 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 the group consisting of halogen; R a2 is selected from the group consisting of 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, and R5 are each independently selected from hydrogen, halogens, unsubstituted or surrounded by one or more R groups. 3a Replacement C 1-8 Alkyl, unsubstituted or with one or more R 3a Replacement C 1-8 Alkoxy, NO2, CN, COOR h OR h SO2OM, SO2NR h R i CONR h R i OCONR h R i NR h R i CONHR j ;R 3a Each is independently selected from halogens; R j Selected from those that have not been replaced or have been replaced by one or more R k Substituted groups include: 5-6 membered heteroaryl, phenyl, R k Each independently selected from CONR h R i ;R h Selected from hydrogen, C 1-8 Alkyl, R i Selected from hydrogen, C 1-8 Alkyl group; M is selected from hydrogen or metal atoms; 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 the group consisting of null, 5-6 membered saturated nitrogen heterocyclyl, substituted or unsubstituted C x substituted C 1-5 alkylene, substituted or unsubstituted C x substituted C 2-5 alkenylene, substituted or unsubstituted C x substituted C 2-5 alkynylene; R x each independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, hydroxyl, halogen; A is selected from none, COL3, NR a6 L3, COOL3, OCOL3, CONR a6 L3, OL3, SL3, SOL3, SO2L3; R a6 selected from hydrogen, C 1-8 alkyl; L3is selected from the group consisting of none, C 1-5 alkylene; R6is selected from hydrogen, hydroxyl, 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, L 10 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, unsubstituted or substituted with one or more R 6a substituted 3-6 membered non-aromatic unsaturated nitrogen 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- 8alkyl, C 1-8 alkoxy, halogen, hydroxyl; R 6b selected from C 1-8 alkyl; L 10 selected from C 1-5 alkylene; R7is selected from hydrogen, halo or unhalo-substituted C 1-8 alkyl, L5R z1 ; R8 is selected from halogenated or non-halogenated C. 1-8 Alkyl, C 1-8 Alkoxy, C 2-5 alkenyl, C 2-5 Alkyne group, 3-8 member saturated cycloalkyl group, unsubstituted or with one or more R groups v Substituted 5-6 aryl heteroaryl, L7R z3 ; or R7, R8are linked to form a 3-8 membered saturated nitrogen-containing heterocycle, a 5-6 membered non-aromatic unsaturated nitrogen-containing heterocycle, a 5-6 membered nitrogen-containing heteroaryl, a 3-8 membered saturated nitrogen-containing heterocycle fused to a benzene ring, which is unsubstituted or substituted by one or more R 7a substituted 3-8 membered saturated nitrogen-containing heterocycle, a 5-6 membered non-aromatic unsaturated nitrogen-containing heterocycle, a 5-6 membered nitrogen-containing heteroaryl, a 3-8 membered saturated nitrogen-containing heterocycle fused to a benzene ring; R 7a each independently selected from C 1-8 alkyl, C 1-8 alkoxy, phenyl, COOR 6d ; R 6d 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 C 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 is 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; 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. The compound according to claim 1, a tautomer thereof, an endo- or exo- racemate 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 as formula II-1, formula II-2, formula II-3, formula II-4, or formula II-5: R1is selected from hydrogen, LR a ; L is selected from the group consisting of nothing, C 1-2 alkylene; R a substituted with one or more R a1 substituted with one or more R 1-3 substituted with one or more R a1 substituted with one or more R 1-3 substituted with one or more R a1 substituted with one or more R 2-3 substituted with one or more R b R c , COOR a2 ; R b is selected from hydrogen, C 1-3 alkyl, R c is selected from hydrogen, C 1-3 alkyl, or R b , R c to form a 3-4 membered saturated nitrogen heterocycle; R a1 each independently is selected from halogen; R a2 is selected from C 1-3 alkyl; R2is selected from hydrogen, CONHR d ; R d is selected from the following groups, which are unsubstituted or substituted by one or more R e 5-6 membered nitrogen heteroaryl, phenyl; R e each independently is selected from CONR f R g ; R f is selected from hydrogen, C 1-3 alkyl, R g is selected from hydrogen, C 1-3 alkyl; R3is selected from the group consisting of hydrogen, halogen, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR 3a substituted C 1-3 alkyl, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR 3a substituted C 1-3 alkyl, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR h substituted C h alkyl, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR h R i substituted C h alkyl, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR i substituted C h alkyl, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR i substituted C j alkyl, unsubstituted or substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR 3a each independently selected from the group consisting of halogen; R j substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR k substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR k each independently selected from the group consisting of CONR h R i ; R h substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR 1-3 substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR i substituted C1-6alkyl, unsubstituted or substituted C1-6alkoxy, NO2, CN, COOR 1-3 substituted C1-6alkyl, unsubstituted or substituted C1-6alk R4is selected from hydrogen, C 1-3 alkyl, alkoxy, COOR m , OR m , OCONR m R n ; R m is selected from hydrogen, C 1-3 alkyl, R n is selected from hydrogen, C 1-3 alkyl; R5is selected from hydrogen, OCONR p R q ; R p is selected from hydrogen, C 1-3 alkyl, R q is selected from hydrogen, C 1-3 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 1-5 alkyl; L2 is selected from the group consisting of null, 5-6 membered saturated nitrogen heterocyclyl, substituted or unsubstituted C x substituted C 1-5 alkylene, substituted or unsubstituted C x substituted C 2-5 alkenylene, substituted or unsubstituted C x substituted C 2-5 alkynylene; R x each independently selected from the group consisting of C 1-5 alkyl, C 1-5 alkoxy, hydroxyl, halogen; A is selected from none, COL3, NR a6 L3, COOL3, OCOL3, CONR a6 L3, OL3, SL3, SOL3, SO2L3; R a6 selected from hydrogen, C 1-5 alkyl; L3is selected from the group consisting of none, C 1-5 alkylene; R6is selected from hydrogen, hydroxyl, 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, L 10 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, unsubstituted or substituted with one or more R 6a substituted 3-6 membered non-aromatic unsaturated nitrogen 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- 5alkyl, C 1-5 alkoxy, halogen, hydroxyl; R 6b selected from C 1-5 alkyl; L 10 selected from C 1-3 alkylene; R7is selected from hydrogen, halo or unhalo-substituted C 1-5 alkyl, L5R z1 ; R8is selected from halo or unhalo genated C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, 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 5-6 membered saturated nitrogen-containing heterocycle, which is unsubstituted or substituted by one or more R 7a substituted 3-6 membered saturated nitrogen-containing heterocycle, 5-6 membered non-aromatic unsaturated nitrogen-containing heterocycle, 5-6 membered nitrogen-containing heteroaryl, 3-6 membered saturated nitrogen-containing heterocycle and benzene ring; R 7a each independently selected from C 1-5 alkyl, C 1-5 alkoxy, phenyl, COOR 6d ; R 6d 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 an unsubstituted or substituted 5-6 membered heteroaryl; R w1 is selected from an unsubstituted or substituted 5-6 membered heteroaryl; R w1 each independently selected from OR w2 , R w2 is selected from 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, which is unsubstituted or substituted by one or more R w5 is selected from the group consisting of 5-6 membered heteroaryl, 3-6 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 1-5 alkyl, 3-6 membered saturated cycloalkyl; L4 is selected from the group consisting of none, C 1-5 alkylene; R y is selected from the group consisting of hydrogen, C 1-5 alkyl, phenyl; L0, R0are as described in claim 1. 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 according to claim 2, characterized in that, in the compounds, the structure selected from L 2c COL3R6, L 2c COOL3R6, L 2c CONR a6 L3R6, L 2d NR a6 L3R6, L 2d OCOL3R6, L 2d OL3R6, L 2d SL3R6, L 2d SOL3R6, L 2d SO2L3R6; wherein, the structure is selected from G x selected from O or S; a is selected from 0, 1, 2 or 3; A1is selected from nothing or O; b is selected from 0, 1, 2, or 3; A2is selected from nothing or O, S, SO, SO2, NHL3, A3L3, unsubstituted or substituted C x substituted C 1-3 alkylene; A3is selected from a 5-6 membered saturated nitrogen heterocyclyl; L3is selected from nothing, C 1-3 alkylene; R x each independently selected from C 1-3 alkyl, C 1-3 alkoxy, hydroxy; For When For R a3 is nothing; the structure selected from R b4 selected from hydrogen, C 1-5 alkyl, R b5 is L 2a A4R6; L 2a selected from nothing, C 1-3 alkylene, C 2-3 alkenylene, A4 is selected from nothing, CO; or R b4 , R b5 together with the nitrogen atom to which they are attached form a 3-6 membered saturated nitrogen heterocycle; L 2b selected from none, C 1-3 alkylene, A5is selected from none, CO; A6 is selected from the group consisting of nothing, CO, NR a6 ; R a6 is selected from the group consisting of hydrogen, C 1-3 alkyl; R 6c selected from the group consisting of unsubstituted or substituted C 6a alkyl, unsubstituted or substituted by one or more R 1-5 alkyl, unsubstituted or substituted by one or more R 6a alkyl, unsubstituted or substituted by one or more R 1-5 alkyl, unsubstituted or substituted by one or more R 6a alkyl, unsubstituted or substituted by one or more R v alkyl, unsubstituted or substituted by one or more R v alkyl, unsubstituted or substituted by one or more R L 2c selected from none, unsubstituted or substituted C x alkylene, unsubstituted or substituted with one or more R 1-5 alkylene, unsubstituted or substituted with one or more R x alkylene, unsubstituted or substituted with one or more R 2-5 alkylene, unsubstituted or substituted with one or more R x alkylene, unsubstituted or substituted with one or more R 2-5 alkynylene; L 2d substituted with one or more R x substituted with one or more R 1-5 substituted with one or more R x substituted with one or more R 2-5 substituted with one or more R x substituted with one or more R 2-5 substituted with one or more R R x each independently selected from C 1-5 alkyl, C 1-5 alkoxy, hydroxy; R a6 selected from hydrogen, C 1-5 alkyl; L3is selected from the group consisting of none, C 1-5 alkylene; R6is as described in claim 2. 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 according to claim 3, 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: wherein the structure selected from G x selected from O or S; a is selected from 0, 1, 2 or 3; A1is selected from nothing or O; b is selected from 0, 1, 2, or 3; A2is selected from nothing or O, S, SO, SO2, NHL3, A3L3, unsubstituted or substituted C x substituted C 1-3 alkylene; A3is selected from a 5-6 membered saturated nitrogen heterocyclyl; L3is selected from nothing, C 1-3 alkylene; R x each independently selected from C 1-3 alkyl, C 1-3 alkoxy, hydroxy; R6, R1, R2, R3, R4, R5, L0, R0are as described in claim 3. 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 according to claim 3, characterized in that, The structure of the compound is shown as formula IV-1, formula IV-2, formula IV-3, formula IV-4, or formula IV-5: wherein, For When For R a3 is nothing; the structure is selected from R b4 selected from hydrogen, C 1-5 alkyl, R b5 is L 2a A4R6; L 2a selected from nothing, C 1-3 alkylene, C 2-3 alkenylene, A4 is selected from nothing, CO; or R b4 , R b5 form a 3-6 membered saturated nitrogen heterocycle; L 2b selected from none, C 1-3 alkylene, A5is selected from none, CO; A6 is selected from the group consisting of nothing, CO, NR a6 ; R a6 is selected from the group consisting of hydrogen, C 1-3 alkyl; R 6c selected from the group consisting of unsubstituted or substituted C 6a alkyl, unsubstituted or substituted by one or more R 1-5 alkyl, unsubstituted or substituted by one or more R 6a alkyl, unsubstituted or substituted by one or more R 1-5 alkyl, unsubstituted or substituted by one or more R 6a alkyl, unsubstituted or substituted by one or more R v alkyl, unsubstituted or substituted by one or more R v alkyl, unsubstituted or substituted by one or more R L 10 R7, R8, R6, R1, R2, R3, R4, R5, L0, R0are as described in claim 3. 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 according to claim 3, characterized in that, in the compounds, the structure selected from L 2c COL3R6, L 2c COOL3R6, L 2c CONR a6 L3R6, L 2d NR a6 L3R6, L 2d OCOL3R6, L 2d OL3R6, L 2d SL3R6, L 2d SOL3R6, L 2d SO2L3R6; L 2c selected from none, unsubstituted or substituted C x alkylene, unsubstituted or substituted with one or more R 1-5 alkylene, unsubstituted or substituted with one or more R x alkylene, unsubstituted or substituted with one or more R 2-5 alkylene, unsubstituted or substituted with one or more R x alkylene, unsubstituted or substituted with one or more R 2-5 alkynylene; L 2d substituted C x substituted C 1-5 substituted C x substituted C 2-5 substituted C x substituted C 2-5 substituted C R x each independently selected from C 1-5 alkyl, C 1-5 alkoxy, hydroxy; R a6 selected from hydrogen, C 1-5 alkyl; L3is selected from the group consisting of none, C 1-5 alkylene; R6is as described in claim 3. 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 according to any one of claims 1-6, characterized in that, in the compounds, The structure of the compound of formula X-1 is shown below: In formula X-1, L0is selected from the group consisting of nothing, C 1-5 alkylene; B ring is selected from phenyl, 5-6 membered heteroaryl; b is selected from 0, 1, 2 or 3; R 1b each independently selected from hydrogen, -O, halogen, C 1-8 alkyl, halogen-substituted C 1-8 alkyl, C 1-8 alkoxy, halogen-substituted C 1-8 alkoxy, CONR 1c R 1d , NR 1c R 1d , COR 1e ; R 1c is selected from hydrogen, C 1-8 alkyl, an amino protecting group, R 1d is selected from hydrogen, C 1-8 alkyl, an amino protecting group, R 1e is selected from hydrogen, C 1-8 alkyl; or, in the compound, The structure of Formula X-2 is shown below: In formula X-2, L0is selected from the group consisting of nothing, C 1-5 alkylene; C ring is selected from a 6-membered saturated nitrogen-containing heterocyclyl group, R 07 selected from hydrogen, =0, C 1-8 alkyl, C 1-8 alkoxy, NR 08 R 09 , R 08 selected from hydrogen, C 1-8 alkyl, an amino protecting group, R 09 selected from hydrogen, C 1-8 alkyl, an amino protecting group; or, in the compound, The structure of Formula X-3 is shown below: In formula X-3, L0is selected from the group consisting of nothing, O, S, D ring is a benzo 5-membered heterocycle; R q1 is selected from the group consisting of hydrogen, C 1-8 alkyl. 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 according to claim 7, characterized in that, In formula X-1, said L0is selected from the group consisting of nothing, C 1-4 alkylene; b is selected from 0, 1, 2 or 3; B ring is selected from phenyl, 5-6 membered heteroaryl; R 1b each independently selected from hydrogen, -O, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, halogen-substituted C 1-6 alkoxy, CONR 1c R 1d , NR 1c R 1d , COR 1e ; R 1c is selected from hydrogen, C 1-6 alkyl, an amino protecting group, R 1d is selected from hydrogen, C 1-6 alkyl, an amino protecting group, R 1e is selected from hydrogen, C 1-6 alkyl; or, shown in formula X-2 The structure of the application is L0is selected from the absence, C 1-3 alkylene; X2is selected from NH, CH2, O, S; R 07 selected from hydrogen, =0, C 1-4 alkyl, C 1-4 alkoxy, NR 08 R 09 , R 08 selected from hydrogen, C 1-4 alkyl, an amino protecting group, R 09 selected from hydrogen, C 1-4 alkyl, an amino protecting group. 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 claim 8, characterized in that, In formula X-1, said L0is selected from the group consisting of nothing, C 1-2 alkylene; b is selected from 0, 1, 2 or 3; B ring is selected from phenyl, 5-6 membered heteroaryl, said 5-6 membered heteroaryl is selected from X1is selected from N, N-O; R 1b each independently selected from hydrogen, -O, halogen, C 1-3 alkyl, halogen-substituted C 1-3 alkyl, C 1-3 alkoxy, halogen-substituted C 1-3 alkoxy, CONR 1c R 1d , NR 1c R 1d , COR 1e ; R 1c is selected from hydrogen, C 1-3 alkyl, an amino protecting group, R 1d is selected from hydrogen, C 1-3 alkyl, an amino protecting group, R 1e is selected from hydrogen, C 1-3 alkyl; Alternatively, in Formula X-2, said L0is selected from the group consisting of null, C 1-2 alkylene; selected from the group consisting of R 07 selected from hydrogen, =0, C 1-4 alkyl, C 1-4 alkoxy, NR 08 R 09 , R 08 selected from hydrogen, C 1-4 alkyl, an amino protecting group, R 09 selected from hydrogen, C 1-4 alkyl, an amino protecting group; Alternatively, in Formula X-3, L0is selected from the group consisting of nothing, C 1-2 alkylene, D ring is R q1 selected from hydrogen, C 1-4 alkyl. 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 claim 9, characterized in that, B ring is at the time, the compound represented by formula X-1 For The compound according to claim 1, a tautomer thereof, an endo- or exo- racemate 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: 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 according to any one of claims 1-11, 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, monohydrogenphosphate, dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, xinafoate or p-toluenesulfonate. A pharmaceutical composition, characterized by It is a preparation obtained by adding a pharmaceutically acceptable adjuvant to the compound according to any one of claims 1 to 12, a tautomer thereof, an entgegen isomer thereof, an entenantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof or a deuterated derivative thereof as an active ingredient. Use of the compound according to any one of claims 1 to 12, a tautomer thereof, an entgegen isomer thereof, an entenantiomer thereof, a diastereomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof or a deuterated derivative thereof for 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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