Tricyclic compound, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a tricyclic compound, a preparation method therefor and the use thereof. The tricyclic compound of the present invention are a tricyclic compound as shown in I', a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof. The tricyclic compound of the present invention is capable of protecting neurons, promoting repair of damaged neurons, inhibiting neuronal apoptosis, and slowing down AD cognitive decline, and have good pharmaceutical prospects.

Description

A class of tri-pericyclic compounds, preparation method and use thereof

[0001] This application claims priority to Chinese patent application 2024110938483, filed on August 9, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmaceutical chemistry and medicine, and specifically relates to a class of tri-pericyclic derivatives represented by general formula I', pharmaceutically acceptable salts and isomers thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds, and the use of the compounds in the preparation of drugs for treating and / or preventing Alzheimer's disease and other neurodegenerative diseases. BACKGROUND

[0003] With the aggravation of population aging, the number of AD patients will be more and more, and it is estimated that the number of AD patients worldwide will reach 152 million by 2050. However, the currently clinically commonly used anti-AD drugs are mainly neurotransmitter and receptor drugs, which can only relieve symptoms and cannot stop or reverse the pathological progression of AD. Moreover, in the past 20 years, the research and development strategy of anti-AD drugs has mainly focused on removing Aβ deposition and Tau protein, but most of the newly developed anti-Aβ and anti-Tau protein drugs have been discontinued due to insignificant clinical benefits. Although recent studies have shown that antibody drugs for removing β-amyloid protein are expected to slow down the disease progression of early AD patients, but currently antibody drugs are still controversial due to their insignificant efficacy and side effects. In fact, synaptic loss and neuronal apoptosis are the key pathological features of AD. Based on previous studies, it has been proved that by regulating the aging-related signaling pathway, inhibiting neuronal apoptosis, inducing neuronal regeneration, increasing the number of neurons, and restoring the function of damaged neurons, it is expected to become an effective strategy for treating AD. SUMMARY

[0004] The purpose of the present application is to overcome the defect that the number of effective AD drugs in the prior art is limited, and therefore the present application provides a class of tri-pericyclic compounds, a preparation method and use thereof. The tri-pericyclic compounds of the present application can regulate AKT and downstream signaling pathways, and also have various advantages: reducing neuroinflammation, reducing oxidative stress, protecting neurons, promoting repair of damaged neurons, inhibiting neuronal apoptosis, slowing down cognitive decline in AD, easily passing through the blood-brain barrier, distributing in the brain and having less systemic side effects.

[0005] The present application solves the above technical problems by the following technical solutions.

[0006] The present application provides a tri-pericyclic compound represented by formula I', a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

[0007] wherein L is selected from -O-, -C(=O)-, -NH-, -NR4-, -S-, -S(O)-, -S(O)2- and -(CH2) x -;

[0008] x is 1, 2 or 3;

[0009] R1, R2, R3and R5are independently selected from the group consisting of a hydrogen atom, halogen, amino, nitro, hydroxy, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R6, -C(O)OR6, -S(O) m R6and -S(O) m NR7R8, wherein said alkyl, heterocyclyl, aryl and heteroaryl are independently optionally substituted with one or more R R1 substituents;

[0010] R4is selected from the group consisting of a hydrogen atom, halogen, amino, nitro, hydroxy, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl and -NR7R8, wherein said alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R R2 substituents;

[0011] each R R1 and each R R2 is independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, carboxy, -NH-alkyl, -N(alkyl)2, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, -S(O) 2- -(alkyl)2, cycloalkyl, heterocyclyl, aryl, -C(O)O-alkyl, -C(O)O-alkyl-O-alkyl, -C(O)O-alkenyl, -C(O)O-alkyl-aryl, -O-alkyl-aryl, -NHC(=O)-O-alkyl-aryl and heteroaryl,

[0012] alternatively, any two adjacent R R2 together form -(CH2) Y -; Y is 1, 2, 3, 4 or 5, wherein 1, 2 or of the -CH2- can optionally be replaced with 1, 2 or 3 of O, S and NH;

[0013] R a and R b are independently selected from the group consisting of a hydrogen atom, halogen, cycloalkyl, heterocyclyl and -NR7R8, wherein said cycloalkyl and heterocyclyl are independently optionally substituted with one or more R R3 substituents:

[0014] each R R3independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0015] R6is selected from the group consisting of hydrogen atom, alkyl, alkenyl, alkoxy, hydroxy, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently optionally substituted with one or more R R4 substituents;

[0016] each R R4 is independently selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0017] R7and R8are independently selected from the group consisting of hydrogen atom, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, carboxylate, cycloalkyl, heterocyclyl, amino protecting group, aryl and heteroaryl, or R7, R8and the attached N atom together form a heterocyclyl or heteroaryl, wherein said alkyl, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R R5 substituents;

[0018] each R R5 is independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] Q is selected from the group consisting of -C-, -N-, -O-, -S-, -S(O)2-, -S(O)(N)- and -C(O)2-;

[0020] m and n are independently selected from the group consisting of 0, 1 and 2.

[0021] The heteroatoms in the above-mentioned heteroaryl and heterocycloalkyl are independently one or more, 1, 2, 3 or 4, selected from the group consisting of N, S and O.

[0022] As one of the preferred embodiments, the above-mentioned tricyclic compound is a tricyclic compound of formula I:

[0023] each of the definitions is as previously described.

[0024] Preferably, R1in formula I is selected from the group consisting of halogen, amino, nitro, hydroxy, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R6, -C(O)OR6, -S(O) m R6and -S(O) m NR7R8, wherein said alkyl, heterocyclyl, aryl and heteroaryl are independently optionally substituted with one or more R R1 substituents.

[0025] As one of the preferred solutions, R1, R2, R3, R4, R5, and each R R1 Each R R2 Each R R3 R6, each R R4 R7, R8 and each R R5 In this context, the halogen is F, Cl, Br, or I.

[0026] As one of the preferred solutions, R1, R2, R3, R4, R5, and each R R1 Each R R2 Each R R3 Each R R4 R6, R7, R8 and each R R5 In the above, the alkyl group is C10. 1-8 Alkyl, preferably C 1-6 Alkyl, more preferably C 1-4 Alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0027] As one of the preferred solutions, R1, R2, R3, R4, R5, and each R R1 Each R R2 Each R R3 R6, each R R4 R7, R8 and each R R5 In the text, the alkoxy group is C64. 1-8 Alkoxy, preferably C 1-6 Alkoxy, more preferably C 1-4 Alkyl groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0028] As one of the preferred solutions, R1, R2, R3, R4, R5, and each R R1 Each R R2 Each R R3 R6, each R R4 R7, R8 and each R R5 In the above, the cycloalkyl group is C10. 3-14 Cycloalkyl, preferably C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0029] As one of the preferred solutions, R1, R2, R3, R4, R5, and each R R1 Each R R2 Each R R3 R6, each R R4 R7, R8 and each R R5In particular, the heteroaryl group is a 3- to 14-membered heteroaryl group, the heteroatoms being selected from one or more of N, S and O, the number of heteroatoms being 1, 2 or 3, preferably a 5- to 6-membered monocyclic heteroaryl group, the heteroatoms being selected from one or more of N, S and O, the number of heteroatoms being 1 or 2, for example a furanyl group, a thienyl group, a thiazolyl group, a 1H-pyrazolyl group, a benzo[d]thiazolyl group or a benzofuranyl group.

[0030] As a preferred variant, R1, R2, R3, R4, R5, each R R1 , each R R2 , each R R3 , R6, each R R4 , R7, R8and each R R5 In particular, the aryl group is a C 6-14 aryl group, preferably a C 6-10 aryl group, and can also be a phenyl group or a naphthyl group.

[0031] As a preferred variant, R1, R2, R3, R4, R5, each R R1 , each R R2 , each R R3 , R6, each R R4 , R7, R8and each R R5 In particular, the heteroaryl group is a 3- to 14-membered heteroaryl group, the heteroatoms being selected from one or more of N, S and O, the number of heteroatoms being 1, 2 or 3, preferably a 5- to 6-membered monocyclic heteroaryl group, the heteroatoms being selected from one or more of N, S and O, the number of heteroatoms being 1 or 2, for example a furanyl group, a thienyl group, a thiazolyl group, a 1H-pyrazolyl group, a benzo[d]thiazolyl group or a benzofuranyl group.

[0032] As a preferred variant, each R R1 and each R R2 In particular, the alkyl group in the -NH-alkyl group, the alkyl group in the -N(alkyl)2 group, the alkyl group in the -S(O) 2- 2-alkyl group, the alkyl group in the -C(O)O-alkyl group, the alkyl group in the -C(O)O-alkyl-aryl group, the alkyl group in the -NHC(=O)-O-alkyl-aryl group and the alkyl group in the -O-alkyl-aryl group is independently a C 1-8 alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-4 alkyl group, for example a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group or a t-butyl group.

[0033] As a preferred variant, each R R1 and each R R2 In particular, the aryl group in the -C(O)O-alkyl-aryl group, the aryl group in the -NHC(=O)-O-alkyl-aryl group and the aryl group in the -O-alkyl-aryl group is independently a C 6-14aryl, preferably C 6-10 aryl, which can also be phenyl or naphthyl.

[0034] as a preferred option, each R R1 and each R R2 of said -C(O)O-alkenyl is C 2-8 alkenyl, preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl, such as propenyl.

[0035] as a preferred option, each R R1 , each R R2 and each R R3 of said haloalkyl is haloC 1-8 alkyl, preferably fluoroC 1-6 alkyl, more preferably fluoroC 1-4 alkyl, such as -CF3.

[0036] as a preferred option, each R R1 , each R R2 and each R R3 of said halo-oxyalkyl is C 1-8 halo-oxyalkyl, preferably C 1-6 halo-oxyalkyl, more preferably C 1-4 fluoro-oxyalkyl, such as -OCF3.

[0037] as a preferred option, each R6is C 2-8 alkenyl, preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl, such as -propenyl.

[0038] as a preferred option, Q is selected from -O-.

[0039] as a preferred option, L is selected from -C(=O)-, -NH- and -NR4-.

[0040] as a preferred option, R1is selected from alkyl, said alkyl being optionally substituted by one or more R R1 , each R R1 being halogen, amino, nitro, cyano, hydroxy or alkoxy.

[0041] more preferably, R1is selected from C 1-6 alkyl.

[0042] most preferably, R1is selected from (e.g. ).

[0043] as a preferred option, R2is selected from a hydrogen atom or -alkyl, said alkyl being optionally substituted by one or more RR1 each R R1 is selected from halogen, carboxyl, cyano, -C(O)O-alkyl, -C(O)O-alkyl-O-alkyl, -C(O)O-alkenyl or -C(O)O-alkyl-aryl.

[0044] Preferably, R2is selected from a hydrogen atom or C 1-6 alkyl, said alkyl being optionally substituted by one or more R R1 each R R1 is selected from halogen, cyano, carboxyl, -C(O)O-C 1-6 alkyl, -C(O)O-C 1-6 alkyl-O-C 1-6 alkyl, -C(O)O-C 2-6 alkenyl or -C(O)O-C 1-6 alkyl-C 6-10 aryl.

[0045] More preferably, R2is selected from H,

[0046] As one of the preferred options, R3is selected from a hydrogen atom, amino, nitro, hydroxy, cyano and -C(O)OR6, R6being selected from a hydrogen atom, alkyl or alkenyl, said alkyl being optionally substituted by one or more R R4 each R R4 is independently selected from halogen, hydroxy, amino, nitro, cyano, alkoxy and aryl.

[0047] Preferably, R3is selected from a hydrogen atom, halogen, amino, nitro, hydroxy, cyano, -C(O)R6and -C(O)OR6, R6being selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl C and hydroxy, said alkyl being optionally substituted by one or more R R4 each R R4 is independently selected from halogen, hydroxy, amino, nitro, cyano, C 1-6 alkoxy and C 6-10 aryl.

[0048] More preferably, R3is selected from H, cyano,

[0049] As one of the preferred options, R4is selected from a hydrogen atom, amino, alkyl, cycloalkyl and aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted by one or more R R2 each R R2 is independently selected from alkyl, haloalkyl, halogen, amino, -N(alkyl)2, nitro, cyano, hydroxy, carboxyl, alkoxy, haloalkoxy, hydroxyalkyl, -S(O)m-alkyl, -S(O)m-aryl, -C(O)O-alkyl, -C(O)O-alkenyl, -C(O)O-aryl, -C(O)N(H)R8, -C(O)N(alkyl)2, -C(O)N(H)OR8, -C(O)N(H)N(H)R8, -C(O)N(H)N(alkyl)2, -C(O)N(alkyl)2R8, -C(O)N(H)OR8, -C(O)N(H)SR8, -C(O)N(H)N(H)SR8, -C(O)N(H)N(H)OR8, -C(O)N(H)N(alkyl)2OR8, -C(O)N(H)N(H)SR8, -C(O)N(H)N(H)N(H)R8, -C(O)N(H)N(H)N(alkyl)2, -C(O)N(H)N(alkyl)2R8, -C(O)N(H)SR8, -C(O)N(H)OR8, -C(O)N(H)R8, -C(O)N(alkyl)2R8, -C(O)N(H)N(H)R8, -C(O)N(H)N(alkyl)2, -C(O)N(alkyl)2, -C(O)OR8, -C(O)R8, -SR8, -OR8, -N(H)R8and -N(alkyl)2, R8being selected from a hydrogen atom, alkyl, haloalkyl, alkenyl, cycloalkyl and aryl.2- -(alkyl)2, cycloalkyl, heterocyclyl, aryl, -O-alkyl-aryl, -NHC(=O)-O-alkyl-aryl, heteroaryl, and, optionally, any two adjacent R R2 together form -(CH2) Y Y is 1, 2, 3, 4 or 5, wherein optionally 1, 2 or 3 of the -CH2- groups can be replaced by 1, 2 or 3 of O, S and NH.

[0050] Preferably, R4 is selected from the group consisting of a hydrogen atom, an amino group, an alkyl group, a C 3-6 cycloalkyl group and a C 6-10 aryl group, wherein said alkyl, cycloalkyl and aryl groups are optionally substituted with one or more R R2 groups; each R R2 is independently selected from the group consisting of a C 1-6 alkyl group, a haloC 1-6 alkyl group, a halogen, an amino group, -N(C 1-6 alkyl)2, a nitro group, a cyano group, a hydroxy group, a carboxy group, a C 1-6 alkoxy group, a haloC 1-6 alkoxy group, a C 1-6 hydroxyalkyl group, a -S(O) 2- -(C 1-6 alkyl)2, a C 3-6 cycloalkyl group, a 5-6 membered heterocyclyl group, a C 6-10 aryl group, -O-C 1-6 alkyl-C 6- 10 aryl group, -NHC(=O)-O-C 1-6 alkyl-C 6-10 aryl group, a 5-6 membered heteroaryl group, and, optionally, any two adjacent R R2 together form -(CH2) Y Y is 1, 2, 3, 4 or 5, wherein optionally 1, 2 or 3 of the -CH2- groups can be replaced by O.

[0051] More preferably, R4 is selected from the group consisting of H,

[0052] As one of the preferred options, R5 is selected from the group consisting of a hydrogen atom or a hydroxy group.

[0053] As one of the preferred options, R a and R b are selected from the group consisting of a hydrogen atom.

[0054] As one of the preferred options, R1, R2, R3, R4 and R5 are not simultaneously a hydrogen atom, preferably R1 and R5 are not simultaneously a hydrogen atom.

[0055] As one of the preferred embodiments, the tricyclic compound of formula I' is of the structure of formula I'b:

[0056] wherein "*" represents either an S-type chiral carbon atom or an R-type chiral carbon atom, and the other groups are as defined in any of the embodiments of the present application. As one of the preferred embodiments, the tricyclic compound of formula I is of the structure of formula Ia:

[0057] wherein "*" represents either an S-type chiral carbon atom or an R-type chiral carbon atom, and the other groups are as defined in any of the embodiments of the present application.

[0058] As one of the preferred embodiments, the tricyclic compound of formula I' is of the structure of formula II, III, IV or V:

[0059] wherein L is -NR4- or -C(=O)-, and the other groups are as defined in any of the embodiments of the present application; in IV or V, R1and R5are not hydrogen at the same time. In IV or V, preferably R5is hydroxy.

[0060] As one of the preferred embodiments, the structure of formula II is of the structure of formula II-1, II-2, II-3 or II-3a:

[0061] wherein "*" and the other groups are as defined in any of the embodiments of the present application.

[0062] Preferably, in formula II-1, II-2, II-3 and II-3a,

[0063] R1is selected from the group consisting of hydrogen atom, halogen, amino, hydroxy, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkyl-O-C

[0064] R R1 selected from the group consisting of hydrogen atom, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, -C(O)O-C 1-6 alkyl, -C(O)O-C 1-6 alkyl-O-C 1-6 alkyl, -C(O)O-C 2-6 alkenyl and -C(O)O-C 1-6 alkyl-C 6-14 aryl;

[0065] R3is selected from the group consisting of hydrogen atom, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl, -NR7R8, C 1-6 alkoxy and -C(O)OR6;

[0066] R6is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy, amino, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl;

[0067] R7and R8are each independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino protecting group, C 6-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl, wherein said C 1-6 alkyl, amino, C 6-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halo, hydroxy and amino;

[0068] More preferably, the structure according to formula II-1, II-2, II-3 and II-3a,

[0069] R1is selected from the group consisting of C 1-6 alkyl;

[0070] R R1 selected from the group consisting of cyano, -C(O)O-C 1-6 alkyl, -C(O)O-C 1-6 alkyl-O-C 1-6 alkyl, -C(O)O-C 2-6 alkenyl or -C(O)O-C 1-6 alkyl-C 6-14 aryl;

[0071] R3is selected from the group consisting of -COOR6, R6is selected from the group consisting of C 1-6 alkyl and C 2-6 alkenyl, R6is optionally substituted with one or more R R4 substituents; each R R4 is selected from the group consisting of -O-C 1-6 alkoxy and -C 6-14 aryl;

[0072] R4is selected from the group consisting of a hydrogen atom.

[0073] As one of the preferred options, the structure according to formula III is a structure according to formula III-1, III-2 or III-2a:

[0074] The definitions of "*" and other groups are the same as those described in any embodiment of this invention.

[0075] Preferably, as in formulas III-1, III-2, and III-2a,

[0076] R1 is selected from hydrogen atom, halogen, amino group, hydroxyl group, cyano group, C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 Alkoxy;

[0077] R3 is selected from hydrogen atom, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, -NR7R8, C 1-6 alkoxy or -C(O)OR6;

[0078] R6 is selected from hydrogen atom, C 1-6 Alkyl, C 1-6 alkenyl, C 1-6 Alkoxy, hydroxy, amino, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl and 6-14 heteroaryl groups;

[0079] R4 is selected from hydrogen atom, C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl and C 6-14 heteroaryl, the C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 The aryl and 6-14 heteroaryl groups are each independently and optionally constituting one or more R groups. R2 replace;

[0080] Each R R2 Independently selected from halogen, amino, carboxyl, -NH-C 1-6 Alkyl, nitro, cyano, hydroxyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl group, -S(O) 2- -(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, -C(O)OC 1-6alkyl, -C(O)O-C 1-6 alkyl, -C(O)O-C 1-6 alkyl, -C(O)O-C 2-6 alkenyl, -C(O)O-C 1-6 alkyl-aryl, -O-C 1-6 alkyl-C 6-14 aryl, -NHC(=O)-O-C 1-6 alkyl-C 6-14 aryl and 3-14 membered heteroaryl;

[0081] or any two R R2 together form -(CH2) Y -, Y is 1, 2, 3, 4 or 5, wherein 1, 2 or of the -CH2- can optionally be replaced by 1, 2 or 3 of O, S and NH.

[0082] More preferably, as in formula III-1, III-2 and III-2a,

[0083] R1is selected from C 1-6 alkyl;

[0084] R3is selected from a hydrogen atom;

[0085] R4is selected from C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and C 6-14 heteroaryl, each independently optionally substituted with one or more R 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl, each independently optionally substituted with one or more R R2 substituents;

[0086] each R R2 is independently selected from halogen, amino, carboxyl, -NH-C 1-6 alkyl, nitro, cyano, hydroxy, -N(C 1-6 alkyl)2, C 1-6 haloC 1-6 alkyl, C 1-6 haloC 1-6 alkoxy, -S(O) 2- -(C 1-6 alkyl)2, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl, -O-C 1-6 alkyl-C 6-14 aryl, -NHC(=O)-O-C 1-6 alkyl-C 6-14aryl and 3-14 membered heteroaryl;

[0087] or any two R R2 together form -(CH2) Y -; Y is 1, 2, 3, 4 or 5, wherein 1, 2 or of the -CH2- groups can optionally be replaced by 1, 2 or 3 of O, S and NH.

[0088] Further preferred, the structure according to formula III is a structure according to formula III-1, III-2 and III-2a:

[0089] R1is selected from C 1-6 alkyl;

[0090] R3is selected from a hydrogen atom;

[0091] R4is selected from C 1-6 alkyl, C 1-6 alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, furanyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, benzothiazolyl, benzofuranyl, benzodioxolyl and benzodioxepinyl; R4is optionally substituted by one or more R R2 substituents;

[0092] each R R2 each is independently optionally substituted by one or more substituents selected from halogen, hydroxy, amino, nitro, cyano, benzyloxycarbonyl, methoxycarbonyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, dimethylamino, methanesulfonyl, ethanesulfonyl, sulfonamido, carboxy, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, furanyl,

[0093] As a preferred option, the structure according to formula III is a structure according to formula III-4:

[0094] each group is defined as in any one of the present invention.

[0095] Preferably, the structure according to formula III-4 is a structure according to formula III-4-1, III-4-2 or III-4-3:

[0096] each group is defined as in any one of the present invention.

[0097] More preferably, the structure according to formula III-4-1, III-4-2 or III-4-3 is a structure according to formula III-4-1-1, III-4-1-2, III-4-2-1, III-4-2-2, III-4-3-1 or III-4-3-2:

[0098] R1is selected from C 1-6 alkyl;

[0099] each R R2 is independently selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy.

[0100] As further preferred, the tricyclic compound according to Formula I' is selected from any one of the following compounds:

[0101] As preferred, the tricyclic compound according to Formula I' is the following compound:

[0102] Compound eluting first or second under the following chromatographic conditions: Compound eluting first or second under the following chromatographic conditions: Compound eluting first or second under the following chromatographic conditions:

[0103] Chromatographic conditions: Column: CHIRALCEL OZ-H, mobile phase MeOH and CAN solution in a volume ratio of 90:10.

[0104] Further preferred, the tricyclic compound according to Formula I' is the following compound:

[0105] Compound eluting first or second under the following chromatographic conditions:

[0106] Compound eluting first or second under the following chromatographic conditions:

[0107] Compound eluting first or second under the following chromatographic conditions:

[0108] Chromatographic conditions: Column: CHIRALCEL OZ-H; mobile phase MeOH and CAN solution in a volume ratio of 90:10; flow rate: 1.0 ml / min; detection wavelength: UV: 254 nm; temperature: 35 °C.

[0109] As preferred, the tricyclic compound as shown in formula I' is

[0110] The optical rotation of the following compound is -0.124 or +0.134 in acetonitrile solution under the test condition of c = 10 mg / ml,

[0111] The optical rotation of the following compound is -0.124 or +0.134 in acetonitrile solution under the test condition of c = 10 mg / ml,

[0112] The optical rotation of the following compound is -0.124 or +0.134 in acetonitrile solution under the test condition of c = 10 mg / ml,

[0113] The test condition of optical rotation is preferably as follows: acetonitrile solution of the tricyclic compound as shown in formula I with a concentration of 10 mg / ml; light source: D line (589.3 nm) of sodium spectrum; length of measuring tube: 1 dm; measuring temperature: 20.0℃±0.5℃; measuring time: 30 minutes.

[0114] The present application also provides a compound as shown in formula A' or A or a pharmaceutically acceptable salt thereof:

[0115] wherein R1, R5, R a and R b are the same as defined above.

[0116] The compound as shown in formula A is preferably

[0117] The present application also provides a preparation method of the above-mentioned tricyclic compound as shown in formula I', a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, which is method 1 or method 2:

[0118] When n is 1, it is method 1, and method 1 comprises the following step: reacting the compound of formula A and the compound of formula B as follows to obtain the tricyclic compound as shown in formula I';

[0119] When n is 1, it is method 2, and method 2 comprises the following step: reacting the compound of formula A and the compound of formula C as follows to obtain the tricyclic compound as shown in formula I';

[0120] wherein R 10selected from the group consisting of halogen, and the definitions of the other radicals are as described above.

[0121] It is another object of the present application to provide a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned tricyclic compound of Formula I', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers (e.g., diluents or excipients).

[0122] It is another object of the present application to use of any of the above-mentioned tricyclic compound of Formula I', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above in the manufacture of a medicament for the treatment or prevention of a neurodegenerative disorder or related disorder, or inhibiting the progression of the neurological disorder or related disorder.

[0123] The neurodegenerative disease or related disorder according to the present application is preferably selected from the group consisting of Alzheimer's disease, Alzheimer's disease-related dementia, mild cognitive impairment, Lewy body dementia (LBD), frontotemporal lobar degeneration (FTD), vascular cognitive impairment and dementia (VCID), pre-dementia state, mild cognitive impairment, age-related memory impairment, age-related cognitive decline, non-dementia cognitive impairment, mild cognitive decline, mild neurocognitive decline, late-life forgetfulness, memory impairment and cognitive impairment, vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, Parkinson's type frontotemporal dementia, Parkinson dementia complex of Guam, HIV dementia, diseases associated with neurofibrillary tangle pathologies, dementia pugilistica, amyotrophic lateral sclerosis, multiple sclerosis, and other mental and neurological diseases epilepsy, depression, and the like.

[0124] In the present application, the scientific and technical terms used herein have the meanings commonly understood by a person of ordinary skill in the art, unless otherwise defined herein, however, for better understanding of the present application, the definitions of some terms are provided below. When the definitions and explanations of the terms provided in the present application are different from the meanings commonly understood by a person of ordinary skill in the art, the definitions and explanations of the terms provided in the present application shall prevail.

[0125] As used herein (including the appended aspects), the singular forms "a", "an", and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0126] The term "or" is used in the sense of the term "and / or" unless the context clearly dictates otherwise.

[0127] The term "alkyl" refers to a hydrocarbon selected from straight-chain and branched-chain saturated hydrocarbon radicals containing 1 to 18 (such as 1 to 12, further such as 1 to 10, more further such as 1 to 8, or 1 to 6, or 1 to 4, or 1 to 3, or 1 to 2) carbon atoms. Examples of alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 Examples of alkyl groups (e.g., C1-C6alkyl) include, but are not limited to, methyl, ethyl, 1 -propyl or n-propyl, 2-propyl or isopropyl, 1 -butyl or n-butyl, 2-methyl-1 -propyl or isobutyl, 1 -methylpropyl or sec-butyl, 1,1 -dimethylethyl or tert-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1 -butyl, 2-methyl-1 -butyl, 1 -hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0128] The term "halogen" refers to fluorine (F), chlorine (CI), bromine (Br), and iodine (I).

[0129] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced with one or more halogen atoms, such as fluorine, chlorine, bromine, and iodine. Examples of haloalkyl groups include haloC 1-8 alkyl, haloC 1-6 alkyl, or haloC 1-4 alkyl, but are not limited to -CF3, -CH2CI, -CH2CF3, -CHCI2, CF3, and the like.

[0130] The term "alkenyl" refers to a hydrocarbon selected from straight-chain and branched-chain hydrocarbon radicals containing at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Examples of alkenyl groups (e.g., C 2-6 Examples of alkenyl groups (e.g., C2-C6alkenyl) include, but are not limited to, ethenyl, prop-1 -enyl, prop-2-enyl, 2-methylprop-1 -enyl, but-1 -enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl.

[0131] The term "alkoxy" refers to an alkyl group as defined above attached to the parent molecular moiety through an oxygen atom. Examples of alkyl oxy groups (e.g., C 1-6 alkoxy, or C 1-4 alkoxy) include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy, pentoxy, and hexoxy, and the like.

[0132] The term "cycloalkyl" refers to a group selected from saturated / unsaturated cyclic hydrocarbons, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl groups.

[0133] For example, a cycloalkyl group can contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further for example, a cycloalkyl group can be selected from monocyclic groups containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In particular, saturated monocyclic cycloalkyl groups (e.g., C 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, the cycloalkyl group is a monocyclic group containing 3 to 6 carbon atoms (abbreviated as C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, the cycloalkyl group is a monocyclic group containing 3 to 6 carbon atoms (abbreviated as C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In preferred embodiments, the cycloalkyl group is a monocyclic group containing 3 to 6 carbon atoms (abbreviated as C

[0134] The term "aryl," used alone or in combination with other terms, refers to a group selected from 6-membered carbocyclic aromatic rings, e.g., phenyl; bicyclic ring systems, such as 7- to 14-membered bicyclic ring systems, wherein the rings are carbocyclic and aromatic, e.g., naphthyl. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 6-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalen-1-yl, naphthalen-2-yl, anthryl, phenanthryl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalen-1-yl or naphthalen-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0135] The term "heteroaryl" refers to a group selected from:

[0136] 5-, 6- or 7-membered aromatic monocyclic ring comprising at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, the heteroatoms being selected from nitrogen (N), sulfur (S) and oxygen (O), the remaining ring atoms being carbon;

[0137] 7- to 12-membered bicyclic ring comprising at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, the heteroatoms being selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0138] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is not greater than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocyclic ring is not greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. A nitrogen atom in one or more rings of a heteroaryl group can be oxidized to form an N-oxide. The term "C-linked heteroaryl" as used herein means that the heteroaryl group is attached to the core molecule through a bond from a C-atom of the heteroaryl ring.

[0139] Examples of rings of heteroaryl groups or monocyclic or bicyclic aromatic heterocyclic rings include, but are not limited to, (as numbered from the indicated priority 1 attachment position) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl), triazinyl, benzothienyl, furanyl, benzofuranyl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl (such as 1,2,3-triazolyl, 1,2,4-triazolyl, or 1,3,4-triazolyl), quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl (such as furazan-2-yl, furazan-3-yl), benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

[0140] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to nonaromatic heterocyclyl groups comprising one or more heteroatoms as ring members selected from nitrogen, oxygen, or optionally oxidized sulfur, and the remaining ring members are carbon, including monocyclic rings, fused rings, bridged rings, and spiro rings, i.e., containing monocyclic heterocyclyl groups, bridged heterocyclyl groups, spiro heterocyclyl groups, and fused heterocyclyl groups.

[0141] Exemplary monocyclic 3- to 14-membered (e.g., 4-, 5-, or 6-membered) heterocyclyl groups include, but are not limited to, (as numbered from the indicated position of priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocin-1-yl, azocin-2-yl, azocin-3-yl, azocin-4-yl, azocin-5-yl, thiiranyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, oxathianyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepin-1-yl, azepin-2-yl, azepin-3-yl, azepin-4-yl, oxepinyl, thiepinyl, 1,4-oxathianyl, 1,4-dioxepinyl, 1,4-oxathiepinyl, 1,4-oxazepinyl, 1,4-dithiepinyl, 1,4-thiazepinyl, 1,4-diazepinyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydronaphthalenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, or 1,1-dioxo-thiomorpholinyl.

[0142] "Pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid, or by reacting an acid group with a suitable base.

[0143] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred embodiment of the present application.

[0144] The reagents and starting materials used in the present application are commercially available.

[0145] The positive progress effect of the present application is that the tricyclic derivative of the present application regulates the AKT and downstream signaling pathways related to aging, reduces neuroinflammation, reduces oxidative stress, protects neurons, promotes the repair of damaged neurons, inhibits neuronal apoptosis, slows down AD cognitive decline, easily passes through the blood-brain barrier, is distributed in the brain, and has fewer systemic side effects. BRIEF DESCRIPTION OF DRAWINGS

[0146] Figure 1 is the effect of compound 13 on the latency of APP / PS1 mice in the water maze, n = 10, ##p < 0.01, #p < 0.05 vs. normal control group, *p < 0.05 vs. model group.

[0147] Figure 2 is the effect of compound 13 on the crossing time of APP / PS1 mice in the water maze, n = 10, ##p < 0.01, #p < 0.05 vs. normal control group, *p < 0.05 vs. model group.

[0148] Figure 3 is the effect of compound 13 on the crossing number of APP / PS1 mice in the water maze, n = 10, ##p < 0.01, #p < 0.05 vs. normal control group, *p < 0.05 vs. model group.

[0149] Figure 4 is the effect of compound 35 on the latency of APP / PS1 mice in the water maze, n = 10, ##p < 0.01, #p < 0.05 vs. normal control group, *p < 0.05 vs. model group.

[0150] Figure 5 is the effect of compound 35 on the crossing time of APP / PS1 mice in the water maze, n = 10, ##p < 0.01, #p < 0.05 vs. normal control group, *p < 0.05 vs. model group.

[0151] Figure 6 is the effect of compound 35 on the crossing number of APP / PS1 mice in the water maze, n = 10, ##p < 0.01, #p < 0.05 vs. normal control group, *p < 0.05 vs. model group. DETAILED DESCRIPTION

[0152] The present application can be further described by the following examples, however, the scope of the present application is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made to the present application without departing from the spirit and scope of the present application.

[0153] Optical rotation test

[0154] 1. Preparation of test sample solution: Take an appropriate amount of compound, dissolve and dilute in acetonitrile to prepare a solution containing about 10 mg per milliliter.

[0155] 2. Test conditions:

[0156] Light source: D line of sodium spectrum (WLG. nm) (589.3 nm); cell length (Lg): 1 dm; measurement temperature (Temp): 20.0°C ± 0.5°C; measurement time (Time): measurement was performed within 30 minutes after solution preparation.

[0157] Preparation Example 1. 3-n-Butylphthalide (b)

[0158] To the reaction flask was added phthalic anhydride (30.0 g, 0.2 mol), then pentanoic anhydride (60 mL, 0.3 mol) and anhydrous acetic anhydride (16.62 g, 0.2 mol) were added, and the reaction was carried out at 200°C, and after the reaction was completed as monitored by TLC, it was cooled to room temperature, a saturated NaHCO3 solution was added, the pH was adjusted to about 7, and it was extracted with DCM three times, the organic phases were combined, and concentrated under reduced pressure for use. To the product of the previous step, a solution of sodium borohydride in sodium hydroxide (sodium borohydride (3.25 g, 0.086 mol), sodium hydroxide (20 g, 0.5 mol) and 50 mL of water) was slowly added dropwise at room temperature, and after the addition was completed, the reaction was carried out at 60°C, and after the reaction was completed as monitored by TLC, it was cooled to room temperature, the reaction solution was washed with DCM three times, the aqueous phase was adjusted to a pH of about 1 with HCl, and then it was incubated at 85°C for 5 hours, and then extracted with DCM three times, the organic phases were combined, and chromatographed on a silica gel column to obtain a light yellow liquid 30.2 g, with a yield of 79.5%.

[0159] Preparation Example 2. 6-nitro-3-n-butylphthalide (c)

[0160] To the reaction flask was added 3-n-butylphthalide (2.0 g, 10.52 mmol), 5 mL of concentrated H2SO4 was added, and a mixture of concentrated HNO3 (0.7 mL, 15.78 mmol) and concentrated H2SO4 (2.2 mL) was added dropwise at 0°C, and after stirring for 2 h, the ice bath was removed, and the stirring was continued at room temperature, and after the reaction was completed as monitored by TLC, H2O was added, and the mixture was extracted with DCM, the organic phases were combined, dried over anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column. The obtained organic solution was concentrated to dryness under reduced pressure to obtain a yellow oily liquid 2.3 g, with a yield of 92.5%.

[0161] 1H NMR (400 MHz, CDC13) δ / ppm 8.68 (dd, J = 7.4, 2.1 Hz, 1H), 8.53 (dt, J = 8.4, 2.3 Hz, 1H), 7.66 (dd, J1= 8.3 Hz, J2= 2.7 Hz, 1H), 5.59 (dd, J1= 7.9 Hz, J2= 4.1 Hz, 1H), 2.11 (ddq, J1= 14.4 Hz, J2= 9.8 Hz, J3= 4.6 Hz, 1H), 1.80 (dddd, J1= 18.6 Hz, J2= 10.1 Hz, J3= 4.7 Hz, J4= 2.3 Hz, 1H), 1.53 - 1.28 (m, 4H), 0.96 - 0.80 (m, 3H).

[0162] Preparation Example 3. 6-amino-3-n-butylphthalide (d)

[0163] Into a reaction flask was added 6-nitro-3-n-butylphthalide (2.3 g, 9.78 mmol), 10 mL EtOH and 3 mL H20, then Fe (5.5 g, 97.8 mmol) and NH4CI (0.5 g, 9.78 mmol) were added. The reaction was heated to reflux under argon protection and monitored by TLC. After the reaction was completed, it was filtered and concentrated under reduced pressure. The obtained organic solution was concentrated to dryness under reduced pressure to give a yellowish solid 1.5 g with a yield of 72.8%.

[0164] 1 H NMR (400 MHz, CDC13) δ / ppm 7.17 (d, J = 8.1 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 6.95 (dd, J1= 8.1 Hz, J2= 2.2 Hz, 1H), 5.36 (dd, J1= 7.7 Hz, J2= 4.2 Hz, 1H), 1.96 (dddd, J1= 14.1 Hz, J2= 10.0 Hz, J3= 6.0 Hz, J4= 4.2 Hz, 1H), 1.76 - 1.61 (m, 1H), 1.52 - 1.29 (m, 4H), 0.89 (t, J = 6.9 Hz, 3H).

[0165] Preparation Example 4. 6-hydroxy-3-n-butylphthalide (e)

[0166] To 6-amino-3-n-butylphthalide (10 g, 48.80 mmol) in 90 mL CH3COOH, heat to 75 °C until completely dissolved, cool to room temperature, during this process, add 30 mL concentrated H2SO4 dropwise, after the dropwise addition is complete, place the reaction flask in an ice-salt bath, when the temperature is reduced to below 0 °C, add a solution of NaNO2(aq) (3.7 g, 53.68 mmol), after 2 h of reaction at 0 °C, add 150 mL ice H2SO4 and urea (293 mg, 4.88 mmol) to the reaction, filter, and reserve the filtrate. Take another reaction flask, add 22.14 mL concentrated H2SO4, 90 mL H2O, and 50 mL PhMe, heat to 145 °C, and add the filtrate from the previous step to the boiling hydrolysis solution in portions (50 mL per portion) dropwise (30 mins). After the dropwise addition is complete, hydrolyze at 145 °C for 10 minutes. Cool to room temperature, separate the organic phase, extract the aqueous phase with EA three times, combine the organic phases, concentrate, and chromatograph on a silica gel column to obtain 6.6 g of a light yellow solid with a yield of 66%.

[0167] 1 H NMR (400 MHz, CDC13) δ 7.42 (d, J = 2.1 Hz, 1H), 7.32 - 7.20 (m, 2H), 5.44 (dd, J = 7.7, 4.2 Hz, 1H), 2.00 (dddd, J = 14.2, 10.0, 5.9, 4.2 Hz, 1H), 1.74 (dddd, J = 14.5, 9.7, 7.8, 5.1 Hz, 1H), 1.54 - 1.22 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H).

[0168] Preparation Example 5. 1 -butyl-5-hydroxy-3-oxo- 1,3-dihydroisobenzofuran-4- carboxaldehyde (f)

[0169] To 6-hydroxy-3-n-butylphthalide (1.37 g, 6.64 mmol) in 10 mL CF3COOH, add HMTA (0.930 g, 6.64 mmol), reflux at 120 °C, after the reaction is complete as monitored by TLC, adjust the pH to about 6 with KOH(aq), filter, wash the filter cake with EA, collect the organic phase, concentrate, and chromatograph on a silica gel column to obtain 845 mg of a white solid with a yield of 54.3%.

[0170] 1H NMR (400 MHz, CDC13) δ / ppm 11.00 (s, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 5.45 (dd, J = 7.8, 4.1 Hz, 1H), 2.04 (dddd, J = 14.1, 9.8, 5.8, 4.0 Hz, 1H), 1.75 (dddd, J = 14.6, 9.9, 7.8, 5.0 Hz, 1H), 1.59 - 1.28 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0171] Example 1. 2-(7-amino-3-butyl-8-cyano-l-oxo-l,9-dihydro-3H-furo[3,4- f]chromen-9-yl)malononitrile

[0172] Compound f (500 mg, 2.14 mmol) was dissolved in anhydrous EtOH 10 mL, then malononitrile (311 mg, 4.71 mmol) and 650 mg of 3 A molecular sieves were added, stirred at room temperature, and the end of the reaction was monitored by TLC. Filtration, washing the filter cake with tetrahydrofuran (THF) 3 times, concentration of the organic phase under reduced pressure, freeze solidification, recrystallization in 85% EtOH, gave the target compound 509 mg with a yield of 68.3%.

[0173] 1 H NMR (400 MHz, DMSO-d6) δ / ppm 7.76 - 7.72 (m, 1H), 7.53 (dd, J = 8.4, 4.3 Hz, 1H), 5.63 (ddd, J = 15.1, 8.0, 3.6 Hz, 1H), 5.19 (dd, J = 32.9, 3.1 Hz, 1H), 4.96 (dd, J = 5.7, 3.1 Hz, 1H), 2.07 (tt, J = 9.4, 4.9 Hz, 1H), 1.68 (ddt, J = 19.7, 13.6, 5.7 Hz, 1H), 1.32 (ddt, J = 23.7, 17.1, 9.6 Hz, 4H), 0.88 (q, J = 7.5 Hz, 3H).

[0174] HRMS (ESI) m / z calcd for C 19 H 17 N4O3 + [M+H] + : 349.1295 found: 349.1280

[0175] Example 2. 7-amino-3-butyl-9-(carboxy(cyano)methyl)-l-oxo-l,9-dihydro-3H- furo[3,4-f]chromene-8-carboxylic acid

[0176] To compound f (500 mg, 2.14 mmol) was dissolved in 10 mL of anhydrous EtOH, then added cyanacetic acid (400 mg, 4.71 mmol) and 650 mg of 3A molecular sieve, stirred at room temperature, and the reaction was monitored by TLC until it was completed. Filtration was performed, the filter cake was washed with tetrahydrofuran (THF) three times, the organic phase was concentrated under reduced pressure, and the target compound was obtained by recrystallization from 85% EtOH in a frozen state in 539 mg with a yield of 65.3%.

[0177] 1 H NMR (500 MHz, DMSO-d6) δ / ppm 7.37 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 5.42 (dt, J = 6.5, 3.0 Hz, 1 H), 4.33 (d, J = 3.4 Hz, 2 H), 3.67 (s, 1 H), 1.96 (dd, J = 13.4, 6.1 Hz, 1 H), 1.64 - 1.56 (m, 1 H), 1.32 (d, J = 14.1 Hz, 4 H), 0.87 (t, J = 6.8 Hz, 3 H).

[0178] HRMS (ESI) m / z calcd for C 19 H 17 N4O3 + [M+H] + :387.1177 found:387.1177

[0179] Example 3. 7-amino-3-butyl-9-(1-cyano-2-methoxy-2-oxoethyl)-1-oxo-1,9-dihydro-3H- furo [3,4-f] chromen-8-carboxylic acid methyl ester

[0180] To compound f (500 mg, 2.14 mmol) was dissolved in 10 mL of anhydrous EtOH, then added cyanacetic acid (400 mg, 4.71 mmol) and 650 mg of 3A molecular sieve, stirred at room temperature, and the reaction was monitored by TLC until it was completed. Filtration was performed, the filter cake was washed with tetrahydrofuran (THF) three times, the organic phase was concentrated under reduced pressure, and the target compound was obtained by recrystallization from 85% EtOH in a frozen state in 539 mg with a yield of 65.3%.

[0181] 1H NMR (400 MHz, DMSO-d6) δ / ppm 7.66 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 5.61 (qt, J = 8.6, 4.2 Hz, 1H), 5.27 (dd, J = 25.5, 3.4 Hz, 1H), 4.19 (d, J = 3.5 Hz, 1H), 3.70 (d, J = 11.1 Hz, 3H), 3.58 (d, J = 4.1 Hz, 3H), 2.14 - 1.98 (m, 1H), 1.70 (q, J = 10.2 Hz, 1H), 1.30 (tt, J = 20.3, 8.3 Hz, 4H), 0.87 (q, J = 7.7 Hz, 3H).

[0182] HRMS (ESI) m / z calcd for C 21 H 23 N2O7 + [M+H] + : 415.1500 found: 415.1513

[0183] Example 4. 7-amino-3-butyl-9-(1-cyano-2-methoxy-2-oxoethyl)-1-oxo-1,9- dihydro-3H-furo[3,4-f]chromen-8-carboxylic acid ethyl ester

[0184] Compound f (500 mg, 2.14 mmol) was dissolved in anhydrous EtOH 10 mL, then ethyl cyanoacetate (533 mg, 4.71 mmol) and 650 mg of 3A molecular sieves were added, stirring at room temperature, monitoring the end of the reaction by TLC. Filtration, washing the filter cake with THF 3 times, concentration of the organic phase under reduced pressure, freeze solidification, recrystallization in 85% EtOH, obtaining 657 mg of the target compound with a yield of 69.4%.

[0185] 1 H NMR (400 MHz, DMSO-d6) δ / ppm 7.66 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 5.61 (qt, J = 8.6, 4.2 Hz, 1H), 5.27 (dd, J = 25.5, 3.4 Hz, 1H), 4.19 (d, J = 3.5 Hz, 1H), 3.70 (d, J = 11.1 Hz, 3H), 3.58 (d, J = 4.1 Hz, 3H), 2.14 - 1.98 (m, 1H), 1.70 (q, J = 10.2 Hz, 1H), 1.30 (tt, J = 20.3, 8.3 Hz, 4H), 0.87 (q, J = 7.7 Hz, 3H).

[0186] HRMS (ESI) m / z calcd for C 23 H27 N2O7 + [M+H] + :443.1813found:443.1813

[0187] Example 5. 7-amino-3-butyl-9-(1-cyano-2-isopropoxy-2-oxoethyl)-1-oxo-1,9- dihydro-3H-furo[3,4-f]chromen-8-carboxylic acid isopropyl ester

[0188] Compound f (500 mg, 2.14 mmol) was dissolved in anhydrous EtOH 10 mL, then added isopropyl cyanoacetate (599 mg, 4.71 mmol) and 650 mg 3A molecular sieves, stirred at room temperature, TLC monitored the end of the reaction. Filtered, the filter cake was washed with THF 3 times, the organic phase was concentrated under reduced pressure, freeze solidification, recrystallized in 85% EtOH, obtained 658 mg of the target compound, the yield was 65.4%.

[0189] 1 H NMR (500 MHz, CDC13) δ / ppm 7.35 (s, 2H), 5.45 (dd, J = 6.7, 3.5 Hz, 2H), 5.13 (p, J = 6.3 Hz, 1H), 4.92 (p, J = 6.3 Hz, 1H), 3.86 (d, J = 3.0 Hz, 1H), 2.02 (ddt, J = 14.5, 9.4, 4.6 Hz, 1H), 1.77 - 1.60 (m, 1H), 1.42 - 1.19 (m, 16H), 0.88 (t, J = 6.8 Hz, 3H).

[0190] HRMS (ESI) m / z calcd for C 25 H 31 N2O7 + [M+H] + :471.2126found:471.2115

[0191] Example 6. 7-amino-9-(2-butoxy-1-cyano-2-oxoethyl)-3-butyl-1-oxo-1,9-dihydro-3H- furo[3,4-f]chromen-8-carboxylic acid butyl ester

[0192] To compound f (500 mg, 2.14 mmol) was dissolved in 10 mL of anhydrous EtOH, then added n-butyl cyanoacetate (665 mg, 4.71 mmol) and 650 mg of 3A molecular sieves, stirred at room temperature, and the reaction was monitored by TLC until it was completed. Filtration was performed, the filter cake was washed with THF three times, the organic phase was concentrated under reduced pressure, and the product was recrystallized from 85% EtOH to obtain 659 mg of the target compound with a yield of 64.6%.

[0193] 1 H NMR (400 MHz, DMSO-d6) δ / ppm 7.65 (dt, J = 8.0, 3.8 Hz, 1H), 7.53 - 7.46 (m, 1H), 5.60 (ddt, J = 19.6, 8.3, 4.0 Hz, 1H), 5.33 (ddd, J = 27.1, 8.2, 3.6 Hz, 1H), 4.23 - 3.86 (m, 6H), 2.07 (s, 1H), 1.71 - 1.49 (m, 5H), 1.42 - 1.25 (m, 8H), 0.93 - 0.86 (m, 9H).

[0194] HRMS (ESI) m / z calcd for C 27 H 35 N2O7 + [M+H] + :499.2439found:499.2481

[0195] Example 7. tert-Butyl 7-amino-9-(2-(tert-butoxy)-1-cyano-2-oxoethyl)-3-butyl-1-oxo- 1,9-dihydro-3H-furo[3,4-f]8-carboxylate

[0196] To compound f (500 mg, 2.14 mmol) was dissolved in 10 mL of anhydrous EtOH, then added n-butyl cyanoacetate (665 mg, 4.71 mmol) and 650 mg of 3A molecular sieves, stirred at room temperature, and the reaction was monitored by TLC until it was completed. Filtration was performed, the filter cake was washed with THF three times, the organic phase was concentrated under reduced pressure, and the product was recrystallized from 85% EtOH to obtain 659 mg of the target compound with a yield of 64.6%.

[0197] 1H NMR (400 MHz, DMSO-d6) δ / ppm 7.61 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 5.62 (dd, J = 7.5, 3.7 Hz, 1H), 5.25 (d, J = 2.7 Hz, 1H), 3.99 (d, J = 2.7 Hz, 1H), 2.05 (tt, J = 10.3, 4.2 Hz, 1H), 1.69 (dt, J = 14.2, 8.7 Hz, 1H), 1.51 (s, 9H), 1.30 (d, J = 26.1 Hz, 13H), 0.85 (t, J = 6.8 Hz, 3H).

[0198] HRMS (ESI) m / z calcd for C 27 H 35 N2O7 + [M+H] + :499.2439found:499.2471

[0199] Example 8. 9-(2-(Allyloxy)-1-cyano-2-oxoethyl)-7-amino-3-butyl-1-oxo-1,9- dihydro-3H-furo[3,4-f]chromen-8-carboxylic acid allyl ester

[0200] Compound f (500 mg, 2.14 mmol) was dissolved in anhydrous EtOH 10 mL, then allyl cyanoacetate (589 mg, 4.71 mmol) and 650 mg of 3A molecular sieves were added, stirring at room temperature, monitoring the end of the reaction by TLC. Filtration, washing the filter cake with THF 3 times, concentration of the organic phase under reduced pressure, freeze solidification, recrystallization in 85% EtOH, obtaining 583 mg of the target compound with a yield of 58.4%.

[0201] 1 H NMR (400 MHz, DMSO-d6) δ / ppm 7.66 (dd, J = 8.4, 3.8 Hz, 1H), 7.55-7.46 (m, 1H), 6.09-5.74 (m, 2H), 5.59 (ddt, J = 21.9, 9.3, 4.1 Hz, 1H), 5.49-5.38 (m, 1H), 5.37-5.30 (m, 1H), 5.30-5.12 (m, 3H), 4.74-4.34 (m, 4H), 4.31-4.17 (m, 1H), 2.13-1.99 (m, 1H), 1.69 (ddt, J = 14.2, 9.2, 5.5 Hz, 1H), 1.51-1.18 (m, 4H), 0.95-0.77 (m, 3H).

[0202] HRMS (ESI) m / z calcd for C 25 H 27 N2O7 + [M+H] + :467.1813found:467.1812

[0203] Example 9. 2-methoxyethyl 7-amino-3-butyl-9-(1-cyano-2-(2-methoxyethoxy)-2- oxoethyl)-1-oxo-1,9-dihydro-3H-furo[3,4-f]8-carboxycoumarin

[0204] Compound f (500 mg, 2.14 mmol) was dissolved in anhydrous EtOH 10 mL, then ethyl methoxy cyanoacetate (674 mg, 4.71 mmol) and 650 mg 3A molecular sieves were added, stirred at room temperature, TLC monitored the end of the reaction. Filtration, the filter cake was washed with THF 3 times, the organic phase was concentrated under reduced pressure, freeze solidification, recrystallized in 85% EtOH, the target compound 606 mg, the yield was 56.4%.

[0205] 1 H NMR (400 MHz, DMSO-d6) δ / ppm 7.66 (dd, J = 8.4, 5.0 Hz, 1H), 7.51 (dd, J = 8.3, 4.2 Hz, 1H), 5.60 (ddd, J = 23.7, 7.8, 3.9 Hz, 1H), 5.39 - 5.20 (m, 1H), 4.36 - 4.13 (m, 4H), 4.01 (dq, J = 12.2, 4.2 Hz, 1H), 3.70 - 3.36 (m, 6H), 3.24 (s, 4H), 2.07 (d, J = 13.8 Hz, 1H), 1.69 (d, J = 15.6 Hz, 1H), 1.30 (q, J = 22.4 Hz, 4H), 0.87 (dt, J = 13.3, 6.6 Hz, 3H).

[0206] HRMS (ESI) m / z calcd for C 25 H 31 N2O9 + [M+H] + :503.2024found:503.2021

[0207] Example 10. 2-ethoxyethyl 7-amino-3-butyl-9-(1-cyano-2-(2-ethoxyethoxy)-2- oxoethyl)-1-oxo-1,9-dihydro-3H-furo[3,4-f]8-carboxycoumarin

[0208] To compound f (500 mg, 2.14 mmol) dissolved in anhydrous EtOH 10 mL, add ethoxyethyl cyanoacetate (704 mg, 4.71 mmol) and 650 mg of 3A molecular sieves, stir at room temperature, monitor the end of the reaction by TLC. Filter, wash the filter cake with THF 3 times, concentrate the organic phase under reduced pressure, freeze solidify, recrystallize in 85% EtOH to obtain 654 mg of the target compound with a yield of 57.4%.

[0209] 1 H NMR (400 MHz, DMSO-d6) δ / ppm 7.66 (dt, J = 10.1, 5.2 Hz, 1H), 7.51 (dd, J = 8.3, 4.2 Hz, 1H), 5.72 - 5.51 (m, 1H), 5.33 (ddd, J = 28.3, 8.1, 3.7 Hz, 1H), 4.21 (tdt, J = 24.8, 13.1, 6.8 Hz, 4H), 4.05 - 3.95 (m, 1H), 3.54 (dddd, J = 55.8, 30.0, 12.3, 6.1 Hz, 8H), 2.07 (s, 1H), 1.83 - 1.61 (m, 1H), 1.38 - 1.02 (m, 10H), 0.87 (qt, J = 7.2, 2.9 Hz, 3H).

[0210] HRMS (ESI) m / z calcd for C 27 H 35 N2O9 + [M+H] + :531.2337 found:531.2348

[0211] Example 11. 7-amino-9-(2-(benzyloxy)-1-cyano-2-oxoethyl)-3-butyl-1-oxo-1,9- dihydro-3H-furo[3,4-f]benzo-8-carboxylic acid benzyl ester

[0212] To compound f (500 mg, 2.14 mmol) dissolved in anhydrous EtOH 10 mL, add ethoxyethyl cyanoacetate (704 mg, 4.71 mmol) and 650 mg of 3A molecular sieves, stir at room temperature, monitor the end of the reaction by TLC. Filter, wash the filter cake with THF 3 times, concentrate the organic phase under reduced pressure, freeze solidify, recrystallize in 85% EtOH to obtain 654 mg of the target compound with a yield of 57.4%.

[0213] 1H NMR (500 MHz, CDC13) δ / ppm 7.36 (q, J = 6.3 Hz, 9 H), 7.26 (q, J = 7.3 Hz, 3 H), 5.60 (q, J = 2.5 Hz, 1 H), 5.39 (ddd, J = 12.1, 8.0, 3.9 Hz, 1 H), 5.33 - 5.20 (m, 2 H), 5.19 - 5.04 (m, 2 H), 3.98 (t, J = 3.1 Hz, 1 H), 2.01 (d, J = 13.5 Hz, 1 H), 1.72 (dq, J = 31.4, 9.5 Hz, 1 H), 1.53 - 1.31 (m, 4 H), 0.93 (dt, J = 23.0, 7.0 Hz, 3 H).

[0214] HRMS (ESI) m / z calcd for C 33 H 31 N2O7 + [M+H] + : 567.2126 found: 567.2126

[0215] Example 12. 7-benzoyl-3-butylbenzo[l,2-b:3,4-c']difuran-l(3H)-one

[0216] To a single necked reaction flask was added compound f (2 g, 8.55 mmol) and 2-bromoacetophenone (1.702 g, 8.55 mmol), then K2CO3 (1.182 g, 8.55 mmol) was dissolved in 20 mL of MeCN and heated to reflux at 120 °C, after completion of the reaction as monitored by TLC, it was cooled, filtered, the organic phase was washed with water and concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure and the target compound was obtained in 2.4 g with a yield of 83.2%.

[0217] 1 H NMR (400 MHz, CDC13) δ / ppm 8.09 - 7.90 (m, 4 H), 7.75 - 7.62 (m, 1 H), 7.60 - 7.44 (m, 3 H), 5.59 (dd, J = 7.8, 4.0 Hz, 1 H), 2.11 (dtd, J = 10.0, 5.4, 2.3 Hz, 1 H), 1.80 (dddd, J = 14.5, 10.2, 7.8, 4.5 Hz, 1 H), 1.56 - 1.33 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H).

[0218] HRMS (ESI) m / z calcd for C 21 H 19 O4 + [M+H]+ :335.1278 found:335.1271

[0219] Example 13. 3-Butyl-7-(4-methylbenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0220] To a single necked reaction flask was added compound f (2 g, 8.55 mmol) and 2-bromo-4'-methylacetophenone (1.822 g, 8.55 mmol), then K2CO3 (1.182 g, 8.55 mmol) dissolved in 20 mL MeCN, heated to reflux at 120 °C, TLC monitored the end of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure, to obtain the target compound 2.4 g, yield 81.2%.

[0221] 1 H NMR (400 MHz, CDC13) δ / ppm 8.03 - 7.86 (m, 4H), 7.50 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 7.9 Hz, 2H), 5.59 (dd, J = 7.9, 4.0 Hz, 1H), 2.47 (s, 3H), 2.22 - 2.03 (m, 1H), 1.80 (dddd, J = 14.5, 10.2, 7.7, 4.3 Hz, 1H), 1.54 - 1.33 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0222] HRMS (ESI) m / z calcd for C 22 H 21 O4 + [M+H] + :349.1434 found:349.1428.

[0223] The target compound (0.3387 g) was subjected to chiral separation under the following chromatographic conditions to obtain compounds 13-1 and 13-2, whose ee values and optical rotation values are as follows:

[0224] Chromatographic conditions for chiral separation:

[0225] HPLC: Shimadzu LC-20AT, CP-HPLC-09; Column: CHIRALCEL OZ-H (OZH0CE-BO005), 0.46 cm I.D. x 25 cm L; Injection: 10 ul; Mobile phase: MeOH / ACN = 90 / 10 (V / V); Flow rate: 1.0 ml / min Wavelength: UV: 254 nm; Temperature: 35 °C.

[0226] Example 14. 3-Butyl-7-(3-methylbenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0227] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-l-m-tolyl-ethanone (92 mg, 0.43 mmol) and 5 mL MeCN was taken in a single necked reaction flask, K2C03(60 mg, 0.43 mmol) was added, heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, to get the target compound 122 mg with 81.6 % yield.

[0228] 1 H NMR (500 MHz, CDC13) δ / ppm 8.05 - 7.90 (m, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.59 - 7.36 (m, 3H), 5.60 (dd, J = 7.9, 3.9 Hz, 1H), 2.47 (s, 3H), 2.12 (ddd, J = 14.4, 9.5, 5.0 Hz, 1H), 1.94 - 1.75 (m, 1H), 1.62 - 1.30 (m, 4H), 0.91 (t, J = 7.0 Hz, 3H).

[0229] HRMS (ESI) m / z calcd for C 22 H 21 O4 + [M+H] + : 349.1434 found: 349.1447

[0230] Example 15. 3-Butyl-7-(2-methylbenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0231] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-l-m-tolyl-ethanone (92 mg, 0.43 mmol) and 5 mL MeCN was taken in a single necked reaction flask, K2C03(60 mg, 0.43 mmol) was added, heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, to get the target compound 122 mg with 81.6 % yield.

[0232] 1H NMR (400 MHz, CDC13) δ / ppm 7.94 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.62 - 7.43 (m, 3H), 7.37 - 7.29 (m, 2H), 5.58 (dd, J = 7.8, 3.9 Hz, 1H), 2.44 (s, 3H), 2.11 (ddt, J = 14.2, 9.7, 4.2 Hz, 1H), 1.79 (dtd, J = 18.5, 9.2, 3.8 Hz, 1H), 1.54 - 1.29 (m, 4H), 0.90 (t, J = 6.9 Hz, 3H).

[0233] HRMS (ESI) m / z calcd for C 22 H 21 O4 + [M+H] + : 349.1434 found: 349.1434

[0234] Example 16. 3-Butyl-7-(4-ethylbenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0235] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-l-(4-methylphenyl)ethanone (98 mg, 0.43 mmol) followed by K2CO3(60 mg, 0.43 mmol) dissolved in 5 mL of MeCN and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The obtained organic solution was concentrated to dryness under reduced pressure to obtain the target compound 122 mg in 78.3% yield.

[0236] 1 H NMR (500 MHz, CDC13) δ / ppm 8.03 - 7.87 (m, 4H), 7.51 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 5.60 (dd, J = 7.9, 3.9 Hz, 1H), 2.77 (q, J = 7.6 Hz, 2H), 2.12 (ddt, J = 14.5, 10.2, 4.8 Hz, 1H), 1.81 (tdd, J = 14.1, 7.7, 4.1 Hz, 1H), 1.59 - 1.36 (m, 4H), 1.31 (t, J = 7.6 Hz, 3H), 0.91 (t, J = 6.9 Hz, 3H).

[0237] HRMS (ESI) m / z calcd for C 23 H 23 O4+ [M+H] + :363.1591found:363.1591

[0238] The target compound (0.3326 g) was separated under the following chiral separation chromatographic conditions to obtain compounds 16-1 and 16-2, with ee values and optical rotation values as follows:

[0239] Chiral separation chromatographic conditions:

[0240] HPLC: Shimadzu LC-20AT, CP-HPLC-09; Column: CHIRALCEL OZ-H (OZH0CE-BO005), 0.46 cm I.D. x 25 cm L; Injection: 5 ul; Mobile phase: MeOH / ACN = 90 / 10 (V / V); Flow rate: 1.0 ml / min Wavelength: UV: 254 nm; Temperature: 35 °C.

[0241] Example 17. 3-Butyl-7-(4-(tert-butyl)benzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0242] The compound f (100 mg, 0.43 mmol) and 2-bromo-l-(4-(tert-butyl)phenyl)ethanone (110 mg, 0.43 mmol) were added to a single-neck reaction flask, and 5 mL of MeCN was added to dissolve and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, and after the reaction was completed as monitored by TLC, it was cooled, filtered, the organic phase was washed with water, concentrated under reduced pressure, and the obtained organic solution was concentrated to dryness under reduced pressure to obtain the target compound 141 mg with a yield of 83.9%.

[0243] 1 H NMR (400 MHz, CDC13) δ / ppm 8.02 - 7.89 (m, 4H), 7.66 - 7.43 (m, 3H), 5.59 (dd, J = 7.9, 4.0 Hz, 1H), 2.17 - 2.06 (m, 1H), 1.81 (dddd, J = 14.5, 10.2, 7.8, 4.4 Hz, 1H), 1.39 (s, 13H), 0.91 (t, J = 7.0 Hz, 3H).

[0244] HRMS (ESI) m / z calcd for C 25 H 27 O4 + [M+H] + :391.1904found:391.1901

[0245] Example 18. 3-Butyl-7-(4-butylbenzoyl)benzo[1,2-b:3,4-c']difuran-1 (3H)-one

[0246] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-1-(4-pentylphenyl)ethanone (110 mg, 0.43 mmol) followed by 5 mL of MeCN dissolved and K2C03(60 mg, 0.43 mmol) and heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure to get the target compound 138 mg with 82.2% yield.

[0247] 1 H NMR (400 MHz, CDC13) δ / ppm 8.05 - 7.89 (m, 4H), 7.60 - 7.45 (m, 1H), 7.43 - 7.31 (m, 2H), 5.60 (dd, J = 7.9, 3.9 Hz, 1H), 2.73 (t, J = 7.7 Hz, 2H), 2.11 (tt, J = 10.0, 3.5 Hz, 1H), 1.88 - 1.75 (m, 1H), 1.70 - 1.59 (m, 2H), 1.55 - 1.31 (m, 6H), 0.94 (dt, J = 17.7, 7.2 Hz, 6H).

[0248] HRMS (ESI) m / z calcd for C 25 H 27 O4 + [M+H] + : 391.1904 found: 391.1903

[0249] Example 19. 3-Butyl-7-(4-fluorobenzoyl)benzo[1,2-b:3,4-c']difuran-1 (3H)-one

[0250] To a single necked reaction flask was taken compound f (0.737 g, 3.15 mmol) and 2-bromo-4'-fluoroacetophenone (0.684 g, 3.15 mmol) followed by 10 mL of MeCN dissolved and K2C03(0.435 g, 3.15 mmol) and heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure to get the target compound 0.927 g with 83.6% yield.

[0251] 1 H NMR (400 MHz, CDC13) δ / ppm 8.21 - 8.06 (m, 2H), 7.94 (t, J = 4.2 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.24 (t, J = 8.6 Hz, 2H), 5.60 (dd, J = 7.9, 3.9 Hz, 1H), 2.12 (tt, J = 9.9, 3.1 Hz, 1H), 1.81 (dddd, J = 14.5, 12.6, 6.1, 3.5 Hz, 1H), 1.55 - 1.37 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H).

[0252] HRMS (ESI) m / z calcd for C 21 H 18 FO4 + [M+H] + :353.1184found:353.1175

[0253] Example 20. 3-Butyl-7-(4-chlorobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0254] To a single necked reaction flask was added compound f (660 mg, 2.82 mmol) and 2-bromo-4'-chloroacetophenone (658 mg, 2.82 mmol) followed by K2CO3(390 mg, 2.82 mmol) dissolved in 10 mL of MeCN and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion of the reaction, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The organic solution was concentrated to dryness under reduced pressure and the target compound was obtained as 860 mg with a yield of 82.9%.

[0255] 1 H NMR (400 MHz, CDC13) δ / ppm 8.21 - 8.06 (m, 2H), 7.94 (t, J = 4.2 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.24 (t, J = 8.6 Hz, 2H), 5.60 (dd, J = 7.9, 3.9 Hz, 1H), 2.12 (tt, J = 9.9, 3.1 Hz, 1H), 1.81 (dddd, J = 14.5, 12.6, 6.1, 3.5 Hz, 1H), 1.55 - 1.37 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H).

[0256] HRMS (ESI) m / z calcd for C 21 H 18 ClO4 + [M+H] + :369.0888found:369.0899

[0257] Example 21. 7-(4-bromobenzoyl)-3-butylbenzo[1,2-b:3,4-c']difuran-1 (3H)-one

[0258] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-4'-bromoacetophenone (120 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2C03(60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, column chromatography over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the desired compound 148 mg with 83.3% yield.

[0259] 1 H NMR (400 MHz, CDC13) δ / ppm 8.02 - 7.84 (m, 4H), 7.78 - 7.65 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 5.60 (dd, J = 7.9, 4.0 Hz, 1H), 2.12 (dddd, J = 14.1, 9.8, 5.7, 4.2 Hz, 1H), 1.80 (dddd, J = 14.5, 10.3, 7.8, 4.6 Hz, 1H), 1.58 - 1.30 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0260] HRMS (ESI) m / z calcd for C 21 H 18 BrO4 + [M+H] + : 413.0383 found: 413.0386

[0261] Example 22. 3-butyl-7-(4-iodobenzoyl)benzo[1,2-b:3,4-c']difuran-1 (3H)-one

[0262] To a single necked reaction flask was taken compound f (130 mg, 0.56 mmol) and 2-bromo-4'-iodoacetophenone (181 mg, 0.56 mmol) followed by 10 mL MeCN dissolved and K2C03(77 mg, 0.56 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, column chromatography over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the desired compound 217 mg with 84.3% yield.

[0263] 1H NMR (400 MHz, CDCI3) δ / ppm 8.03 - 7.89 (m, 4 H), 7.83 - 7.68 (m, 2 H), 7.53 (d, J = 8.7 Hz, 1 H), 5.60 (dd, J = 7.9, 4.0 Hz, 1 H), 2.25 - 2.03 (m, 1 H), 1.92 - 1.71 (m, 1 H), 1.55 - 1.28 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H).

[0264] HRMS (ESI) m / z calcd for C 21 H 18 IO4 + [M+H] + :461.0244found:461.0240

[0265] Example 23. 3-Butyl-7-(3,4-dichlorobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0266] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and a-bromo-3,4-dichloroacetophenone (116 mg, 0.43 mmol) followed by K2CO3(60 mg, 0.43 mmol) dissolved in 10 mL MeCN and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion of the reaction, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 146 mg with a yield of 84.6%.

[0267] 1 H NMR (400 MHz, CDCI3) δ / ppm 8.03 - 7.89 (m, 4 H), 7.83 - 7.68 (m, 2 H), 7.53 (d, J = 8.7 Hz, 1 H), 5.60 (dd, J = 7.9, 4.0 Hz, 1 H), 2.25 - 2.03 (m, 1 H), 1.92 - 1.71 (m, 1 H), 1.55 - 1.28 (m, 4 H), 0.91 (t, J = 7.0 Hz, 3 H).

[0268] HRMS (ESI) m / z calcd for C 21 H 17 Cl2O4 + [M+H] + :403.0498found:403.0496

[0269] Example 24. 3-Butyl-7-(3,4-difluorobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0270] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and a-bromo-3,4-difluoroacetophenone (101 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure to get the target compound 133 mg with 83.4% yield.

[0271] 1 H NMR (400 MHz, CDC13) δ / ppm 8.05 - 7.83 (m, 4H), 7.55 (d, J = 8.5 Hz, 1H), 7.36 (dt, J = 9.5, 7.8 Hz, 1H), 5.60 (dd, J = 7.9, 4.0 Hz, 1H), 2.25 - 2.01 (m, 1H), 1.89 - 1.71 (m, 1H), 1.57 - 1.32 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0272] HRMS (ESI) m / z calcd for C 21 H 17 F2O4 + [M+H] + : 371.1089 found: 371.1084

[0273] Example 25. 3-Butyl-7-(2,4-difluorobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0274] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and a-bromo-3,4-difluoroacetophenone (101 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure to get the target compound 133 mg with 83.4% yield.

[0275] 1H NMR (400 MHz, CDC13) δ / ppm 7.98 - 7.83 (m, 2 H), 7.74 (td, J = 8.3, 6.3 Hz, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.10 - 6.94 (m, 2 H), 5.59 (dd, J = 7.9, 4.0 Hz, 1 H), 2.11 (dt, J = 9.6, 4.9 Hz, 1 H), 1.89 - 1.74 (m, 1 H), 1.50 - 1.34 (m, 4 H), 0.91 (t, J = 7.1 Hz, 3 H).

[0276] HRMS (ESI) m / z calcd for C 21 H 17 F2O4 + [M+H] + : 371.1089 found: 371.1082

[0277] Example 26. 3-Butyl-7-(3,4,5-trifluorobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0278] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-2',3',4'-difluoroacetophenone (109 mg, 0.43 mmol) followed by K2CO3(60 mg, 0.43 mmol) dissolved in 10 mL of MeCN and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion of the reaction, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The obtained organic solution was concentrated to dryness under reduced pressure to obtain the target compound 142 mg with a yield of 85.2%.

[0279] 1 H NMR (400 MHz, CDC13) δ / ppm 8.04 (d, J = 1.0 Hz, 1 H), 7.96 (dd, J = 8.5, 1.0 Hz, 1 H), 7.87 - 7.74 (m, 2 H), 7.57 (d, J = 8.7 Hz, 1 H), 5.61 (dd, J = 7.9, 4.0 Hz, 1 H), 2.28 - 2.03 (m, 1 H), 1.81 (dddd, J = 14.5, 10.3, 7.7, 4.4 Hz, 1 H), 1.61 - 1.34 (m, 4 H), 0.91 (t, J = 7.1 Hz, 3 H).

[0280] HRMS (ESI) m / z calcd for C 21 H 16 F3O4 + [M+H] +: 389.0995 found: 389.0990

[0281] Example 27. 3-Butyl-7-(4-(trifluoromethyl)benzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0282] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-4'-(trifluoromethyl)acetophenone (115 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 146 mg with 84.6% yield.

[0283] 1 H NMR (400 MHz, CDC13) δ / ppm 8.15 (d, J = 8.1 Hz, 2H), 8.07 - 7.76 (m, 4H), 7.54 (t, J = 8.2 Hz, 1H), 5.61 (dd, J = 7.9, 4.0 Hz, 1H), 2.12 (tt, J = 9.7, 5.2 Hz, 1H), 1.97 - 1.74 (m, 1H), 1.61 - 1.35 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H).

[0284] HRMS (ESI) m / z calcd for C 22 H 18 F3O4 + [M+H] + : 403.1152 found: 403.1150

[0285] Example 28. 3-Butyl-7-(2-(trifluoromethyl)benzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0286] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-2'-(trifluoromethyl)acetophenone (115 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 147 mg with 85.0% yield.

[0287] 1 H NMR (400 MHz, CDC13) δ / ppm 7.94 (d, J = 8.6 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.76 - 7.67 (m, 2H), 7.65 - 7.49 (m, 3H), 5.59 (dd, J = 7.9, 3.9 Hz, 1H), 2.11 (ddt, J = 14.5, 9.8, 5.3 Hz, 1H), 1.79 (tdd, J = 14.2, 7.5, 4.2 Hz, 1H), 1.53 - 1.28 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H).

[0288] HRMS (ESI) m / z calcd for C 22 H 18 F3O4 + [M+H] + :403.1152found:403.1154

[0289] Example 29. 3-Butyl-7-(3-(trifluoromethyl)benzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one (NS12-33)

[0290] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-2'-(trifluoromethyl)acetophenone (115 mg, 0.43 mmol), then 10 mL of MeCN was added followed by K2CO3(60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC was used to monitor the completion of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure, to get the target compound 148 mg with a yield of 85.6%.

[0291] 1 H NMR (400 MHz, CDC13) δ / ppm 8.38 - 8.19 (m, 2H), 8.06 - 7.90 (m, 3H), 7.72 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 5.61 (dd, J = 7.9, 4.0 Hz, 1H), 2.13 (ddt, J = 14.2, 9.8, 5.2 Hz, 1H), 1.81 (dddd, J = 14.4, 10.2, 7.7, 4.1 Hz, 1H), 1.56 - 1.32 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H).

[0292] HRMS (ESI) m / z calcd for C 22 H 18F3O4 + [M+H] + :403.1152found:403.1157

[0293] Example 30. 3-Butyl-7-(3-(trifluoromethyl)benzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0294] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 3',5'-bistrifluoromethyl-2-bromoacetophenone (144 mg, 0.43 mmol), followed by 10 mL of MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored the end of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the resulting organic solution was concentrated to dryness under reduced pressure, to obtain the target compound 170 mg, with a yield of 84.3%.

[0295] 1 H NMR (400 MHz, CDC13) δ / ppm 8.54 (s, 2H), 8.13 (d, J = 29.4 Hz, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 5.61 (dd, J = 7.8, 3.9 Hz, 1H), 2.12 (tt, J = 9.9, 4.9 Hz, 1H), 1.84 - 1.76 (m, 1H), 1.42 (s, 4H), 0.91 (t, J = 6.8 Hz, 3H).

[0296] HRMS (ESI) m / z calcd for C 22 H 18 F3O4 + [M+H] + :471.1026found:471.1025

[0297] Example 31. 3-Butyl-7-(4-nitrobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0298] To a single necked reaction flask was taken compound f (900 mg, 3.85 mmol) and 2-bromo-4'-nitroacetophenone (863 mg, 3.85 mmol) followed by 10 mL MeCN dissolved and K2CO3 (532 mg, 3.85 mmol) and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The organic solution was concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel to get the desired compound 1.260 g in 86.3 % yield.

[0299] 1 H NMR (400 MHz, CDC13) δ / ppm 8.46 - 8.36 (m, 2H), 8.27 - 8.17 (m, 2H), 8.06 - 7.92 (m, 2H), 7.57 (d, J = 8.5 Hz, 1H), 5.62 (dd, J = 7.9, 3.9 Hz, 1H), 2.13 (ddd, J = 14.2, 9.4, 4.6 Hz, 1H), 1.90 - 1.75 (m, 1H), 1.52 - 1.32 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H).

[0300] HRMS (ESI) m / z calcd for C 21 H 18 NO6 + [M+H] + : 380.1129 found: 380.1120

[0301] Example 32. 3-Butyl-7-(3-nitrobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0302] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-3'-nitroacetophenone (105 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol) and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The organic solution was concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel to get the desired compound 141 mg in 86.7 % yield.

[0303] 1H NMR (400 MHz, CDC13) δ / ppm 8.92 (t, J = 2.0 Hz, 1H), 8.52 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.39 (dt, J = 7.7, 1.4 Hz, 1H), 8.07 - 7.94 (m, 2H), 7.79 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 5.61 (dd, J = 7.9, 3.9 Hz, 1H), 2.21 - 2.06 (m, 1H), 1.81 (tdd, J = 12.6, 6.8, 4.2 Hz, 1H), 1.56 - 1.33 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0304] HRMS (ESI) m / z calcd for C 21 H 18 NO6 + [M+H] + : 380.1129 found: 380.1123

[0305] Example 33. 3-Butyl-7-(2-nitrobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0306] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-2'-nitroacetophenone (105 mg, 0.43 mmol) followed by 10 mL of MeCN dissolved and K2CO3 (60 mg, 0.43 mmol) and heated to reflux at 120 °C, TLC was used to monitor the completion of the reaction, after cooling, the organic phase was washed with water and concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to obtain the target compound 145 mg with a yield of 88.9%.

[0307] 1 H NMR (400 MHz, CDC13) δ / ppm 8.30 (dd, J = 8.2, 1.2 Hz, 1H), 7.91 - 7.74 (m, 3H), 7.69 - 7.59 (m, 2H), 7.51 (d, J = 8.6 Hz, 1H), 5.57 (dd, J = 7.8, 4.0 Hz, 1H), 2.16 - 2.05 (m, 1H), 1.78 (dddd, J = 12.3, 10.1, 7.7, 4.3 Hz, 1H), 1.54 - 1.32 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H).

[0308] HRMS (ESI) m / z calcd for C 21 H18 NO6 + [M+H] + :380.1135found:380.1135

[0309] Example 34. 4-(3-Butyl-l-oxo-l,3-dihydrobenzo[l,2-b:3,4-c']difuran-7- carbonyl)benzonitrile

[0310] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-4'-cyanoacetophenone (96 mg, 0.43 mmol) followed by 10 mL of MeCN dissolved and K2CO3 (60 mg, 0.43 mmol) and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion of the reaction, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The obtained organic solution was concentrated to dryness under reduced pressure to obtain the target compound 136 mg with a yield of 83.4%.

[0311] 1 H NMR (400 MHz, CDC13) δ / ppm 8.24 - 8.08 (m, 2H), 8.02 - 7.79 (m, 4H), 7.56 (d, J = 8.5 Hz, 1H), 5.61 (dd, J = 7.9, 3.9 Hz, 1H), 2.24 - 2.01 (m, 1H), 1.81 (dddd, J = 14.5, 10.3, 7.7, 4.5 Hz, 1H), 1.40 (tdd, J = 10.3, 8.2, 6.1 Hz, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0312] HRMS (ESI) m / z calcd for C 22 H 18 NO4 + [M+H] + :360.1230found:360.1230

[0313] Example 35. 3-Butyl-7-(4-methoxybenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0314] To a single necked reaction flask was added compound f (950 mg, 4.06 mmol) and 2-bromo-4'-methoxyacetophenone (930 mg, 4.06 mmol), followed by 10 mL of MeCN dissolved and K2CO3 (561 mg, 4.06 mmol), heated to reflux at 120 °C, TLC monitored the end of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the resulting organic solution was concentrated to dryness under reduced pressure, to obtain the target compound 1.780 g, yield 79.8%.

[0315] 1 H NMR (400 MHz, CDC13) δ / ppm 8.13 - 7.95 (m, 2H), 7.93 (dt, J = 10.5, 1.5 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 8.9, 1.6 Hz, 2H), 5.59 (dd, J = 8.0, 3.9 Hz, 1H), 3.97 - 3.79 (m, 3H), 2.11 (tt, J = 9.8, 4.7 Hz, 1H), 1.93 - 1.69 (m, 1H), 1.53 - 1.31 (m, 4H), 0.91 (dt, J = 7.2, 3.8 Hz, 3H).

[0316] HRMS (ESI) m / z calcd for C 22 H 21 O5 + [M+H] + :365.1384found:365.1383

[0317] The target compound (0.3738 g) was subjected to chiral separation under the following chromatographic conditions to obtain compounds 35-1 and 35-2, with the ee values and optical rotation values as follows:

[0318] Chromatographic conditions:

[0319] HPLC: Shimadzu LC-20AT, CP-HPLC-09; Column: CHIRALCEL OZ-H (OZH0CE-BO005), 0.46 cm I.D. x 25 cm L; Injection: 5 ul; Mobile phase: MeOH / ACN = 90 / 10 (V / V); Flow rate: 1.0 ml / min; Detection wavelength: UV: 254 nm; Temperature: 35 °C.

[0320] Example 36. 3-Butyl-7-(3-methoxybenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0321] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-3'-methoxyacetophenone (99 mg, 0.43 mmol), 10 mL of MeCN was added and K2CO3 (60 mg, 0.43 mmol) was added, heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, the target compound was obtained in 126 mg with 80.2% yield.

[0322] 1 H NMR (400 MHz, CDC13) δ / ppm 7.94 (td, J = 4.3, 0.9 Hz, 2H), 7.62 (dt, J = 7.6, 1.3 Hz, 1H), 7.54 - 7.43 (m, 3H), 7.20 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 5.59 (dd, J = 7.8, 3.9 Hz, 1H), 3.89 (s, 3H), 2.12 (dddd, J = 14.2, 9.9, 6.3, 4.2 Hz, 1H), 1.89 - 1.73 (m, 1H), 1.54 - 1.30 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0323] HRMS (ESI) m / z calcd for C 22 H 21 O5 + [M+H] + :365.1384found:365.1380

[0324] Example 37. 3-Butyl-7-(4-hydroxybenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0325] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-3'-methoxyacetophenone (99 mg, 0.43 mmol), 10 mL of MeCN was added and K2CO3 (60 mg, 0.43 mmol) was added, heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, the target compound was obtained in 126 mg with 80.2% yield.

[0326] 1H NMR (400 MHz, CDCI3) δ / ppm 8.14 - 7.85 (m, 4 H), 7.52 (dd, J=8.7, 2.8 Hz, 1 H), 7.02 (dd, J=9.2, 2.4 Hz, 2 H), 5.63 (dd, J=7.9, 3.9 Hz, 1 H), 2.14 (q, J=4.7 Hz, 1 H), 1.87 (s, 1 H), 1.56 - 1.31 (m, 4 H), 0.98 - 0.86 (m, 3 H).

[0327] HRMS (ESI) m / z calcd for C 21 H 19 O5 + [M+H] + :351.1227found:351.1221

[0328] Example 38. 7-(4-Aminobenzoyl)-3-butylbenzo[l,2-b:3,4-c']difuran-l(3H)-one

[0329] To a solution of 3-butyl-7-(4-nitrobenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one (225 mg, 0.59 mmol) in ethanol (10 mL) and water (4.5 mL), Fe (330 mg, 5.9 mmol) and NH4CI (25 mg, 0.59 mmol) were added, and the mixture was refluxed under argon protection at 100 °C. After TLC monitoring, the reaction was completed, the mixture was filtered while hot, concentrated under reduced pressure, extracted with DCM for 3 times, the organic phases were combined, concentrated, dried, and the target compound was obtained by silica gel column chromatography with a yield of 149 mg, 72.3%.

[0330] 1 H NMR (400 MHz, CDCI3) δ / ppm 8.14 - 7.85 (m, 4 H), 7.52 (dd, J=8.7, 2.8 Hz, 1 H), 7.02 (dd, J=9.2, 2.4 Hz, 2 H), 5.63 (dd, J=7.9, 3.9 Hz, 1 H), 2.14 (q, J=4.7 Hz, 1 H), 1.87 (s, 1 H), 1.56 - 1.31 (m, 4 H), 0.98 - 0.86 (m, 3 H).

[0331] HRMS (ESI) m / z calcd for C 21 H 20 NO4 + [M+H] + :350.1387found:350.1381

[0332] Example 39. 3-Butyl-7-(3,4-dimethoxybenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0333] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-3',4'-dimethoxy acetophenone (112 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2C03(60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, to get the target compound 145 mg with 85.7% yield.

[0334] 1 H NMR (400 MHz, CDC13) δ / ppm 7.93 (d, J = 7.1 Hz, 2H), 7.79 (dd, J = 8.4, 2.1 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 5.59 (dd, J = 7.8, 4.0 Hz, 1H), 3.98 (d, J = 7.9 Hz, 6H), 2.20 - 1.98 (m, 1H), 1.85 - 1.74 (m, 1H), 1.58 - 1.30 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H).

[0335] HRMS (ESI) m / z calcd for C 23 H 23 O6 + [M+H] + :395.1489 found:395.1488

[0336] Example 40. 3-Butyl-7-(2,5-dimethoxybenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0337] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-3',4'-dimethoxy acetophenone (112 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2C03(60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, to get the target compound 145 mg with 85.7% yield.

[0338] 1 H NMR (400 MHz, CDC13) δ / ppm 7.90 (dd, J = 8.6, 1.0 Hz, 1H), 7.73 (d, J = 1.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.13 - 6.86 (m, 3H), 5.57 (dd, J = 7.9, 3.9 Hz, 1H), 3.77 (d, J = 22.0 Hz, 6H), 2.15 - 2.03 (m, 1H), 1.92 - 1.71 (m, 1H), 1.47 - 1.33 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H).

[0339] HRMS (ESI) m / z calcd for C 23 H 23 O6 + [M+H] + : 395.1489 found: 395.1483

[0340] Example 41. 3-Butyl-7-(3,4,5-trimethoxybenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0341] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-3',4',5'-trimethoxyacetophenone (115 mg, 0.43 mmol), followed by 10 mL of MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored the end of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the resulting organic solution was concentrated under reduced pressure to dryness, to obtain the target compound 155 mg, with a yield of 85.1%.

[0342] 1 H NMR (400 MHz, CDC13) δ / ppm 7.94 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.31 (s, 2H), 5.59 (dd, J = 7.9, 3.9 Hz, 1H), 3.96 (d, J = 10.7 Hz, 9H), 2.18 - 2.02 (m, 1H), 1.80 (dddd, J = 14.5, 10.3, 7.7, 4.3 Hz, 1H), 1.56 - 1.26 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0343] HRMS (ESI) m / z calcd for C 24 H 25 O7+ [M+H] + :425.1595found:425.1588

[0344] Example 42. 3-Butyl-7-(2,4-dimethoxybenzoyl)benzo[1,2-b:3,4-c']difuran-1 (3H)- one

[0345] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-2',4'-dimethoxyacetophenone (112 mg, 0.43 mmol) followed by 10 mL of MeCN dissolved and K2CO3 (60 mg, 0.43 mmol) and heated to reflux at 120 °C, TLC was used to monitor the completion of the reaction, after cooling, the organic phase was washed with water and concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 145 mg with a yield of 85.6%.

[0346] 1 H NMR (400 MHz, CDC13) δ / ppm 7.89 (dd, J = 8.5, 1.0 Hz, 1H), 7.72 (d, J = 0.9 Hz, 1H), 7.50 (dd, J = 30.1, 8.4 Hz, 2H), 6.65 - 6.47 (m, 2H), 5.57 (dd, J = 7.9, 3.9 Hz, 1H), 3.84 (d, J = 40.2 Hz, 6H), 2.21 - 2.04 (m, 1H), 1.79 (dddd, J = 14.4, 10.2, 7.8, 4.4 Hz, 1H), 1.54 - 1.32 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H).

[0347] HRMS (ESI) m / z calcd for C 23 H 23 O6 + [M+H] + :395.1489found:395.1482

[0348] Example 43. 3-Butyl-7-(2-fluoro-4-methoxybenzoyl)benzo[1,2-b:3,4-c']difuran-1 (3H)- one

[0349] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-2'-fluoro-4'-methoxyacetophenone (107 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, chromatographed over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the target compound 134 mg with 81.6 % yield.

[0350] 1 H NMR (400 MHz, CDC13) δ / ppm 7.98 - 7.81 (m, 2H), 7.70 (t, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.5, 0.7 Hz, 1H), 6.90 - 6.61 (m, 2H), 5.58 (dd, J = 7.8, 4.0 Hz, 1H), 3.90 (s, 3H), 2.26 - 1.95 (m, 1H), 1.79 (dddd, J = 14.5, 10.3, 8.9, 4.6 Hz, 1H), 1.56 - 1.28 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H).

[0351] HRMS (ESI) m / z calcd for C 22 H 20 FO5 + [M+H] + :383.1289found:383.1285

[0352] Example 44. 7-(4-(benzyloxy)benzoyl)-3-butylbenzo[l,2-b:3,4-c']difuran-l(3H)-one

[0353] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-4'-benzyloxyacetophenone (132 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, chromatographed over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the target compound 160 mg with 84.5 % yield.

[0354] 1H NMR (400 MHz, CDC13) δ / ppm 8.14 - 8.03 (m, 2H), 7.94 (d, J = 7.9 Hz, 2H), 7.54 - 7.30 (m, 6H), 7.17 - 7.06 (m, 2H), 5.60 (dd, J = 7.9, 4.0 Hz, 1H), 5.19 (s, 2H), 2.12 (dddd, J = 14.1, 9.9, 5.8, 3.9 Hz, 1H), 1.81 (dddd, J = 14.5, 10.3, 7.8, 4.6 Hz, 1H), 1.58 - 1.35 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H).

[0355] HRMS (ESI) m / z calcd for C 28 H 25 O5 + [M+H] + : 441.1697 found: 441.1723

[0356] Example 45. 1 -Butyl-7-(4-(trifluoromethoxy)benzoyl)benzo[1,2-b:3,4-c']difuran-1 (3H)- one

[0357] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-1 -4-(trifluoromethoxy)phenyl ethanone (122 mg, 0.43 mmol) followed by 10 mL of MeCN dissolved and K2C03(60 mg, 0.43 mmol) and heated to reflux at 120 °C, TLC was used to monitor the completion of the reaction, cooled, filtered, washed the organic layer with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 152 mg with 84.3% yield.

[0358] 1 H NMR (400 MHz, CDC13) δ / ppm 8.14 - 8.03 (m, 2H), 7.94 (d, J = 7.9 Hz, 2H), 7.54 - 7.30 (m, 6H), 7.17 - 7.06 (m, 2H), 5.60 (dd, J = 7.9, 4.0 Hz, 1H), 5.19 (s, 2H), 2.12 (dddd, J = 14.1, 9.9, 5.8, 3.9 Hz, 1H), 1.81 (dddd, J = 14.5, 10.3, 7.8, 4.6 Hz, 1H), 1.58 - 1.35 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H).

[0359] HRMS (ESI) m / z calcd for C 22 H 18 F3O5+ [M+H] + :419.1101found:419.1093

[0360] Example 46. 3-Butyl-7-(3,4-dihydro-2H-benzo[b][l,4]dioxine-7-carbonyl)benzo[l,2- b:3,4-c']difuran-l(3H)-one

[0361] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-l-(3,4-dihydro-l,5-benzoxepin-7-yl)ethanone (117 mg, 0.43 mmol), followed by 10 mL of MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored the end of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the resulting organic solution was concentrated to dryness under reduced pressure, to obtain the target compound 146 mg, with a yield of 83.5%.

[0362] 1 H NMR (500 MHz, CDC13) δ / ppm 7.94 (t, J = 4.3 Hz, 2H), 7.76 - 7.64 (m, 2H), 7.50 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 5.59 (dd, J = 7.9, 3.9 Hz, 1H), 4.36 (dt, J = 28.2, 5.8 Hz, 4H), 2.28 (p, J = 5.9 Hz, 2H), 2.12 (td, J = 9.6, 4.8 Hz, 1H), 1.87 - 1.75 (m, 1H), 1.50 - 1.26 (m, 4H), 0.91 (t, J = 6.9 Hz, 3H).

[0363] HRMS (ESI) m / z calcd for C 24 H 23 O6 + [M+H] + :407.1489found:407.1483

[0364] Example 47. 7-(Benzo[d][l,3]dioxol-5-carbonyl)-3-butylbenzo[l,2-b:3,4-c']difuran-l(3H)- one

[0365] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 1-(1,3- benzoxazol-2-yl)ethanone (105 mg, 0.43 mmol) and 10 mL MeCN was taken and K2CO3 (60 mg, 0.43 mmol) was added and heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, to get the target compound 134 mg with 83.5% yield.

[0366] 1 H NMR (400 MHz, CDC13) δ / ppm 7.93 (d, J = 8.3 Hz, 2H), 7.72 (dd, J = 8.1, 1.8 Hz, 1H), 7.56 - 7.46 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.11 (s, 2H), 5.59 (dd, J = 7.9, 3.9 Hz, 1H), 2.12 (dddd, J = 14.2, 9.9, 5.7, 3.9 Hz, 1H), 1.80 (dddd, J = 14.5, 10.3, 7.8, 4.6 Hz, 1H), 1.56 - 1.32 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0367] HRMS (ESI) m / z calcd for C 22 H 19 O6 + [M+H] + : 379.1176 found: 379.1168

[0368] Benzyl (4-(3-butyl-1-oxo-1,3-dihydrobenzo[1,2-b:3,4-c']difuran-7-carbonyl)phenyl)carbamate

[0369] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and [4-(bromoacetyl)phenyl]carbamic acid benzyl ester (150 mg, 0.43 mmol) and 10 mL MeCN was taken and K2CO3 (60 mg, 0.43 mmol) was added and heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, to get the target compound 178 mg with 85.6% yield.

[0370] 1H NMR (500 MHz, CDC13) δ / ppm 8.16 - 7.83 (m, 4 H), 7.61 (d, J = 8.2 Hz, 2 H), 7.50 (d, J = 8.5 Hz, 1 H), 7.38 (q, J = 8.5 Hz, 4 H), 7.19 (s, 1 H), 5.59 (s, 1 H), 5.23 (s, 2 H), 2.11 (s, 1 H), 1.56 - 1.32 (m, 4 H), 0.91 (t, J = 6.8 Hz, 3 H).

[0371] HRMS (ESI) m / z calcd for C 29 H 26 NO6 + [M+H] + : 484.1755 found: 484.1735

[0372] Example 49. 3-Butyl-7-(4-(dimethylamino)benzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0373] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-l-(4-dimethylaminophenyl)ethanone (104 mg, 0.43 mmol) followed by K2CO3(60 mg, 0.43 mmol) dissolved in 10 mL of MeCN and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion of the reaction, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The obtained organic solution was concentrated to dryness under reduced pressure to obtain the target compound 138 mg with a yield of 85.3%.

[0374] 1 H NMR (400 MHz, CDC13) δ / ppm 8.13 - 7.99 (m, 2 H), 7.97 - 7.80 (m, 2 H), 7.45 (dd, J = 8.4, 2.4 Hz, 1 H), 6.83 - 6.62 (m, 2 H), 5.57 (dd, J = 7.8, 4.0 Hz, 1 H), 3.11 (d, J = 2.6 Hz, 7 H), 2.10 (d, J = 14.5 Hz, 1 H), 1.89 - 1.73 (m, 1 H), 1.43 (dtt, J = 22.4, 15.3, 7.0 Hz, 4 H), 0.91 (dt, J = 7.4, 3.7 Hz, 3 H).

[0375] HRMS (ESI) m / z calcd for C 23 H 24 NO4 + [M+H] +:378.1700 found:378.1720

[0376] Example 50. 3-Butyl-7-(4-(pyrrolidin-1-yl)benzoyl)benzo[1,2-b:3,4-c']difuran-1 (3H)- one

[0377] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-4'-(1 -pyrrolidinyl) acetophenone (116 mg, 0.43 mmol), followed by 10 mL of MeCN dissolved and K2CO3(60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored the end of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, chromatographed on silica gel column, the obtained organic solution was concentrated to dryness under reduced pressure, to obtain the target compound 147 mg, with a yield of 84.6%.

[0378] 1 H NMR (400 MHz, CDC13) δ / ppm 8.14 - 8.00 (m, 2H), 7.98 - 7.83 (m, 2H), 7.44 (d, J = 8.5 Hz, 1H), 6.67 - 6.50 (m, 2H), 5.58 (dd, J = 7.9, 4.0 Hz, 1H), 3.48 - 3.34 (m, 4H), 2.21 - 2.00 (m, 5H), 1.80 (dddd, J = 14.4, 10.2, 7.8, 4.5 Hz, 1H), 1.56 - 1.31 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0379] HRMS (ESI) m / z calcd for C 25 H 26 NO4 + [M+H] + :404.1856 found:404.1855

[0380] Example 51. 7-(4-(1H-Pyrazol-1-yl)benzoyl)-3-butylbenzo[1,2-b:3,4-c']difuran-1 (3H)- one

[0381] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 1-(4-(1H- pyrazol-1-yl)phenyl)-2-bromoethan-1-one (124 mg, 0.43 mmol) was taken, to this 10 mL of MeCN was taken and K2CO3 (60 mg, 0.43 mmol) was taken, heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, to get the title compound 147 mg with 85.5% yield.

[0382] 1 H NMR (500 MHz, CDC13) δ / ppm 8.23 - 8.16 (m, 2H), 8.07 (d, J = 2.6 Hz, 1H), 8.00 (d, J = 1.0 Hz, 1H), 7.96 (dd, J = 8.5, 0.9 Hz, 1H), 7.93 - 7.90 (m, 2H), 7.80 (d, J = 1.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 6.59 - 6.51 (m, 1H), 5.61 (dd, J = 7.9, 4.0 Hz, 1H), 2.13 (dddd, J = 14.2, 10.1, 5.7, 4.1 Hz, 1H), 1.81 (dddd, J = 14.5, 10.5, 7.8, 4.2 Hz, 1H), 1.55 - 1.35 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H).

[0383] HRMS (ESI) m / z calcd for C 24 H 21 N2O4 + [M+H] + : 401.1496; found: 401.1483

[0384] Example 52. 3-Butyl-7-(4-morpholinobenzoyl)benzo[1,2-b:3,4-c']difuran-1 (3H)-one

[0385] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-1-(4- morpholinophenyl)-1-ethanone (122 mg, 0.43 mmol) was taken, to this 10 mL of MeCN was taken and K2CO3 (60 mg, 0.43 mmol) was taken, heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water, concentrated under reduced pressure, the organic solution obtained was concentrated to dryness under reduced pressure, to get the title compound 180 mg with 84.3% yield.

[0386] 1 H NMR (400 MHz, CDC13) δ / ppm 8.29 (d, J = 2.1 Hz, 1H), 8.10 - 7.86 (m, 3H), 7.52 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 5.60 (dd, J = 7.9, 4.0 Hz, 1H), 3.92 (t, J = 4.5 Hz, 4H), 3.32 - 3.16 (m, 4H), 2.22 - 2.02 (m, 1H), 1.81 (dddd, J = 14.6, 10.3, 7.6, 4.2 Hz, 1H), 1.54 - 1.33 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H).

[0387] HRMS (ESI) m / z calcd for C 25 H 26 NO5 + [M+H] + : 420.1805; found: 420.1809

[0388] Example 53. 3-Butyl-7-(4-(methylsulfonyl)benzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0389] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-l-(4-methylsulfonyl)acetophenone (119 mg, 0.43 mmol), then K2CO3 (60 mg, 0.43 mmol) was added in 10 mL of MeCN, heated to reflux at 120 °C, TLC was used to monitor the completion of the reaction, then cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure, to give the target compound 152 mg, with a yield of 85.6%.

[0390] 1 H NMR (400 MHz, CDC13) δ / ppm 8.26 - 8.13 (m, 4H), 8.04 - 7.90 (m, 2H), 7.57 (d, J = 8.5 Hz, 1H), 5.61 (dd, J = 7.9, 3.9 Hz, 1H), 3.15 (s, 3H), 2.13 (ddd, J = 14.1, 10.4, 5.6 Hz, 1H), 1.91 - 1.77 (m, 1H), 1.40 (p, J = 7.1 Hz, 4H), 0.92 (t, J = 7.1 Hz, 3H).

[0391] HRMS (ESI) m / z calcd for C 22 H 21O6S + [M+H] + :413.1053;found:413.1051

[0392] Example 54. 7-([1,1 '-Biphenyl]-4-carbonyl)-3-butylbenzo[1,2-b:3,4-c']difuran-1 (3H)- one

[0393] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2- bromo-4-phenylacetylbenzene (118 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored the completion of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 152 mg with 86.4% yield.

[0394] 1 H NMR (400 MHz, CDC13) δ / ppm 8.19 - 8.11 (m, 2H), 8.03 - 7.93 (m, 2H), 7.81 - 7.75 (m, 2H), 7.70 - 7.65 (m, 2H), 7.55 - 7.48 (m, 3H), 7.47 - 7.40 (m, 1H), 5.61 (dd, J = 7.9, 3.9 Hz, 1H), 2.13 (dddd, J = 14.1, 10.0, 6.2, 4.0 Hz, 1H), 1.92 - 1.77 (m, 1H), 1.54 - 1.34 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H).

[0395] HRMS (ESI) m / z calcd for C 27 H 23 O4 + [M+H] + :411.1591 ; found: 411.1590

[0396] Example 55. 7-(2-Naphthalenoyl)-3-butylbenzo[1,2-b:3,4-c']difuran-1 (3H)-one

[0397] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-2-acetylnaphthalene (107 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, column chromatography over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the desired compound 134 mg with 81.2 % yield.

[0398] 1 H NMR (400 MHz, CDC13) δ / ppm 8.60 (s, 1H), 8.07 - 7.90 (m, 6H), 7.70 - 7.48 (m, 3H), 5.61 (dd, J = 7.9, 3.9 Hz, 1H), 2.13 (tt, J = 10.0, 4.6 Hz, 1H), 1.82 (q, J = 7.5 Hz, 1H), 1.59 - 1.32 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H).

[0399] HRMS (ESI) m / z calcd for C 25 H 21 O4 + [M+H] + : 385.1434; found: 385.1432

[0400] Example 56. 3-Butyl-7-(7-methoxy-2-naphthalenoyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0401] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-(bromoacetyl)-7-methoxynaphthalene (120 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase washed with water, concentrated under reduced pressure, column chromatography over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the desired compound 149 mg with 83.9 % yield.

[0402] 1H NMR (400 MHz, CDC13) δ / ppm 8.55 (d, J = 1.8 Hz, 1H), 8.07 (dd, J = 8.5, 1.8 Hz, 1H), 8.01 - 7.95 (m, 2H), 7.88 (dd, J = 18.1, 8.8 Hz, 2H), 7.52 (d, J = 8.5 Hz, 1H), 7.27 - 7.19 (m, 2H), 5.60 (dd, J = 7.8, 4.0 Hz, 1H), 3.98 (s, 3H), 2.21 - 2.05 (m, 1H), 1.82 (dddd, J = 14.4, 10.2, 7.8, 4.6 Hz, 1H), 1.61 - 1.28 (m, 4H), 0.92 (t, J = 7.1 Hz, 3H).

[0403] HRMS (ESI) m / z calcd for C 26 H 23 O5 + [M+H] + :415.1540; found: 415.1535

[0404] Example 57. 4-(3-butyl-l-oxo-l,3-dihydrobenzo[l,2-b:3,4-c']difuran-7- carbonyl)benzoic acid

[0405] To a single necked flask was added compound f (200 mg, 0.85 mmol) and 4-(2-bromoacetyl)benzoic acid tert-butyl ester (281 mg, 0.85 mmol), then K2CO3(60 mg, 0.43 mmol) was dissolved in 10 mL MeCN, heated to reflux at 120 °C, TLC monitored the reaction was completed, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, chromatographed on silica gel column, the obtained organic solution was concentrated to dryness under reduced pressure, to obtain a white solid, for use. The product obtained in the previous step (187 mg, 0.43 mmol) was dissolved in DCM, CF3COOH (0.32 mL, 4.3 mmol) was added at 0 °C, stirred at 0 °C, TLC monitored the reaction was completed, concentrated, added DCM and 1 N HCl, collected the organic phase, concentrated, dried, chromatographed on silica gel column, to obtain the target compound 168 mg, yield 52.3%.

[0406] 1H NMR (500 MHz, DMSO-d6) δ / ppm 8.26 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 8.6 Hz, 4H), 7.88 (d, J = 8.6 Hz, 1H), 7.84 (s, 1H), 5.78 (dd, J = 7.8, 3.7 Hz, 1H), 2.16 (ddt, J = 14.5, 9.3, 4.3 Hz, 1H), 1.76 (ddt, J = 18.2, 14.1, 6.8 Hz, 1H), 1.34 (pt, J = 12.6, 5.6 Hz, 4H), 0.86 (t, J = 7.0 Hz, 4H).

[0407] HRMS (ESI) m / z calcd for C 22 H 19 O6 + [M+H] + : 379.1176; found: 379.1170

[0408] Example 58. 4-(3-butyl-l-oxo-l,3-dihydrobenzo[l,2-b:3,4-c']difuran-7- carbonyl)-3-fluorobenzoic acid methyl ester

[0409] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and methyl 4-(2-bromoacetyl)benzoate (111 mg, 0.43 mmol), followed by 10 mL of MeCN dissolved and K2CO3 (60 mg, 0.43 mmol), heated to reflux at 120 °C, TLC monitored the end of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure, to obtain the target compound 145 mg, with a yield of 82.4%.

[0410] 1 H NMR (400 MHz, CDC13) δ / ppm 8.26-8.16 (m, 2H), 8.14-8.05 (m, 2H), 7.95 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 8.6 Hz, 1H), 5.60 (dd, J = 7.8, 3.9 Hz, 1H), 3.98 (s, 3H), 2.20-2.03 (m, 1H), 1.89-1.71 (m, 1H), 1.55-1.26 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0411] HRMS (ESI) m / z calcd for C 23 H 20 FO6 + [M+H]+ : 411.1238; found: 411.1230

[0412] Example 59. 3-Butyl-7-(thiophene-2-carbonyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0413] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-l-(2-thiophene) ethanone (88 mg, 0.43 mmol) followed by 10 mL of MeCN dissolved and K2CO3 (60 mg, 0.43 mmol) and heated to reflux at 120 °C, TLC was used to monitor the completion of the reaction, after cooling, the organic phase was washed with water and concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 122 mg with a yield of 83.6%.

[0414] 1 H NMR (400 MHz, CDC13) δ / ppm 8.25 (dd, J = 3.9, 1.1 Hz, 1H), 8.13 (d, J = 0.9 Hz, 1H), 7.94 (dd, J = 8.5, 1.0 Hz, 1H), 7.81 (dd, J = 4.9, 1.1 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.34 - 7.19 (m, 1H), 5.59 (dd, J = 7.9, 4.0 Hz, 1H), 2.12 (dddd, J = 14.2, 10.0, 6.3, 4.0 Hz, 1H), 1.80 (tdd, J = 12.7, 6.8, 4.2 Hz, 1H), 1.56 - 1.26 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0415] HRMS (ESI) m / z calcd for C 19 H 17 O4S + [M+H] + : 341.0842; found: 341.0840

[0416] Example 60. 3-Butyl-7-pyridinecarbonylbenzo[l,2-b:3,4-c']difuran-l(3H)-one

[0417] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-l-(2-pyridyl)-l-ethanone hydrobromide (121 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2C03(120 mg, 0.86 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, column chromatography over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the desired compound 123 mg with 85.3% yield.

[0418] 1 H NMR (400 MHz, CDC13) δ / ppm 8.85 (td, J = 11.8, 4.9 Hz, 2H), 8.23 (t, J = 7.2 Hz, 1H), 7.96 (dd, J = 13.2, 7.0 Hz, 2H), 7.55 (dt, J = 31.3, 7.4 Hz, 2H), 5.73 - 5.48 (m, 1H), 2.18 - 2.05 (m, 1H), 1.80 (dd, J = 18.1, 8.9 Hz, 1H), 1.54 - 1.30 (m, 4H), 0.91 (p, J = 6.0 Hz, 3H).

[0419] HRMS (ESI) m / z calcd for C 19 H 18 NO4 + [M+H] + : 336.1230; found: 336.1231

[0420] Example 61. 3-Butyl-7-(furan-2-ylcarbonyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0421] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-l-(2-pyridyl)-l-ethanone hydrobromide (121 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2C03(120 mg, 0.86 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, column chromatography over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the desired compound 123 mg with 85.3% yield.

[0422] 1H NMR (400 MHz, CDC13) δ / ppm 8.35 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 3.6 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.68 (dd, J = 3.6, 1.7 Hz, 1H), 5.59 (dd, J = 7.9, 3.9 Hz, 1H), 2.19 - 2.01 (m, 1H), 1.80 (dddd, J = 14.5, 10.3, 7.8, 4.3 Hz, 1H), 1.60 - 1.28 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H).

[0423] HRMS (ESI) m / z calcd for C 19 H 17 O5 + [M+H] + : 325.1071; found: 325.1091

[0424] Example 62. 7-(benzofuran-2-carbonyl)-3-butylbenzo[l,2-b:3,4-c']difuran-l(3H)-one

[0425] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and l-(l-benzofuran-2-yl)-2-bromoethanone (103 mg, 0.43 mmol) followed by 10 mL of MeCN dissolved and K2CO3 (120 mg, 0.86 mmol), heated to reflux at 120 °C, TLC monitored for completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 138 mg with 85.9% yield.

[0426] 1 H NMR (400 MHz, CDC13) δ / ppm 8.08 (dd, J = 8.8, 1.5 Hz, 2H), 7.96 - 7.89 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.06 - 6.99 (m, 2H), 5.59 (dd, J = 8.0, 3.9 Hz, 1H), 3.92 (d, J = 1.6 Hz, 3H), 2.11 (tt, J = 9.7, 4.8 Hz, 1H), 1.80 (qd, J = 9.4, 3.9 Hz, 1H), 1.42 (ddt, J = 29.4, 15.4, 7.9 Hz, 4H), 0.95 - 0.87 (m, 3H).

[0427] HRMS (ESI) m / z calcd for C 23 H 19 O5 + [M+H] + :375.1227; found: 375.1253

[0428] Example 63. 3-Butyl-7-(thiazole-2-carbonyl)benzo[l,2-b:3,4-c']difuran-l(3H)- one

[0429] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-l-(thiazol-2-yl)ethanone (89 mg, 0.43 mmol) followed by K2CO3(120 mg, 0.86 mmol) dissolved in 10 mL of MeCN and heated to reflux at 120 °C. The reaction was monitored by TLC and upon completion of the reaction, cooled, filtered, washed the organic phase with water and concentrated under reduced pressure. The resulting organic solution was concentrated to dryness under reduced pressure to obtain the target compound 125 mg in 85.3% yield.

[0430] 1 H NMR (400 MHz, CDC13) δ / ppm 9.07 - 8.90 (m, 2H), 8.54 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 5.59 (dd, J = 7.9, 3.9 Hz, 1H), 2.11 (ddd, J = 14.4, 9.6, 4.6 Hz, 1H), 1.84 - 1.74 (m, 1H), 1.39 (dt, J = 17.4, 7.5 Hz, 4H), 0.91 (t, J = 7.0 Hz, 3H).

[0431] HRMS (ESI) m / z calcd for C 18 H 16 NO4S + [M+H] + :342.0795; found: 342.0792

[0432] Example 64. 7-(Benzo[d]thiazole-2-carbonyl)-3-butylbenzo[l,2-b:3,4-c']difuran-l(3H)- one

[0433] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 1-(1,3-benzothiazol-2-yl)-2-bromo-1-ethanone (167 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (120 mg, 0.86 mmol), heated to reflux at 120 °C, TLC monitoring of completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, chromatographed over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the desired compound 143 mg with 84.9 % yield.

[0434] 1 H NMR (400 MHz, CDC13) δ / ppm 9.13 (s, 1H), 8.42 - 8.33 (m, 1H), 8.12 - 7.93 (m, 2H), 7.70 - 7.51 (m, 3H), 5.61 (dd, J = 7.9, 4.0 Hz, 1H), 2.13 (dddd, J = 14.2, 9.9, 5.8, 4.0 Hz, 1H), 1.82 (dddd, J = 14.5, 10.2, 7.8, 4.4 Hz, 1H), 1.56 - 1.37 (m, 4H), 0.92 (t, J = 7.0 Hz, 3H).

[0435] HRMS (ESI) m / z calcd for C 22 H 18 NO4S + [M+H] + : 392.0951; found: 392.0944;

[0436] Example 65. 3-Butyl-7-(3-chloro-1-methyl-1H-pyrazole-4-carbonyl)benzo[1,2- b:3,4-c']difuran-1(3H)-one

[0437] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 2-bromo-1-(4-chloro-1-methyl-1H-pyrazol-3-yl)ethanone (102 mg, 0.43 mmol) followed by 10 mL MeCN dissolved and K2CO3 (120 mg, 0.86 mmol), heated to reflux at 120 °C, TLC monitoring of completion of reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, chromatographed over silica gel, the organic solution obtained was concentrated to dryness under reduced pressure to get the desired compound 133 mg with 83.5 % yield.

[0438] 1H NMR (400 MHz, CDC13) δ / ppm 8.52 (d, J = 0.9 Hz, 1H), 7.93 (dd, J = 8.5, 1.0 Hz, 1H), 7.56 - 7.45 (m, 2H), 5.58 (dd, J = 7.9, 4.0 Hz, 1H), 4.06 (s, 3H), 2.11 (tt, J = 10.0, 3.5 Hz, 1H), 1.83 - 1.71 (m, 1H), 1.58 - 1.31 (m, 4H), 0.91 (t, J = 7.1 Hz, 3H).

[0439] HRMS (ESI) m / z calcd for C 19 H 18 ClN2O4 + [M+H] + :373.0950; found:373.0944

[0440] Example 66. 3-Butyl-7-(cyclohexanecarbonyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0441] To a single necked reaction flask was added compound f (100 mg, 0.43 mmol) and 2-bromo-l-cyclohexylethanone (88 mg, 0.43 mmol), followed by 10 mL of MeCN dissolved and K2CO3 (120 mg, 0.86 mmol), heated to reflux at 120 °C, TLC monitored the end of the reaction, cooled, filtered, washed the organic phase with water, concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure, to obtain the target compound 117 mg, with a yield of 80.2%.

[0442] 1 H NMR (400 MHz, CDC13) δ / ppm 7.96 (d, J = 0.9 Hz, 1H), 7.88 (dd, J = 8.5, 0.9 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 5.58 (dd, J = 7.9, 4.0 Hz, 1H), 3.20 (tt, J = 11.5, 3.4 Hz, 1H), 2.11 (dddd, J = 14.1, 9.9, 5.8, 3.9 Hz, 1H), 1.99 - 1.92 (m, 2H), 1.87 (dt, J = 12.8, 3.4 Hz, 2H), 1.82 - 1.72 (m, 2H), 1.60 - 1.51 (m, 2H), 1.40 (dtdt, J = 12.2, 10.4, 6.2, 2.6 Hz, 6H), 1.29 (tt, J = 12.4, 3.4 Hz, 1H), 0.94 - 0.87 (m, 3H).

[0443] HRMS (ESI) m / z calcd for C 21 H 25 O4 + [M+H] + :341.1747; found: 341.1743

[0444] Example 67. 3-Butyl-7-neopentanoylbenzo[l,2-b:3,4-c']difuran-l(3H)-one

[0445] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 1-bromoadamantane (0.06 mL, 0.43 mmol) and then 10 mL of MeCN was taken and K2CO3 (120 mg, 0.86 mmol) was added and heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water and concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 108 mg with 89.6% yield.

[0446] 1 H NMR (400 MHz, CDC13) δ / ppm 7.96 (d, J = 1.0 Hz, 1H), 7.87 (dd, J = 8.5, 1.0 Hz, 1H), 7.47 (dd, J = 8.5, 0.7 Hz, 1H), 5.57 (dd, J = 7.8, 4.0 Hz, 1H), 2.18 - 2.03 (m, 1H), 1.78 (dddd, J = 14.5, 10.3, 7.8, 4.6 Hz, 1H), 1.44 (s, 13H), 0.90 (t, J = 7.1 Hz, 3H).

[0447] HRMS (ESI) m / z calcd for C 19 H 23 O4 + [M+H] + :315.1591; found: 315.1588

[0448] Example 68. 3-Butyl-3-hydroxy-7-(4-methoxybenzoyl)benzo[l,2-b:3,4-c']difuran-l(3H)-one

[0449] To a single necked reaction flask was taken compound f (100 mg, 0.43 mmol) and 1-bromoadamantane (0.06 mL, 0.43 mmol) and then 10 mL of MeCN was taken and K2CO3 (120 mg, 0.86 mmol) was added and heated to reflux at 120 °C, TLC was monitored for completion of reaction, cooled, filtered, organic phase was washed with water and concentrated under reduced pressure, the obtained organic solution was concentrated to dryness under reduced pressure to get the target compound 108 mg with 89.6% yield.

[0450] The product obtained in the previous step was dissolved in 60 mL of DCM, and pyridine (6 mL, 75.46 mmol) and DMP (20 g, 48.02 mmol) were added, and stirred at room temperature. After the reaction was completed as monitored by TLC, saturated NaHCO3 solution was added, extracted with DCM, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the target compound 2.59 g with a yield of 49.5%.

[0451] 1 H NMR (400 MHz, CDC13) δ 8.03 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.10 - 6.94 (m, 2H), 3.92 (d, J = 1.1 Hz, 3H), 2.27 (d, J = 14.8 Hz, 1H), 2.13 (s, 1H), 1.51 - 1.18 (m, 4H), 0.86 (t, J = 7.2 Hz, 3H).

[0452] HRMS (ESI) m / z calcd for C 22 H 21 O6 + [M+H] + : 381.1333; found: 381.1357;

[0453] Example 69. 3-(1-hydroxybutyl)-7-(4-methoxybenzoyl)benzo[1,2-b:3,4-c']difuran-1(3H)-one

[0454] (1) Synthesis of methyl 6-bromo-2-formyl-3-hydroxybenzoate

[0455] Methyl 2-bromo-5-hydroxybenzoate (10 g, 43.28 mmol) was dissolved in 40 mL of trifluoroacetic acid, and HMTA (9.101 g, 64.92 mmol) was added, and heated to reflux. After the reaction was completed as monitored by TLC, the pH was adjusted to 6 with a 4M KOH solution, extracted with EA, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain a white solid 4.70 g with a yield of 42.0%.

[0456] 1 H NMR (400 MHz, DMSO-D6) δ 10.18 (s, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 3.78 (s, 3H).

[0457] (2) Synthesis of methyl 5-bromo-2-(4-methoxybenzoyl)benzofuran-4-carboxylate

[0458] To a solution of 6-bromo-2-formyl-3-hydroxybenzoic acid methyl ester (2.251 g, 8.69 mmol) in 50 mL of acetonitrile was added 2-bromo-l-(4-methoxyphenyl)ethan-l-one (1.991 g, 8.69 mmol) and K2CO3(1.201 g, 8.69 mmol) and heated to reflux. The reaction was monitored by TLC and upon completion, cooled to room temperature and concentrated under reduced pressure. The residue was washed with water and filtered. The filtrate was recrystallized from ethanol to give 2.88 g of a white solid in 85.2% yield.

[0459] (3) Synthesis of (E)-methyl 2-(4-methoxybenzoyl)-5-(pent-l-en-l-yl)benzofuran-4- carboxylate

[0460] To a solution of (E)-methyl 2-(4-methoxybenzoyl)-5-(pent-l-en-l-yl)benzofuran-4- carboxylate (1.975 g, 5.22 mmol) in 50 mL of DCM was added m-CPBA (1.351 g, 7.83 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 mins and then at room temperature. Upon completion, the reaction was monitored by TLC and 686 mg of sodium sulfite was added. The mixture was filtered and the filtrate was washed with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound 845 mg in 42.3% yield.

[0461] (4) Synthesis of Example 69

[0462] To a solution of (E)-methyl 2-(4-methoxybenzoyl)-5-(pent-l-en-l-yl)benzofuran-4- carboxylate (1.975 g, 5.22 mmol) in 50 mL of DCM was added m-CPBA (1.351 g, 7.83 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 mins and then at room temperature. Upon completion, the reaction was monitored by TLC and 686 mg of sodium sulfite was added. The mixture was filtered and the filtrate was washed with saturated sodium bicarbonate solution and extracted with DCM. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound 845 mg in 42.3% yield.

[0463] 1 H NMR (400 MHz, DMSO-D6) δ 8.26 - 8.15 (m, 1H), 8.13 - 8.03 (m, 3H), 7.94 - 7.73 (m, 1H), 7.21 - 7.08 (m, 2H), 5.67 - 5.49 (m, 1H), 5.29 (dd, J = 12.4, 6.4 Hz, 1H), 3.90 (s, 3H), 1.57 - 1.44 (m, 3H), 1.35 (dtt, J = 11.1, 7.3, 3.3 Hz, 1H), 0.89 (td, J = 7.1, 4.2 Hz, 3H).

[0464] HRMS (ESI) m / z calcd for C 22 H 21 O6 + [M+H] + :381.1333;found:381.1339;

[0465] Example 70 3-Butyl-7-(4-hydroxybenzoyl)benzo[1,2-b:3,4-c']difuran-1(3H)-one

[0466] To the solution of Example 35 (2 g, 5.49 mmol) in 20 mL of DCM, BBr3(0.79 mL, 8.24 mmol) was added dropwise at 0 °C. After stirring at 0 °C for 2 h, the reaction was stirred at room temperature. After the reaction was completed by TLC monitoring, the reaction solution was added with an appropriate amount of water, and the pH was adjusted to 7 with saturated NaHCO3solution. The product was extracted with DCM, and concentrated under reduced pressure. The target compound was separated by silica gel column chromatography, and the yield was 877 mg, 45.6%.

[0467] 1 H NMR (500 MHz, DMSO) δ 8.23 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.91 - 7.68 (m, 2H), 6.98 (d, J = 8.5 Hz, 2H), 5.77 (dd, J = 7.9, 3.7 Hz, 1H), 2.26 - 2.09 (m, 1H), 1.75 (d, J = 6.9 Hz, 1H), 1.43 - 1.26 (m, 4H), 0.87 (t, J = 6.9 Hz, 3H).

[0468] HRMS (ESI) m / z calcd for C 21 H 19 O5 + [M+H] + :351.1227;found:351.1221;

[0469] Pharmacological experiments

[0470] Example 1 Promoting the survival of nerve cells in vitro

[0471] The reduction of the number of neurons is a hallmark event in the development of Alzheimer's disease. APP / S-KN cells are an ideal cell model for simulating Alzheimer's disease in vitro. The precursor APP of beta amyloid protein is overexpressed in the cells. The inventors used the oxygen-glucose deprivation model to simulate the cell damage caused by Alzheimer's disease in primary cultured neurons and APP / S-KN cells, and observed the effect of NS series compounds on promoting the survival and proliferation of nerve cells.

[0472] 1. Promoting survival of primary cultured neurons injured by oxygen glucose deprivation (OGD)

[0473] Experimental method:

[0474] Primary neuron culture: After the Wistar rat fetus was anesthetized with ether, the abdominal skin was disinfected with 75% ethanol, and the fetus was taken out under sterile conditions, placed in a 100 mm sterile culture dish, and the brain tissue was quickly separated, the tissue was cut into small pieces, and a pre-warmed 0.25% trypsin digestion solution was added, and the digestion was carried out at 37°C for 30 min. After digestion, the brain tissue was transferred to a centrifuge tube, 10 ml of culture medium containing serum (40 ml DMEM + 5 ml FBS + 5 ml HS + 0.5 ml PS + 0.5 ml Glu) was added, and the tissue was gently blown with a fine-bore pipette, filtered with a 200-mesh sieve, and then centrifuged at 800 rpm / min for 5 min. The supernatant was discarded, and an appropriate amount (10-20 ml) of inoculation medium was added, mixed well, and then counted on a counting plate, inoculated, and placed in a 5% CO2 37°C incubator for culture. After 4 hours of cell inoculation, the medium was changed to maintenance medium (48 ml neurobasal + 1 ml B27 + 0.5 ml PS + 0.5 ml Glu). Every 3-4 days, half of the maintenance medium was changed.

[0475] Oxygen glucose deprivation (OGD) injury and CCK8 detection: After the culture medium was discarded, 100 μl of normal maintenance medium was added and the culture was continued; the normal culture medium was discarded in the model group and the drug administration group, and the low-sugar culture medium was washed once. 90 μl of low-sugar culture medium and 10 μl of drug solution were added to each well of the 96-well plate, and the culture was carried out in a three-gas incubator (carbon dioxide, 5%, oxygen content 1%, nitrogen 94%). After 3 hours, the low-sugar culture medium was discarded and replaced with normal culture medium, 90 μl of normal culture medium was added to each well of the 96-well plate, and 10 μl of the working solution of the compound to be screened was added. The original culture medium was discarded, 10% CCK-8 solution was added to each well, and the plate was incubated in the incubator for 4 hours. The absorbance (OD value) at 450 nm was measured by a microplate reader to detect the cell survival rate. The percentage increase in cell survival rate after drug administration relative to the model group was calculated.

[0476] Survival rate increase = (OD 给药组 - OD 模型组 ) / OD 给药组 * 100%

[0477] The experimental results are shown in Table 1-1:

[0478] Table 1-1. Effect of NS series compounds (3 μM) on increasing the survival rate of primary neurons in the OGD model

[0479] Table 1-2. Effect of NS series compounds (10 μM) on improving cell survival rate of primary neuron OGD model

[0480] The above experimental results show that the model group (model) can improve the cell survival rate of primary cultured neurons subjected to oxygen-glucose deprivation injury.

[0481] 2. Promoting the survival of APP / S-KN cells subjected to oxygen-glucose deprivation injury

[0482] Experimental method:

[0483] APP / SK-N cell culture, lysis and collection: APP / SK-N cells with a confluence of 80%-90% were subcultured and seeded at a density of 2*10 5 6-well plates for Western Blot experiments), and cultured for 24 h. The original culture medium was discarded, and 2 mL of complete culture medium (containing 10% FBSD MEM medium) containing the test compound (final concentration of 3, 10 μM) was added to each well of the 6-well plate. The drug was allowed to act for 48 h. The Control group was added with the same volume of cell culture medium and cultured for the same time.

[0484] The OGD model was established and the CCK8 detection method was the same as above. The percentage of cell survival rate improvement relative to the model group was calculated. Survival rate improvement = (OD 给药组 -OD 模型组 ) / OD 给药组 * 100%

[0485] The experimental results are shown in Table 1-3:

[0486] Table 1-3. Effect of NS series compounds on the survival of OGD model APP / S-KN cells

[0487] The in vitro cell survival screening results show that, compared with the model group, the compounds of the present application can significantly improve the survival of neurons and APP / S-KN cells subjected to OGD injury, and have obvious effects of promoting the survival and regeneration of nerve cells.

[0488] Example 2: In vitro reduction of nerve cell death (apoptosis)

[0489] Apoptosis of neurons is also a hallmark event in the development of late-stage Alzheimer's disease. APP / S-KN cells are an ideal cell model for simulating Alzheimer's disease in vitro. The inventors used the oxygen-glucose deprivation model to simulate cell apoptosis caused by Alzheimer's disease in primary cultured neurons and APP / S-KN cells, and observed the effect of NS series compounds on reducing nerve cell apoptosis.

[0490] 1. Reducing the apoptosis of APP / SK-N cells damaged by oxygen-glucose deprivation

[0491] Experimental method:

[0492] APP / SK-N cell culture and establishment of oxygen-glucose deprivation model are the same as in Example 1.

[0493] Flow cytometry detection of apoptosis: neurons were seeded in a 6-well plate at a density of 5 x 10 5 cells / mL, and after a certain period of culture, they were divided into a blank control group (Control) and an OGD / R group (Model and drugs) for treatment; cell collection: digestion was performed using 0.125% Trypsin, and PBS was used for washing 2-3 times to prepare a single cell suspension, which was centrifuged at 800 rpm for 5 min to precipitate the cells, and the cells were resuspended using 1 x Annexin V binding buffer in the kit, and the cell density was adjusted to 1 x 10 6 cells / mL with a volume of 100 μL; cell labeling: 5 μL of 1 x Annexin V working solution and 1 μL of 1 x PI working solution were added to each 100 μL of cell suspension, and incubation was performed at room temperature for 15 min in the dark; after incubation, 400 μL of 1 x Annexin V binding buffer was added, and the mixture was gently mixed and placed on ice; machine detection: the cell suspension was transferred to a flow detection tube, and machine detection was performed, with FL1 detecting 530 nm excitation light and FL3 detecting > 575 nm excitation light.

[0494] The experimental results are shown in Tables 2-1 and 2-2:

[0495] Table 2-1. Effect of different concentrations of compounds on the apoptosis of APP / SK-N cells damaged by OGD model P<0.05, ##P<0.01 indicates statistical significance compared with the control group. *P<0.05, **P<0.01 indicates statistical significance compared with the model group.

[0496] Table 2-2. Effect of different concentrations of compounds on the apoptosis of APP / SK-N cells damaged by OGD model P<0.05, ##P<0.01 indicates statistical significance compared with the control group. *P<0.05, **P<0.01 indicates statistical significance compared with the model group.

[0497] The above experimental results show that, compared with the model group, the tested compounds of the application can significantly reduce the total apoptosis rate of APP / SK-N cells damaged by OGD, and have a significant anti-apoptotic effect.

[0498] Experimental method:

[0499] The method for culturing primary neurons and establishing the oxygen-glucose deprivation model is the same as that in Example 1.

[0500] The method for detecting apoptosis by flow cytometry is the same as above.

[0501] The experimental results are shown in Tables 2-3:

[0502] Table 2-3. Effects of different compounds on apoptosis of cortical neurons injured by OGD

[0503] Compared with the control group: #P<0.05, ##P<0.01. Compared with the model group: *P<0.05, **P<0.01

[0504] Table 2-3

[0505] The above experiments show that the compounds of Examples 13, 35, and 16 can significantly reduce the apoptosis of neurons and APP / S-KN cells caused by OGD injury, and have obvious anti-apoptotic effects.

[0506] Example 3: Improvement of learning and memory in APP / PS1 transgenic mice and scopolamine-induced dementia mice

[0507] 1. Improvement of learning and memory in APP / PS1 transgenic mice by NS series compounds

[0508] The APP / PS1 transgenic mouse model is a classic animal model for evaluating learning and memory improvement. The inventors used this whole-body animal model to evaluate the improvement of cognitive dysfunction in APP / PS1 transgenic mice by Example 13 and Example 35 in the water maze test.

[0509] Experimental method:

[0510] Experimental animals: APP / PS1 transgenic mice, 12 months old, purchased from Changzhou Cavens Experimental Animal Co., Ltd. Experimental groups: normal control group (WT group), model group (Model group), Example 13 10 mg / kg group, n=10 in each group; normal control group (WT group), model group (Model group), Example 35 10 mg / kg group, n=10 in each group;

[0511] Morris water maze: The Morris water maze mainly consists of a metal cylindrical pool (pool height 60 cm, diameter 120 cm) and automatic display, monitoring, recording device and safety island (diameter 10 cm platform). The pool wall and platform are pasted with black self-adhesive plastic paper in advance to make them black, so that the pool water appears black, and the water surface is 15 mm higher than the platform, so that the animals cannot reach the platform through hearing and olfaction, in order to detect the animal's memory ability for spatial location. The water temperature is maintained at 25±1℃, and the pool is divided into 4 quadrants (northeast, southeast, northwest, southwest), and the platform is placed in the center of the northwest quadrant. The swimming activity of each mouse is monitored and recorded by a monitor directly connected to a computer for processing and analysis. The positioning navigation experiment is performed continuously for 4 days. Each mouse receives 2 training to find the platform per day, with the head facing the pool wall. The interval between the two training is 10 minutes. The time to find the platform (latency) is recorded, and the results of the two experiments per day are averaged. If the mouse does not find the platform within 90 seconds, the latency is calculated as 90 seconds. Whether the mouse finds the platform within 90 seconds or not, it stays on the platform for 30 seconds. The time to find the platform (latency) index reflects the mouse's learning and memory ability for spatial location. The spatial exploration experiment is performed on the second day after the last training, i.e. on the 5th day. Remove the platform and let the mouse swim freely for 90 seconds to find the platform, and record the time and number of times the mouse crosses the target platform for the first time.

[0512] Results of the experiment:

[0513] As shown in Figures 1-6, in the Morris water maze experiment, Example 13 and Example 35 (10 mg / kg) can significantly reduce the water maze latency of APP / PS1 transgenic mice, reduce the first crossing time during the exploration period, and increase the crossing frequency, showing an obvious effect of improving the cognitive impairment of APP / PS1 mice.

[0514] As shown in Figures 4-6, Example 35 10 mg / kg significantly reduces the water maze latency of APP / PS1 transgenic mice, reduces the first crossing time during the exploration period, and increases the crossing frequency, showing an effect of improving the cognitive dysfunction of APP / PS1 mice.

[0515] 2. Improvement of scopolamine-induced learning and memory impairment in mice by Examples 13, 16 and 35

[0516] The scopolamine-induced dementia mouse model is also a classic animal model for evaluating learning and memory improvement. The inventors used this whole-body animal model to evaluate the improvement of cognitive dysfunction by NS series compounds in the platform test.

[0517] Experimental method:

[0518] Experimental animals: ICR mice, 22-24 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.; APP / PS1 transgenic mice, 12 months old, purchased from Changzhou Cavens Experimental Animals Co., Ltd.

[0519] The jump stand instrument is a square electric shock device, which is divided into 5 compartments. The bottom of each compartment is an iron fence that can carry 36-volt alternating current. An electrically insulated circular rubber platform with a diameter of about 3 cm is placed at a corner of the bottom. Mice can stand on it to avoid electric shock. The four sides are plastic boards, one of which is transparent towards the observer, and the other three are black and opaque. The top is open for taking and placing animals. The mice are placed in one compartment of the jump stand instrument. On the first day, they are adapted for 5 minutes. On the second day, the power is turned on, and the animals are shocked. Training lasts for 3 minutes. Twenty-four hours after training, the jump stand power is turned on, and the mice are carefully placed on the safe platform. The latency of the first jump off the safe platform and the number of shocks within 3 minutes are recorded to determine the passive avoidance response ability of the animals.

[0520] Experimental results:

[0521] In the jump stand experiment of scopolamine-induced dementia mice, Example 35 significantly reduced the number of scopolamine-induced dementia mice jumping off the platform and had a tendency to reduce the latency of scopolamine-induced dementia mice jumping off the platform. Example 13 had a tendency to reduce the number of scopolamine-induced dementia mice jumping off the platform and the latency of scopolamine-induced dementia mice jumping off the platform. Example 16 significantly reduced the number of scopolamine-induced dementia mice jumping off the platform and had a tendency to reduce the latency of scopolamine-induced dementia mice jumping off the platform. All three compounds showed an effect of improving cognitive dysfunction in mice.

[0522] Table 3-1. Effect of compounds on jump stand latency and error number of scopolamine-induced dementia mice n = 10, # p < 0.05 vs. normal control group, * p < 0.05 vs. model group.

[0523] Table 3-2. Effect of compounds on jump stand latency and error number of scopolamine-induced dementia mice n = 10, # p < 0.05, ## p < 0.01 vs. normal control group, * p < 0.05 vs. model group.

[0524] The results of the above two whole animal model experiments show that the compounds of the present application, including Example 13, Example 35 and Example 16, can significantly improve the cognitive dysfunction of APP / PS1 transgenic mouse models and scopolamine-induced dementia mouse models.

[0525] Results of acute toxicity experiment of NS series compounds of Effect Example 4

[0526] The NS series compounds show obvious effects of improving cognitive dysfunction, as represented by Example 13, Example 35 and Example 16, and the acute toxicity effects on ICR mice are observed.

[0527] Experimental method:

[0528] Experimental animals: ICR mice, 22-24 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0529] Experimental grouping: The experimental animals were evenly distributed into each group according to the animal weight, with 5 female mice and 5 male mice in each group. They were divided into the Example 13 100 mg / kg group, the Example 13 200 mg / kg group, the Example 13 500 mg / kg group, the Example 13 800 mg / kg group, the Example 35 100 mg / kg group, the Example 35 200 mg / kg group, the Example 35 500 mg / kg group, the Example 35 800 mg / kg group, the Example 16 100 mg / kg group, the Example 16 200 mg / kg group, the Example 16 500 mg / kg group, and the Example 16 800 mg / kg group, totally 12 groups.

[0530] Experimental method: After the experimental animals were grouped, they were given a dose of drugs according to the dosages, with the drug administration volume of 10 ml / kg, and the animal death was observed within 14 days, and the animal death time and reason were recorded.

[0531] Experimental results:

[0532] The body weight of the ICR mice in each administration group steadily increased, and the ICR mice in the Example 13, Example 35 and Example 16 groups had no death within 14 days after the single administration of the three compounds at the dosages of 100 mg / kg, 200 mg / kg, 500 mg / kg and 800 mg / kg, and the LD 50 of the three compounds were all >800 mg / kg.

[0533] Table 5-1, survival of animals in acute toxicity experiment of NS compounds

[0534] The animal survival was observed within 14 days after the administration, and no animal died.

[0535] The above results show that the LD 50 of the Example 13, Example 35 and Example 16 are all >800 mg / kg, while the effective dosage of the Example 13, Example 35 and Example 16 in the behavior is 10 mg / kg, which indicates that the safety window of the active compounds of the embodiments of the present application, including the Example 13, Example 35 and Example 16, is wide, and the acute toxicity effect is not observed.

Claims

A tricyclic compound as shown in Formula I', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: wherein L is selected from -0-, -C(=0)-, -NH-, -NR4-, -S-, -S(O)-, -S(0)2-, and -(CH2) x -; x is 1, 2 or 3; R1, R2, R3, and R5 are independently selected from hydrogen, halogen, amino, nitro, hydroxyl, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R6, -C(O)OR6, and -S(O). m R6 and -S(O) m NR7R8, wherein the alkyl, heterocyclic, aryl, and heteroaryl groups are independently and optionally composed of one or more R groups. R1 replace; R4is selected from the group consisting of a hydrogen atom, halogen, amino, nitro, hydroxyl, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, and -NR7R8, wherein each of said alkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R R2 substituents; each R R1 and each R R2 is independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, carboxyl, -NH-alkyl, -N(alkyl)2, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, -S(O) 2- -(alkyl)2, cycloalkyl, heterocyclyl, aryl, -C(O)O-alkyl, -C(O)O-alkyl-O-alkyl, -C(O)O-alkenyl, -C(O)O-alkyl-aryl, -O-alkyl-aryl, -NHC(=O)-O-alkyl-aryl, and heteroaryl, or, any two R adjacent to one another R2 together form -(CH2) Y - Y is 1, 2, 3, 4 or 5, wherein 1, 2 or any -CH2- can be optionally replaced by 1, 2 or 3 of O, S and NH; R a and R b are independently selected from the group consisting of a hydrogen atom, a halogen, a cycloalkyl group, a heterocyclyl group and -NR7R8, wherein said cycloalkyl and heterocyclyl groups are independently optionally substituted with one or more R R3 substituents: Each R R3 It is independently selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; R6is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkoxy group, a hydroxy group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein said alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group are independently optionally substituted with one or more R R4 substituents; Each R R4 The radicals are selected from alkyl, halogen, hydroxyl, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl. R7and R8are independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxy group, an amino group, a carboxylate group, a cycloalkyl group, a heterocyclyl group, an amino protecting group, an aryl group, and a heteroaryl group, or R7, R8, and the attached N atom together form a heterocyclyl group or a heteroaryl group, wherein each of said alkyl group, amino group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more R R5 substituents; Each R R5 Independently selected from alkyl, halogen, hydroxyl, amino, carboxylic acid ester group, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups; Q is selected from the group consisting of -C-, -N-, -O-, -S-, -S(O)2-, -S(O)(N)- and -C(O)2-; M and n are independently selected from 0, 1 and 2. The tricyclic compound as shown in Formula I', the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof according to Claim 1, wherein The tricyclic compound as shown in formula I' is a structure shown in formula I'b: The tricyclic compound as shown in Formula I', the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof according to Claim 1, wherein The tricyclic compound as shown in formula I' is a structure shown in formula I or Ia: wherein, "*" represents an S-type chiral carbon atom or an R-type chiral carbon atom. The tricyclic compound according to claim 1 or 2, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof represented by formula I', characterized in that, which satisfies one or more of the following conditions: (1) R1, R2, R3, R4, R5, each R R1 Each R R2 Each R R3 R6, each R R4 R7, R8 and each R R5 In this context, the halogen is F, Cl, Br, or I; (2) R1, R2, R3, R4, R5, each R R1 Each R R2 Each R R3 Each R R4 R6, R7, R8 and each R R5 In the above, the alkyl group is C10. 1-8 Alkyl, preferably C 1-6 Alkyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (3) R1, R2, R3, R4, R5, and each R R1 Each R R2 Each R R3 R6, each R R4 R7, R8 and each R R5 In the text, the alkoxy group is C64. 1-8 Alkoxy, preferably C 1-6 Alkyl groups, more preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; (4) R1, R2, R3, R4, R5, each R R1 , each R R2 , each R R3 , R6, each R R4 , R7, R8and each R R5 , each R 3-14 cycloalkyl, preferably C 3-6 cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (5) R1, R2, R3, R4, R5, each R R1 , each R R2 , each R R3 , R6, each R R4 , R7, R8and each R R5 Among them, the heterocyclic group is a 3-14 membered heterocyclic group, the heteroatom is selected from one or more of N, S and O, the number is 1, 2 or 3, preferably a 5-6 membered monocyclic heterocyclic group, the heteroatom is selected from one or more of N, S and O, the number is 1 or 2, more preferably a pyrrolyl group or a morpholinyl group; (6) R1, R2, R3, R4, R5, each R R1 , each R R2 , each R R3 , R6, each R R4 , R7, R8and each R R5 , each R 6-14 , each R 6-10 , each R (7) R1, R2, R3, R4, R5, each R R1 , each R R2 , each R R3 , R6, each R R4 , R7, R8and each R R5 , the heteroaryl group is a 3-14 membered heteroaryl group, the heteroatom is selected from one or more of N, S and O, the number is 1, 2 or 3, preferably a 5-6 membered monocyclic heteroaryl group or an 8-10 membered bicyclic heteroaryl group, the heteroatom is selected from one or more of N, S and O, the number is 1 or 2, and can also be a furanyl group, a thienyl group, a thiazolyl group, a 1H-pyrazolyl group, a benzo[d]thiazolyl group or a benzofuranyl group; (8) each R R1 and each R R2 Among them, the alkyl in said -NH-alkyl, the alkyl in said -N(alkyl)2, the alkyl in said -S(O) 2- alkyl in said -C(O)O-alkyl, the alkyl in said -C(O)O-alkyl-aryl, the alkyl in said -NHC(=O)-O-alkyl-aryl and the alkyl in said -O-alkyl-aryl is independently C 1-8 alkyl, preferably C 1-6 alkyl, more preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl; (9) each R R1 and each R R2 Among them, the aryl in said -C(O)O-alkyl-aryl, the aryl in said -NHC(=O)-O-alkyl-aryl and the aryl in said -O-alkyl-aryl is independently C 6-14 aryl, preferably C 6-10 aryl, can also be phenyl or naphthyl; (10) each R R1 and each R R2 Among them, the alkenyl in the -C(O)O-alkenyl is C 2-8 alkenyl, preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl, for example -propenyl; (11) each R R1 , each R R2 , and each R R3 , is haloalkyl, preferably haloC 1-8 alkyl, more preferably haloC 1-6 alkyl, even more preferably haloC 1-4 alkyl, for example -CF3; (12) each R R1 , each R R2 , and each R R3 , the haloalkoxy is C 1-8 haloalkoxy, preferably C 1-6 haloalkoxy, more preferably C 1-4 fluoroalkoxy, for example -OCF3; and (13) in each R6, said alkenyl is C 2-8 alkenyl, preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl, e.g., -propenyl. The tricyclic compound according to claim 1 or 2, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof represented by formula I', characterized in that, which satisfies one or more of the following conditions: (1) Q is selected from -O-; (2) L is selected from -C(=O)-, -NH- and -NR4-; (3) R1is selected from alkyl, said alkyl being optionally substituted with one or more R R1 substituents, each R R1 is halo, amino, nitro, cyano, hydroxy, or alkoxy; Preferably, R1is selected from C 1-6 alkyl; More preferably, R1is selected from (4) R2is selected from a hydrogen atom or -alkyl, said alkyl being optionally substituted by one or more R R1 substituents, each R R1 selected from halogen, carboxyl, cyano, -C(O)O-alkyl, -C(O)O-alkyl-O-alkyl, -C(O)O-alkenyl or -C(O)O-alkyl-aryl; R2is selected from a hydrogen atom or a C 1-6 alkyl group, said alkyl group being optionally substituted by one or more R R1 groups, each R R1 group is selected from halogen, cyano, carboxyl, -C(O)O-C 1-6 alkyl, -C(O)O-C 1-6 alkyl-O-C 1-6 alkyl, -C(O)O-C 2-6 alkenyl or -C(O)O-C 1-6 alkyl-C 6-10 aryl; More preferably, R2is selected from H, (5) R3is selected from the group consisting of a hydrogen atom, an amino group, a nitro group, a hydroxyl group, a cyano group, and -C(O)OR6, R6is selected from the group consisting of a hydrogen atom, an alkyl group, or an alkenyl group, said alkyl group is optionally substituted with one or more R R4 substituents, each R R4 is independently selected from the group consisting of a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, and an aryl group; Preferably, R3is selected from the group consisting of a hydrogen atom, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, -C(O)R6and -C(O)OR6, R6being selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group and a hydroxyl group, said alkyl group being optionally substituted by one or more R R4 groups, each R R4 being independently selected from the group consisting of a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a C 1-6 alkoxy group and a C 6-10 aryl group; More preferably, R3is selected from H, cyano, (6) R4is selected from the group consisting of hydrogen, amino, alkyl, cycloalkyl and aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one or more R R2 substituents; each R R2 is independently selected from the group consisting of alkyl, haloalkyl, halo, amino, -N(alkyl)2, nitro, cyano, hydroxy, carboxy, alkoxy, haloalkoxy, hydroxyalkyl, -S(O) 2- -alkyl)2, cycloalkyl, heterocyclyl, aryl, -O-alkyl-aryl, -NHC(=O)-O-alkyl-aryl, heteroaryl, and, optionally, any two adjacent R R2 together form -(CH2) Y -; Y is 1, 2, 3, 4 or 5, wherein 1, 2 or of the -CH2- can optionally be replaced with 1, 2 or 3 of O, S and NH; R4is selected from the group consisting of hydrogen, amino, alkyl, C 3-6 cycloalkyl, and C 6-10 aryl, wherein said alkyl, cycloalkyl and aryl are optionally substituted with one or more R R2 each R R2 is independently selected from the group consisting of C 1-6 alkyl, haloC 1-6 alkyl, halo, amino, -N(C 1-6 alkyl)2, nitro, cyano, hydroxy, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 hydroxyalkyl, -S(O) 2- -(C 1-6 alkyl)2, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, C 6-10 aryl, -O-C 1-6 alkyl-C 6- 10 aryl, -NHC(=O)-O-C 1-6 alkyl-C 6-10 aryl, 5-6 membered heteroaryl, and, optionally, any two R R2 together form -(CH2) Y -, Y is 1, 2, 3, 4 or 5, wherein optionally 1, 2 or of the -CH2- can be optionally replaced by O; More preferably, R4is selected from H, (7) R a and R b is selected from a hydrogen atom; (8) R5 is selected from a hydrogen atom or a hydroxyl group; and (9) R1, R2, R3, R4 and R5 are not simultaneously a hydrogen atom, preferably R1 and R5 are not simultaneously a hydrogen atom. The tricyclic compound according to claim 1 or 2, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof represented by formula I', characterized in that, The tricyclic compound of Formula I is a structure of Formula II, III, IV, or V: wherein, L is -NR4- or -C(=O)-; in IV or V, R1 and R5 are not simultaneously a hydrogen atom. The tricyclic compound according to claim 6 represented by formula I', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, which satisfies (1) and / or (2): (1) the structure according to Formula II is a structure according to Formula II-1, II-2, II-3, or II-3a: in formula II-3a, "*" represents an S-type chiral carbon atom or an R-type chiral carbon atom; (2) the structure according to Formula III is a structure according to Formula III-1, III-2, or III-2a: in formula II-3a and formula III-2a, "*" represents an S-type chiral carbon atom or an R-type chiral carbon atom. The tricyclic compound according to claim 7, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof represented by formula I', characterized in that, which satisfies (1) and / or (2): (1) as in formula II-1, II-2, II-3 and II-3a, R1is selected from the group consisting of a hydrogen atom, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy; R R1 selected from a hydrogen atom, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a -C(O)O-C 1-6 alkyl group, a -C(O)O-C 1-6 alkyl group, a -C(O)O-C 1-6 alkyl group, a -C(O)O-C 2-6 alkenyl group and a -C(O)O-C 1-6 alkyl group, a -C(O)O-C 6-14 aryl group; R3is selected from the group consisting of a hydrogen atom, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, -NR7R8, C 1-6 alkoxy and -C(O)OR6; R6is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy, amino, 3-14 membered cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl; R7and R8are each independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl, amino protecting group, C 6-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl, wherein said C 1-6 alkyl, amino, C 6-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, halo, hydroxy and amino; preferably, as in formula II-1, II-2, II-3 and II-3a, R1is selected from C 1-6 alkyl; R R1 selected from cyano, -C(O)O-C 1-6 alkyl, -C(O)O-C 1-6 alkyl-O-C 1-6 alkyl, -C(O)O-C 2-6 alkenyl or -C(O)O-C 1-6 alkyl-C 6-14 aryl; R3is selected from -COOR6, R6is selected from C 1-6 alkyl and C 2-6 alkenyl, R6is optionally substituted with one or more R R4 each R R4 is selected from -O-C 1-6 alkoxy and -C 6-14 aryl; R4 is selected from a hydrogen atom; (2) as in formula III-1, III-2 and III-2a, R1is selected from the group consisting of a hydrogen atom, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy; R3is selected from a hydrogen atom, halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, -NR7R8, C 1-6 alkoxy or -C(O)OR6; R6is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, hydroxy, amino, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl; R4is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 3-14 cycloalkyl, 3- to 14-membered heterocyclyl, C 6-14 aryl and C 6-14 heteroaryl, each independently optionally substituted with one or more R 1-6 alkyl, C 3-14 cycloalkyl, 3- to 14-membered heterocyclyl, C 6-14 aryl and 6- to 14-membered heteroaryl, each independently optionally substituted with one or more R R2 substituents; Each R R2 Independently selected from halogen, amino, carboxyl, -NH-C 1-6 Alkyl, nitro, cyano, hydroxyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl group, -S(O) 2- -(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, -C(O)OC 1-6 Alkyl, -C(O)OC 1-6 Alkyl-OC 1-6 Alkyl, -C(O)OC 2-6 alkenyl, -C(O)OC 1-6 Alkyl-aryl, -OC 1-6 Alkyl-C 6-14 Aryl, -NHC(=O)-OC 1-6 Alkyl-C 6-14 Aryl and 3-14 heteroaryl groups; or any two R adjacent to each other R2 together form -(CH2) Y - Y is 1, 2, 3, 4 or 5, wherein 1, 2 or any -CH2- can be optionally replaced by 1, 2 or 3 of O, S and NH; preferably, as in formula III-1, III-2 and III-2a, R1is selected from C 1-6 alkyl; R3 is selected from a hydrogen atom; R4is selected from C 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and C 6-14 heteroaryl, each independently optionally substituted with one or more R 1-6 alkyl, C 3-14 cycloalkyl, 3-14 membered heterocyclyl, C 6-14 aryl and 6-14 membered heteroaryl, each independently optionally substituted with one or more R R2 substituents; Each R R2 Independently selected from halogen, amino, carboxyl, -NH-C 1-6 Alkyl, nitro, cyano, hydroxyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl groups, -S(O) 2- -(C 1-6 Alkyl)2, C 3-14 Cycloalkyl, 3-14 membered heterocyclic groups, C 6-14 Aryl, -OC 1-6 Alkyl-C 6-14 Aryl, -NHC(=O)-OC 1-6 Alkyl-C 6-14 Aryl and 3-14 heteroaryl groups; or any two R adjacent to each other R2 together form -(CH2) Y - Y is 1, 2, 3, 4 or 5, wherein 1, 2 or any -CH2- can be optionally replaced by 1, 2 or 3 of O, S and NH; more preferably, as in formula III-1, III-2 and III-2a, R1is selected from C 1-6 alkyl; R3 is selected from a hydrogen atom; R4is selected from C 1-6 alkyl, C 1-6 alkyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, furanyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzothiazolyl, benzofuranyl, benzodioxolyl and benzodioxepinyl; R4is optionally substituted with one or more R R2 substituents; each R R2 each independently is optionally substituted with a member selected from the group consisting of halogen, hydroxy, amino, nitro, cyano, benzyloxy, methoxycarbonyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkyl, dimethylamino, methanesulfonyl, ethanesulfonyl, sulfonamido, carboxy, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, thienyl, thiazolyl, isothiazolyl, furanyl, The tricyclic compound according to claim 6, the pharmaceutically acceptable salt thereof, the solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof represented by formula I', characterized in that, The structure as shown in Formula III is a structure as shown in Formula III-4: Preferably, the structure as shown in formula III-4 is a structure as shown in formula III-4-1, III-4-2, or III-4-3: more preferably, as in formula III-4-1, III-4-2 or III-4-3, R1is selected from C 1-6 alkyl; each R is independently selected from C R2 is independently selected from C 1-6 alkyl, haloC 1-6 alkyl, C 1-6 alkoxy and haloC 1-6 alkoxy. The tricyclic compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, represented by Formula I' selected from any one of the following compounds: the tricyclic compound as shown in formula I' according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, is selected from any one of the following compounds: In some embodiments, the compound elutes first or last under the following chromatographic conditions: In some embodiments, the compound elutes first or last under the following chromatographic conditions: in the following chromatographic conditions, the compound eluted first or the compound eluted last: chromatographic conditions: column: CHIRALCEL OZ-H, mobile phase: MeOH and CAN solution in a volume ratio of 90:

10. A compound of Formula A' or A or a pharmaceutically acceptable salt thereof: wherein, R1, R5, R a and R b are as defined in any one of claims 1 to 11 ; The compound as shown in Formula A is preferably A tricyclic compound as shown in Formula I', a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, as described in any one of claims 1-11, characterized in that, which is method 1 or method 2: When n is 1, it is Method 1, which comprises the step of reacting a compound of Formula A and a compound of Formula B as follows to obtain said tricyclic compound of Formula I': When n is 1, it is Method 2, which comprises the following steps: reacting a compound of Formula A with a compound of Formula C, as follows, to form the tricyclic compound of Formula I': wherein R 10 selected from halogen. A pharmaceutical composition, characterized by a pharmaceutical composition comprising a therapeutically effective amount of a tricyclic compound as shown in formula I' according to any one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. the use of a salt of a tricyclic compound as shown in formula I' according to any one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating or preventing a neurodegenerative disorder or a related disorder, inhibiting the progression of the neurological disorder or the related disorder. The neurodegenerative disease or related condition is preferably selected from the group consisting of Alzheimer's disease, dementia associated with Alzheimer's disease, mild cognitive impairment, dementia with Lewy bodies, frontotemporal lobar degeneration, vascular cognitive impairment and dementia, pre-dementia states, mild cognitive impairment, age-related memory impairment, age-related cognitive decline, non-demented cognitive impairment, mild cognitive decline, mild neurocognitive decline, late-life forgetfulness, memory and cognitive impairment, vascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, Parkinson's type frontotemporal dementia, Parkinson dementia complex of Gaum, HIV dementia, diseases associated with neurofibrillary tangle pathologies, dementia pugilistica, amyotrophic lateral sclerosis, multiple sclerosis, and other diseases of the central nervous system epilepsy and depression.

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