TW202221003A - Polycyclic biological regulator, preparation method and application thereof - Google Patents

Abstract

The present invention relates to a biological regulator, preparation method and application thereof. In particular, the present invention relates to compounds represented by the general formula (II), their preparation methods and pharmaceutical compositions containing the compounds, and their application in the treatment or prevention of cancer and other related diseases.

Description

Polycyclic bioregulator, its preparation method and application

The invention belongs to the field of pharmaceutical synthesis, and particularly relates to a polycyclic biological regulator, a preparation method and application thereof.

Aberrant translation of messenger RNA (mRNA) is a common feature of malignancies, manifested by the upregulation of oncoproteins, growth factors, and signaling proteins associated with proliferation, survival, and metastasis. The expression of oncogenic drivers is under strict translational control and is regulated by the eukaryotic translation initiation factor 4F (eukaryotic translation initiation factor 4F) complex, which mediates the recruitment of ribosomes to mRNA and initiates the translation of mRNA to protein. The eIF4F complex consists of three subunits of the mRNA 5' cap-binding protein eIF4E, the scaffold protein eIF4G and the RNA helicase eIF4A. eIF4F recognizes the 5'-mRNA cap structure by eIF4E, eIF4A unravels the mRNA 5'-UTR secondary structure in an ATP-dependent manner, cyclizes mRNA by binding to polyA-binding protein, and recruits the 40S subunit for ribosome scanning and translation starts. The eIF4F subunit is frequently overexpressed in various malignancies, thus targeting components of the eIF4F complex to renormalize deregulated translation is an emerging strategy for anticancer drug discovery.

Excessive activation of eIF4A, eIF4E, and eIF4G is associated with poor prognosis in related diseases, including lymphoma, lung, colorectal, liver, breast, and ovarian cancer. eIF4A is divided into free type and complex type according to whether it is combined with ribosomes, and the activity of free type is 1/20 of that of complex type. There are 3 members of the eIF4A family One: eIF4A1, eIF4A2 and eIF4A3, all belong to a family of helicase proteins called DEAD-box, and their family proteins all have 9 conserved motifs, which are involved in RNA binding or ATP hydrolysis, respectively.

It has been reported that there are natural products that inhibit eIF4A-mediated translation and exhibit antiproliferative and antitumor phenotypes in vivo and in vitro. In the case of silvestrol and rocaglamide A, which have been shown to bind and stabilize untranslated RNA/eIF4A complexes. These stable eIF4A·RocA complexes block the scanning of ribosomes, thereby inhibiting the translation of target mRNAs, and regulating the expression of related oncogenic factors by inhibiting eIF4A-mediated translation. There are currently many research and development eIF4A inhibitors for the development of anti-tumor drugs. The current major challenges for this class of drugs are: metabolic instability, poor solubility, and the development of a robust synthetic method to produce the desired drug substance to support clinical development. Therefore, it is an urgent problem to develop an eIF4A inhibitor drug with improved physicochemical properties, good logP and water solubility to support clinical control of the optimal therapeutic dose of intravenous administration.

At present, the eIF4A inhibitor eFT226 disclosed in eFFECTOR Therapeutics International Application WO 2017091585 has been shown in preclinical experiments to inhibit the proliferation of RTK solid tumors and lymphomas, oncogenic protein translation (FGFR1/2, HER2, KRAS) and resistance in preclinical models. It has good receptivity and has entered the first phase of clinical research. As an emerging strategy for anti-cancer drug discovery, the regulation of translation is intended to provide a novel anti-tumor drug that inhibits the activity of eIF4A to meet the huge tumor market demand.

The object of the present invention is to provide a kind of compound shown in general formula (I), its stereoisomer or its pharmaceutically acceptable salt, and its structure is as follows:

in,

X is selected from O, S, S(O), S(O) ₂ , C(O), NR or CRR';

Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, which cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted as required;

R and R' are each independently selected from hydrogen, deuterium, halogen, amine, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amine, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally further substituted;

R ₁ is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amine, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkyne radicals, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

R2 and _R2 ' are each independently selected from _hydrogen , deuterium, halogen, amine, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkane Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amine, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkyi Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

_R3 and _R3 ' are each independently selected from hydrogen, deuterium, halogen, amine, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkane Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n1 R _a , -(CH ₂ ) _n1 NR _a OR _b , -(CH ₂ ) _n1 C(O)NR _a R _b , -(CH ₂ ) _n1 NR _a C(O)R _b , -(CH ₂ ) _n1 S(O) _m1 R _a , -(CH ₂ ) _n1 S(O) _m1 NR _a R _b , -(CH ₂ ) _n1 NR _a S(O) _m1 R _b , -(CH ₂ ) _n1 NR _a R _b or -(CH ₂ ) _n1 NR _a (CH ₂ ) _n2 R _b , the amine group , alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, as appropriate can be further substituted;

_R4 and _R4 ' are each independently selected from hydrogen, deuterium, halogen, amine, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkane Oxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n3 R _c , -(CH ₂ ) _n3 NR _c OR _d , -(CH ₂ ) _n3 C(O)NR _c R _d , -(CH ₂ ) _n3 NR _c C(O)R _d , -(CH ₂ ) _n3 S(O) _m2 R _c , -(CH ₂ ) _n3 S(O) _m2 NR _c R _d , -(CH ₂ ) _n3 NR _c S(O) _m2 R _d , -(CH ₂ ) _n3 NR _c R _d or -(CH ₂ ) _n3 NR _c (CH ₂ ) _n4 R _d , the amine group , alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, as appropriate can be further substituted;

R ₅ is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amine, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkyne radicals, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

^Ra is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkyne radical, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amine, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkyne radicals, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

Alternatively, R ^a and R ₄ are linked to the carbon atom or heteroatom to which they are attached to form a cycloalkyl or heterocyclyl group, which may be further substituted as required;

R _a , R _b , R _c and R _d are each independently selected from hydrogen, deuterium, halogen, amine, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkane radical, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amine, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally further substituted;

x is 0, 1, 2, 3, 4, or 5;

n1~n4 are 0, 1, 2, 3, 4 or 5; and

m1 and m2 are 0, 1 or 2.

In a preferred embodiment of the present invention, the ring A is selected from C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, _C1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C ₁ One or more of _-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl substituted by a substituent;

In a further preferred embodiment of the present invention, the ring A is selected from C _6-10 aryl or 5-10 membered heteroaryl;

In a further preferred embodiment of the present invention, the ring A is selected from 5-6 membered nitrogen-containing heteroaryl groups;

In a further preferred embodiment of the present invention, the ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl or pyrazolyl.

In a further preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is further shown in general formula (II):

in,

R ₁ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, optionally further substituted by one or more _R8 ;

R ₂ and R ₂ ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 Cycloalkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl substituted by one or more substituents;

R ₃ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 Membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, -(CH ₂ ) _n1 R _a , -(CH ₂ ) _n1 NR _a OR _b , -(CH ₂ ) _n1 C(O) NR _a R _b , -(CH ₂ ) _n1 NR _a C(O)R _b , -(CH ₂ ) _n1 S(O) _m1 R _a , -(CH ₂ ) _n1 S(O) _m1 NR _a R _b , -(CH ₂ ) _n1 NR _a S(O) _m1 R _b , -(CH ₂ ) _n1 NR _a R _b or -(CH ₂ ) _n1 NR _a (CH ₂ ) _n2 R _b , the C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1 -6} alkylthio, _C1-6 haloalkoxy, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, further if necessary Deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, substituted by one or more substituents in C _6-14 aryl and 5-14 membered heteroaryl;

R ₄ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 Member heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, -(CH ₂ ) _n3 R _c , -(CH ₂ ) _n3 NR _c OR _d , -(CH ₂ ) _n3 C(O) NR _c R _d , -(CH ₂ ) _n3 NR _c C(O)R _d , -(CH ₂ ) _n3 S(O) _m2 R _c , -(CH ₂ ) _n3 S(O) _m2 NR _c R _d , -(CH ₂ ) _n3 NR _c S(O) _m2 R _d , -(CH ₂ ) _n3 NR _c R _d or -(CH ₂ ) _n3 NR _c (CH ₂ ) _n4 R _d , the C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1 -6} alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, if necessary, Further by deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkane base, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl , C _6-14 aryl and 5-14 membered heteroaryl substituted by one or more substituents;

R ₆ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, _C6-14 -membered aryl and 5-14-membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, _{C1-6 alkyl} , C2- ₆ alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkyl sulfide One or more substituents in the group, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl replace;

Alternatively, R ₆ and R ₄ are linked to the carbon atoms to which they are attached to form C _5-14 cycloalkyl or 5-14 membered heterocyclyl, the C _5-14 cycloalkyl and 5-14 membered heterocyclyl, depending on optionally further deuterium, halogen, amine, hydroxyl, cyano, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 deuterium Substituted alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 ring Substituted by one or more substituents in alkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl;

R ₇ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, _C6-14 -membered aryl and 5-14-membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, _{C1-6 alkyl} , C2- ₆ alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkyl sulfide One or more substituents in the group, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl replace;

R ₈ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, oximo, azide, mercapto, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl, 5-14-membered heteroaryl, -C(O)R _e or -P(O)R _e R _f , The oximo group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 deuterated alkyl group, C _1-6 haloalkyl group, C _1-6 hydroxyalkyl group, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5- 14-membered heteroaryl and -C(O)-, optionally further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, thio, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl substituted by one or more substituents;

R _a , R _b , R _c , R _d , _Re and R _f are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkane base, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 Heteroaryl, the amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1- 6} -hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl groups, optionally further deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, C _1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, One of C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl or more substituents;

n1~n4 are 0, 1, 2, 3, 4 or 5; and

m1 and m2 are 0, 1 or 2;

。 When R ₁ and R ₂ are phenyl, and R ₈ is halogen, cyano or C _1-6 haloalkyl, R ₄ is not hydroxyl, or R ₂ ' is not hydrogen, or R ₃ is not

.

In a preferred embodiment of the present invention, the R ₁ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne base, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy base, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, optionally further substituted by one or more R ₈ ;

R ₈ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, oximo, mercapto, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy , C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -C(O)R _e , -SR _e , -OR _e , -NR _e R _f , -C(O)NR _e R _f , -NR _e C(O)R _f , -OC(O)R _e R _f , -C(O)OR _e , -S(O) ₂ R _e , -S(O)R _e , -S(O) ₂ NR _e R _f , -S(O)NR _e R _f , -NR _e S(O) ₂ R _f , -NR _e S(O)R _f , -P(O)R _e R _f , the amine group, oximo group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 deuterated alkyl group, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 Member heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, Thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5- 14-membered heteroaryl is substituted with one or more substituents;

In a further preferred embodiment of the present invention, the R ₈ is selected from deuterium, halogen, cyano, azido, oximo, nitro, amino, C _1-3 alkyl, C _2-3 alkenyl, C _{2 -3} alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl, -C(O)R _e , -SR _e , -NR _e R _f , -C(O)NR _e R _f , -NR _e C(O)R _f or -P(O)R _e R _f , the amine group, oximo group, C _1-3 alkyl group, C _{2 -3} alkenyl, C _2-3 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl, optionally further deuterium, cyano, hydroxyl, halogen, pendant oxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _2-3 alkenyl, C _2-3 alkynyl, C ₃ -Substituted with one or more substituents in ₈ -cycloalkyl, 3-8-membered heterocyclyl, C _6-10 -membered aryl and 5-10-membered heteroaryl;

In a further preferred embodiment of the present invention, the R ₈ is selected from cyano, azido, nitro, oximo, amine, mercapto, methyl, ethynyl, cyclopropyl, oxetanyl, nitrogen Hetetanyl, tetrazolyl, -SR _e , -NR _e R _f , -C(O)NR _e R _f , -NR _e C(O)R _f or -P(O)R _e R _f , The methyl group, ethynyl group, cyclopropyl group, oxetanyl group, azetidinyl group and tetrazolyl group are optionally further substituted by cyano, hydroxyl, fluorine, chlorine, bromine, pendant oxy, methyl substituted with one or more substituents in the trifluoromethyl group;

、

、

、

、

、

、

、

、

、

、

、

、

或

； In a further preferred embodiment of the present invention, the R ₈ is selected from -CN, -P(O)(CH ₃ ) ₂ , -N ₃ , -NO ₂ , -SCF ₃ , -SCN, -NCH ₃ C(O) CH ₃ , -C(O)N(CH ₃ ) ₂ , -N(CN) ₂ , -CH(CN) ₂ , -C(CN) ₃ , -(C≡C)CN,

,

,

,

,

,

,

,

,

,

,

,

,

or

;

R _e and R _f are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Substituted with one or more substituents of haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl.

In a preferred embodiment of the present invention, the R ₁ is selected from C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl, optionally further substituted with one or more _R8 ;

In a further preferred embodiment of the present invention, the R ₁ is selected from phenyl or bicyclo[1.1.1]pentane, the phenyl and bicyclo[1.1.1]pentane, optionally further surrounded by one or more R ₈ replaced;

R ₈ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _{1 -3} haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl or -P(O)R _e R _f ;

Preferably cyano or -P(O)R _e R _f ;

R _e and R _f are each independently selected from hydrogen, deuterium, halogen, amine, hydroxy, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterium Substituted alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy;

Preferred are cyano, trifluoromethyl, methyl, ethyl or propyl.

In a further preferred embodiment of the present invention, R ₁ is selected from C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl, optionally further substituted with one or more _R8 ,

Preferably phenyl, the phenyl, optionally further substituted by one or more R ₈ ;

R ₈ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oximo, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterium Substituted alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 haloalkoxy, C _3-8 ring Alkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heteroaryl,

Preferred are cyclopropyl, nitro or oximo.

In a preferred embodiment of the present invention, the R ₂ is selected from C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, _C6-10 membered aryl and 5-10 membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, _C1-3 alkyl , C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C ₁ One or more of _-3 alkylthio, C _1-3 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl substituted by a substituent;

In a further preferred embodiment of the present invention, the R ₂ is selected from phenyl or bicyclo[1.1.1]pentane;

In a further preferred embodiment of the present invention, the R ₂ is selected from phenyl;

R ₂ ' is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy;

In a further preferred embodiment of the present invention, the R ₂ ' is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl.

In a preferred embodiment of the present invention, the R ₃ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -(CH ₂ ) _n1 R _a , -( CH ₂ ) _n1 NR _a OR _b , -(CH ₂ ) _n1 C(O)NR _a R _b , -(CH ₂ ) _n1 OC(O)R _a , -(CH ₂ ) _n1 NR _a C(O)R _b , -(CH ₂ ) _n1 S(O) _m1 R _a , -(CH ₂ ) _n1 S(O) _m1 NR _a R _b , -(CH ₂ ) _n1 NR _a S(O) _m1 R _b , -( CH ₂ ) _n1 NR _a R _b or -(CH ₂ ) _n1 NR _a (CH ₂ ) _n2 R _b , the amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, nitro , azido, mercapto, pendant oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 halogen Alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocycle substituted with one or more substituents in base, C _6-14 aryl and 5-14 membered heteroaryl;

R _a and R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Haloalkoxy, cyano-substituted C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkylene, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C ₆ -Substituted with one or more substituents in ₁₄ -membered aryl and 5-14-membered heteroaryl;

n1 and n2 are 0, 1, 2, 3, 4, or 5; and

m1 is 0, 1 or 2.

In a preferred embodiment of the present invention, the R ₃ is selected from -(CH ₂ ) _n1 R _a , -(CH ₂ ) _n1 NR _a OR _b , -(CH ₂ ) _n1 C(O)NR _a R _b , - (CH ₂ ) _n1 NR _a C(O)R _b , -(CH ₂ ) _n1 S(O) _m1 R _a , -(CH ₂ ) _n1 S(O) _m1 NR _a R _b , -(CH ₂ ) _n1 NR _a S(O) _m1 R _b , -(CH ₂ ) _n1 NR _a R _b or -(CH ₂ ) _n1 NR _a (CH ₂ ) _n2 R _b ;

In a further preferred embodiment of the present invention, the R ₃ is selected from -CH ₂ R _a , -C(O)NR _a R _b , -S(O) ₂ R _b , -CH ₂ NR _a Rb _d , -CH ₂ ) NR _a CH ₂ R _b or -CH ₂ NR _a (CH ₂ ) ₂ R _b ;

R _a and R _b are each independently selected from hydrogen, halogen, hydroxy, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or 4-8 nitrogen-containing heterocyclic group, the C _1-3 alkyl group, C _1-3 hydroxyalkyl group, C _1-3 haloalkyl group, C _1-3 alkoxy group and 4-8-membered nitrogen-containing heterocyclic group, depending on optionally further substituted with hydrogen, deuterium, hydroxyl, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C1-3 haloalkyl, _C1-3 alkoxy, halogen, cyano, cyano substituted by one or more substituents in C _1-3 alkyl or C _1-3 alkoxy-C _1-3 alkylene;

Preferred hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, 2-hydroxyisopropyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, (1R,5S)-3-oxa-8- Azabicyclo[3.2.1]octyl, the methyl, ethyl, methoxy, 2-hydroxyisopropyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, azetidine Alkyl, 2-oxa-6-azaspiro[3.3]heptyl, (1R,5S)-8-azabicyclo[3.2.1]octane base, (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octyl, optionally further substituted by hydrogen, deuterium, hydroxyl, methyl, ethyl, methoxy, difluoro Substituted with one or more substituents of methyl, trifluoromethyl, fluorine, chlorine, bromine, cyano, monofluoromethyl, cyanomethylene, and methoxymethylene;

n1 and n2 are 0, 1, 2, 3, 4, or 5; and

m1 is 0, 1 or 2.

In a preferred embodiment of the present invention, the R ₄ is selected from -OH, -(CH ₂ ) _n3 R _c , -(CH ₂ ) _n3 NR _c OR _d , -(CH ₂ ) _n3 C(O)NR _c R _d , -(CH ₂ ) _n3 NR _c C(O)R _d , -(CH ₂ ) _n3 S(O) _m2 R _c , -(CH ₂ ) _n3 S(O) _m2 NR _c R _d , -(CH ₂ ) _n3 NR _c S(O) _m2 R _d , -(CH ₂ ) _n3 NR _c R _d or -(CH ₂ ) _n3 NR _c (CH ₂ ) _n4 R _d

In a further preferred embodiment of the present invention, the R ₄ is selected from -OH, -(CH ₂ ) _n3 NR _c R _d or -(CH ₂ ) _n3 NR _c OR _d ;

R _c and R _d are each independently selected from hydrogen, halogen, hydroxy, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl or C _1-3 alkoxy, the C _{1-3 -3} alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl and C _1-3 alkoxy, optionally further replaced by hydrogen, deuterium, hydroxyl, C _1-3 alkyl, C _1- substituted by one or more substituents in ₃ hydroxyalkyl, C _1-3 haloalkyl or C _1-3 alkoxy;

n3 and n4 are 0, 1, 2, 3, 4, or 5; and

m2 is 0, 1 or 2.

In a preferred embodiment of the present invention, the R ₃ and R ₄ , and the carbon atoms where they are located are linked together to form a C _3-12 cycloalkyl group, a 3-12 membered heterocyclic group, a C _6-14 aryl group or a 5- 14-membered heteroaryl, the C _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl, if necessary, further deuterium, halogen, amino , hydroxyl, cyano, nitro, azido, mercapto, side oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated Alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkane substituted by one or more substituents among the group, 3-12-membered heterocyclic group, C _6-14 -membered aryl group and 5-14-membered heteroaryl group.

In a preferred embodiment of the present invention, R ₃ and R ₄ and the carbon atoms where they are located are linked together to form a 3-12-membered heterocyclic group, and the 3-12-membered heterocyclic group, if necessary, is further deuterium, halogen , amine, hydroxyl, cyano, nitro, azide, mercapto, pendant oxy, thio, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _{1- 3} -deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 haloalkoxy, C _3- Substituted by one or more substituents in ₈ -cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl

In a preferred embodiment of the present invention, R ₃ and R ₄ , and the carbon atoms where they are located are linked together to form the following heterocyclic group

、

、

、

或

，該雜環基，視需要地進一步被氘、氟、氯、溴、甲基、乙基、丙基、側氧基或環丙基中的一個或多個取代基所取代。

,

,

,

or

, the heterocyclic group, optionally further substituted by one or more substituents in deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, pendant oxy or cyclopropyl.

In a preferred embodiment of the present invention, the R ₆ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy;

In a further preferred embodiment of the present invention, the R ₆ is selected from methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In a preferred embodiment of the present invention, the R ₇ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy;

In a further preferred embodiment of the present invention, the R ₇ is selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

In a preferred embodiment of the present invention, the R ₄ and R ₆ are linked with the carbon atoms to which they are attached to form a C _5-14 cycloalkyl or a 5-14 membered heterocyclyl, the C _5-14 cycloalkyl and 5 -14-membered heterocyclyl, optionally further deuterium, halogen, amino, hydroxyl, cyano, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 deuterium Substituted alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 ring Substituted by one or more substituents in alkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl;

In a further preferred embodiment of the present invention, the R ₄ and R ₆ and the carbon atoms to which they are attached together form a 5-12-membered heterocyclic group, and the 5-12-membered heterocyclic group is optionally further substituted by deuterium, halogen , amino, hydroxyl, cyano, pendant oxy, thio, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _{1- 3} haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 haloalkoxy, C _3-8 cycloalkyl, 3-8 members substituted by one or more substituents in heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl;

、

、

、

、

或

，該雜環基，視需要地進一步被氘、氟、氯、溴、甲基、乙基、側氧基或環丙基中的一個或多個取代基所取代。 In a further preferred embodiment of the present invention, the R ₄ and R ₆ together with the carbon atoms to which they are attached form the following heterocyclic group:

,

,

,

,

or

, the heterocyclic group, optionally further substituted by one or more substituents in deuterium, fluorine, chlorine, bromine, methyl, ethyl, pendant oxy or cyclopropyl.

In a further preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is further shown in the general formula (III):

The R ₃ , R ₇ and R _d are as defined above.

In a further preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is further shown in the general formula (IV):

In a preferred embodiment of the present invention, the R ₂ ' is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy;

In a further preferred embodiment of the present invention, the R ₂ ' is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl;

In a preferred embodiment of the present invention, the R ₃ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -(CH ₂ ) _n1 R _a , -( CH ₂ ) _n1 NR _a OR _b , -(CH ₂ ) _n1 C(O)NR _a R _b , -(CH ₂ ) _n1 OC(O)R _a , -(CH ₂ ) _n1 NR _a C(O)R _b , -(CH ₂ ) _n1 S(O) _m1 R _a , -(CH ₂ ) _n1 S(O) _m1 NR _a R _b , -(CH ₂ ) _n1 NR _a S(O) _m1 R _b , -( CH ₂ ) _n1 NR _a R _b or -(CH ₂ ) _n1 NR _a (CH ₂ ) _n2 R _b , the amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, nitro , azido, mercapto, pendant oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 halogen Alkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocycle substituted with one or more substituents in base, C _6-14 aryl and 5-14 membered heteroaryl;

R _a and R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Haloalkoxy, cyano-substituted C _1-6 alkyl, C _1-6 alkoxy-C _1-6 alkylene, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C ₆ -Substituted with one or more substituents in ₁₄ -membered aryl and 5-14-membered heteroaryl;

n1 and n2 are 0, 1, 2, 3, 4, or 5; and

m1 is 0, 1 or 2.

In a preferred embodiment of the present invention, the R ₇ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy;

In a further preferred embodiment of the present invention, the R ₇ is selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

In a preferred embodiment of the present invention, the R ₈ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -SR _e , -OR _e , -NR _e R _f , -C(O)R _e , -C=NR _e , -C(O)NR _e R _f , -NR _e C(O)R _f , -OC(O)R _e R _f , -C ( O)OR _e , -S(O) ₂ R _e , -S(O)R _e , -S(O) ₂ NR _e R _f , -S(O)NR _e R _f , -NR _e S(O) ₂ R _f , -NR _e S(O)R _f , -P(O)R _e R _f , the amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, azide , nitro, mercapto, pendant oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkane group, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkoxyalkyl, C _{1-6 cyano-substituted alkyl, C 1-6 alkylthio} , C _1- Substituted by one or more substituents in ₆ -haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclic group, C _6-14 -membered aryl and 5-14-membered heteroaryl;

In a further preferred embodiment of the present invention, the R ₈ is selected from deuterium, halogen, cyano, azido, nitro, amino, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkyne base, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl, -SR _e , -NR _e R _f , -C(O)R _e , -C=NR _e , -C(O)NR _e R _f , -NR _e C(O)R _f or -P(O)R _e R _f , the amine group, C _1-3 alkyl group, C _{2 -3} alkenyl, C _2-3 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl, optionally further deuterium, cyano, hydroxyl, amine, halogen, pendant oxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkyl Oxyalkyl, cyano-substituted C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 substituted with one or more substituents in aryl and 5-10 membered heteroaryl;

In a further preferred embodiment of the present invention, the R ₈ is selected from cyano, azido, nitro, amine, mercapto, methyl, ethynyl, cyclopropyl, oxetanyl, azetidine Alkyl, pyrrolidinyl, tetrazolyl, 2-oxa-6-azaspiro[3.3]heptane, (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole, - SR _e , -NR _e R _f , -C(O)R _e , -C=NR _e , -C(O)NR _e R _f , -NR _e C(O)R _f or -P(O)R _e R _f , the methyl, ethynyl, cyclopropyl, oxetanyl, azetidinyl and tetrazolyl groups, optionally further cyano, hydroxy, amine, fluorine, chlorine, bromine , one of pendant oxy, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, methoxymethyl, hydroxymethyl, hydroxyisopropyl and cyanomethyl or replaced by multiple substituents;

In a further preferred embodiment of the present invention, the R ₈ is selected from cyano, azido, nitro, C _3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 1- 4-6 membered heterocyclic group containing nitrogen or oxygen atoms, 7-8 membered spiroheterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, 7-8 membered heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen fused heterocyclic group, optionally further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, C _1-3 alkyl, C _1-3 alkoxy , C _1-3 haloalkyl or one or more substituents in C _1-3 alkyl substituted by cyano group;

、

、

、

、

、

、

、

、

、

、

、

、

或

； In a further preferred embodiment of the present invention, the R ₈ is selected from -CN, -P(O)(CH ₃ ) ₂ , -N ₃ , -NO ₂ , -SCF ₃ , -SCN, -NCH ₃ C(O) CH ₃ , -C(O)N(CH ₃ ) ₂ , -N(CN) ₂ , -CH(CN) ₂ , -C(CN) ₃ , -(C≡C)CN,

,

,

,

,

,

,

,

,

,

,

,

,

or

;

R _e and R _f are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Substituted with one or more substituents of haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl.

In a further preferred embodiment of the present invention, the compound represented by the general formula (IV), its stereoisomer or its pharmaceutically acceptable salt, wherein,

R ₂ ' is selected from hydrogen;

R ₃ is selected from -(CH ₂ ) _n1 NR _a C(O)R _b or -(CH ₂ ) _n1 NR _a R _b ;

R _a or R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy;

Alternatively, R _a and R _b and adjacent nitrogen atoms form a 4-8 membered heterocyclic group containing 1-2 atoms selected from nitrogen or oxygen, optionally further substituted by halogen, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 haloalkyl or C _1-3 hydroxyalkyl substituted by one or more substituents;

R ₇ is selected from cyano or C _1-3 alkoxy;

R ₈ is selected from cyano, azido, nitro, C _3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4-6 membered containing 1 nitrogen or oxygen atom Heterocyclic group, 7-8-membered spiroheterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, 7-8-membered fused heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, and further if necessary by deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl or cyano substituted with one or more of the substituents in the C _1-3 alkyl substituted by the group.

In a further preferred embodiment of the present invention, the compound represented by the general formula (IV), its stereoisomer or its pharmaceutically acceptable salt, wherein,

R ₂ ' is selected from hydrogen;

R ₃ is selected from -(CH ₂ ) _n1 NR _a R _b ;

R _a or R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy; preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl or C _1-3 haloalkyl; more preferably methyl;

R ₇ is selected from cyano or C _1-3 alkoxy; more preferably methoxy;

R ₈ is selected from cyano, azido, oximo, nitro, C _3-6 cycloalkyl; more preferably oximo, nitro or cyclopropyl;

n1 is 1.

In a further preferred embodiment of the present invention, the compound, its stereoisomer or its pharmaceutically acceptable salt is further shown in general formula (V):

R ₂ ' is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy,

preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl; more preferably hydrogen;

R ₆ and R ₇ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterium Substituted alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy,

More preferably cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

R ₈ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, oximo, mercapto, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy , C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -SR _e , -OR _e , -NR _e R _f , -C(O )NR _e R _f , -NR _e C(O)R _f , -OC(O)R _e R _f , -C(O)OR _e , -S(O) ₂ R _e , -S(O)R _e , -S(O) ₂ NR _e R _f , -S(O)NR _e R _f , -NR _e S(O) ₂ R _f , -NR _e S(O)R _f , -P(O)R _e R _f , the amine group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 deuterated alkyl group, C _1-6 haloalkyl group, C _1-6 hydroxy group Alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1- 6} alkoxyalkyl, cyano-substituted C _1-6 alkyl, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl , C _6-14 aryl and 5-14 membered heteroaryl substituted with one or more substituents,

Preferably cyano, azido, oximo, nitro, C _3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4-membered heteroaryl containing 1 nitrogen or oxygen atom 6-membered heterocyclic group, 7-8-membered spiro heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, 7-8-membered fused heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen; as required further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl Or substituted by one or more substituents in C _1-3 alkyl substituted by cyano group;

R _a and R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 substituted by one or more substituents in haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

Alternatively, R _a and R _b and adjacent nitrogen atoms form a 4-10-membered heterocyclic group containing 1-3 atoms selected from nitrogen or oxygen, optionally further deuterium, halogen, amino, hydroxyl, cyano , nitro, azide, mercapto, pendant oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 substituted with one or more substituents in membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

R _e and R _f are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 substituted by one or more substituents in haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl;

n1 and n2 are 0, 1, 2, 3, 4, or 5; and

m1 is 0, 1 or 2.

In a preferred embodiment of the present invention, the R ₆ and R ₇ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _{2 -3} alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy;

In a further preferred embodiment of the present invention, the R ₆ and R ₇ are selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

In a preferred embodiment of the present invention, the R ₈ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -SR _e , -OR _e , -NR _e R _f , -C(O)R _e , -C=NR _e , -C(O)NR _e R _f , -NR _e C(O)R _f , -OC(O)R _e R _f , -C ( O)OR _e , -S(O) ₂ R _e , -S(O)R _e , -S(O) ₂ NR _e R _f , -S(O)NR _e R _f , -NR _e S(O) ₂ R _f , -NR _e S(O)R _f , -P(O)R _e R _f , the amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, azide , nitro, mercapto, pendant oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkane group, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkoxyalkyl, C _{1-6 cyano-substituted alkyl, C 1-6 alkylthio} , C _1- Substituted by one or more substituents in ₆ -haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclic group, C _6-14 -membered aryl and 5-14-membered heteroaryl;

In a further preferred embodiment of the present invention, the R ₈ is selected from deuterium, halogen, cyano, azido, nitro, amino, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkyne base, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl, -SR _e , -NR _e R _f , -C(O)R _e , -C=NR _e , -C(O)NR _e R _f , -NR _e C(O)R _f or -P(O)R _e R _f , the amine group, C _1-3 alkyl group, C _{2 -3} alkenyl, C _2-3 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl, optionally further deuterium, cyano, hydroxyl, amine, halogen, pendant oxy, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkyl Oxyalkyl, cyano-substituted C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 substituted with one or more substituents in aryl and 5-10 membered heteroaryl;

In a further preferred embodiment of the present invention, the R ₈ is selected from cyano, azido, nitro, amine, mercapto, methyl, ethynyl, cyclopropyl, oxetanyl, azetidine Alkyl, pyrrolidinyl, tetrazolyl, 2-oxa-6-azaspiro[3.3]heptane, (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole, - SR _e , -NR _e R _f , -C(O)R _e , -C=NR _e , -C(O)NR _e R _f , -NR _e C(O)R _f or -P(O)R _e R _f , the methyl, ethynyl, cyclopropyl, oxetanyl, azetidinyl and tetrazolyl groups, optionally further cyano, hydroxy, amine, fluorine, chlorine, bromine , one of pendant oxy, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, methoxymethyl, hydroxymethyl, hydroxyisopropyl and cyanomethyl or replaced by multiple substituents;

In a further preferred embodiment of the present invention, the R ₈ is selected from cyano, azido, nitro, C _3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 1- 4-6 membered heterocyclic group containing nitrogen or oxygen atoms, 7-8 membered spiroheterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, 7-8 membered heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen fused heterocyclic group, optionally further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, C _1-3 alkyl, C _1-3 alkoxy , C _1-3 haloalkyl or one or more substituents in C _1-3 alkyl substituted by cyano group;

、

、

、

、

、

、

、

、

、

、

、

、

或

； In a further preferred embodiment of the present invention, the R ₈ is selected from -CN, -P(O)(CH ₃ ) ₂ , -N ₃ , -NO ₂ , -SCF ₃ , -SCN, -NCH ₃ C(O) CH ₃ , -C(O)N(CH ₃ ) ₂ , -N(CN) ₂ , -CH(CN) ₂ , -C(CN) ₃ , -(C≡C)CN,

,

,

,

,

,

,

,

,

,

,

,

,

or

;

R _e and R _f are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Substituted with one or more substituents of haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl.

In a further preferred embodiment of the present invention, the compound represented by the general formula (V), its stereoisomer or its pharmaceutically acceptable salt, wherein,

R ₂ ' is selected from hydrogen;

R _a or R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy; preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl or C _1-3 haloalkyl; more preferably methyl;

R ₆ and R ₇ are each independently selected from cyano or C _1-3 alkoxy; more preferably methoxy;

R ₈ is selected from cyano, azido, oximo, nitro, C _3-6 cycloalkyl; more preferably oximo, nitro or cyclopropyl.

The present invention further provides a compound represented by the intermediate general formula (M), its stereoisomer or its pharmaceutically acceptable salt:

_R is selected from -C(O)R _g ;

R _g is selected from hydroxyl, C _1-3 alkoxy or -NR _a R _b ;

R ₄ , R ₆ , R ₇ , R ₈ , _Ra or R _b are as previously described.

The present invention further provides a method for preparing a compound of general formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

The general formula (M-2) is obtained by the reaction of the general formula (M-1), the general formula (M-3) is obtained by the reaction of the general formula (M-2), and the general formula (VI) is obtained by the reduction of the general formula (M-3);

Pg is selected from C _1-3 alkoxy;

R ₄ , R ₆ , R ₇ , R ₈ , _Ra or R _b are as previously described.

In one embodiment of the present invention, in the general formulae (M-1), (M-2) and (M-3), R ₄ is preferably a hydroxyl group.

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients Form.

On the other hand, the object of the present invention is to provide a compound comprising the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment and/or prevention of ATP dependence. The use of the medicament for the RNA helicase-related diseases, especially the use in the medicament for the treatment and/or prevention of the eukaryotic initiation factor 4A (eIF4A) inhibitor-related diseases.

On the other hand, the object of the present invention is to provide a compound comprising the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment and/or prevention of cancer, Use in medicine for myelodysplastic syndrome, Alzheimer's disease, Parkinson's disease, X-chromosome fragile syndrome and autism and other related diseases.

The present invention also relates to a method for treating and/or preventing related diseases such as cancer, myelodysplastic syndrome, Alzheimer's disease, Parkinson's disease, X-chromosome fragile disorder and autism. On the other hand, the object of the present invention is to provide the compound of general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the treatment and/or prevention of cancer, bone marrow Use in related diseases such as dysplasia, Alzheimer's disease, Parkinson's disease, X-chromosome fragile disorder and autism.

In the above technical solution, the cancer-related disease is selected from hematological tumors, preferably colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma , lung cancer, melanoma, myeloma, pancreatic cancer, renal cell cancer, cervical cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.

Detailed description of the invention

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms An alkyl group of carbon atoms, further preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4 -Dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-di Methylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2 -Ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl- 2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and Its various branched chain isomers, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, th Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl base, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2 -Methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted, when substituted, the substituent Can be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane Sulfanyl, pendant oxy, carboxyl or carboxylate groups, preferred in the present invention are methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and Hydroxy substituted alkyl.

The term "(alkylene) alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means -CH ₂ -, "ethylidene" means -(CH ₂ ) ₂ -, "extend""Propyl" refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ - and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 20 carbon atoms. 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term "spirocycloalkyl" refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated π electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl, double-spiro-cycloalkyl or poly-spiro-cycloalkyl, preferably mono-spirocycloalkyl Cycloalkyl and double spirocycloalkyl. More preferably it is 3-member/6-member, 3-member/5-member, 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

和

等；

and

Wait;

Also included are spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, non-limiting examples include:

和

等。

and

Wait.

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

和

等。

and

Wait.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings has complete Conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl, etc. Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, C(O) or a heteroatom of S(O) _m (where m is an integer from 0 to 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms; most preferably contains 3 to 8 ring atoms; and further preferably contains 1 to 3 nitrogen atoms. -8-membered heterocyclic group, optionally substituted by 1-2 oxygen atoms, sulfur atoms, pendant oxygen groups, including nitrogen-containing monocyclic heterocyclic group, nitrogen-containing spiro heterocyclic group or nitrogen-containing fused heterocyclic group.

Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyran base, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azetyl, 1 ,4-diazacycloheptyl, pyranyl or tetrahydrothiopyran dioxide group, etc.; preferably oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydro pyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl dioxide, pyrrolidinyl, morpholine base, piperidinyl, piperazinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azetyl, 1,4-diazepanyl and piperazinyl; more preferably piperidinyl, piperazinyl, Pyrrolidinyl, morpholinyl, oxetanyl or azetidinyl. Polycyclic heterocyclic groups include spiro, condensed and bridged heterocyclic groups; the spiro, condensed and bridged heterocyclic groups involved may be connected to other groups through single bonds as required, or by means of single bonds. Additional cycloalkyls, heterocyclyls, aryls, and heteroaryls are further cyclolinked by any two or more atoms on the ring.

The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiro-heterocyclyl . More preferably 3-member/5-member, 3-member/6-member, 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

等。

Wait.

The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), the remaining rings Atom is carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclyl groups include:

和

等。

and

Wait.

The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group of any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a complete common The pi-electron system of the yoke, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

和

等。

and

Wait.

The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

和

等。

and

Wait.

Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, e.g. Phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered heteroaryl Alkyl, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heteroalkyl, wherein the heterocyclic group contains 1-3 nitrogen atoms, oxygen atoms, A heterocyclic group of sulfur atom; or a three-membered nitrogen-containing fused ring containing a benzene ring.

Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

和

等。

and

Wait.

Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 members, more preferably 5 members Or 6-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. , preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl or thiazolyl; more preferably tetrazolyl, pyridyl, oxadiazole pyrazolyl, pyrrolyl, thiazolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:

和

等。

and

Wait.

Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, alkoxy may be is optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero Cycloalkylthio, carboxyl or carboxylate.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.

"Alkenyl" refers to an alkenyl group, also known as an alkenyl group, wherein the alkenyl group may be further substituted with other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino , halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio , carboxyl or carboxylate.

"Alkynyl" refers to (CH≡C-), wherein the alkynyl group may be further substituted with other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen , mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio, heterocycloalkylthio, carboxyl or carboxylate.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carbonyl" or "pendant oxy" refers to -C(O)-.

"Carboxyl" refers to -C(O)OH.

"THF" refers to tetrahydrofuran.

"Ethyl acetate" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPEA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"TEA" refers to triethylamine.

"MeCN" means acetonitrile.

"DMA" refers to N,N-dimethylacetamide.

" _Et2O " refers to diethyl ether.

"DCM" refers to dichloromethane.

"DMAP" refers to 4-dimethylaminopyridine.

"DCC" refers to dicyclohexylcarbodiimide.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodobutadiimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd2(dba _{)3 "} refers to tris(dibenzylideneacetone)dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"KHMDS" means potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyl lithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

"Amino acid residue" refers to a natural amino acid residue or a non-natural amino acid residue.

"Natural amino acid" refers to 20 conventional amino acids, namely alanine (A), cysteine (C), aspartic acid (D), glutamic acid (E), phenylalanine (F) ), Glycine (G), Histidine (H), Isoleucine (I), Lysine (K), Leucine (L), Methionine (M), Asparagine (N), Proline (P), Glutamine (Q), Arginine (R), Serine (S), Threonine (T), Valine (V), Tryptophan (W) and tyrosine (Y).

"Non-natural amino acid" refers to amino acids that are not naturally encoded or found in the genetic code of any organism, which may be, for example, pure synthetic compounds.

"Thioamino acid" refers to an amino acid in which the oxygen atom on the amino acid is replaced by a sulfur atom, and the oxygen atom can be an oxygen atom in a carbonyl group (C=O) or a hydroxyl group (OH).

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" etc. all express the same Meaning, that means X can be any one or more of A, B, and C.

The hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by deuterium atom.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those of ordinary skill in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amine groups or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.

The present invention is further described below in conjunction with the examples, but these examples do not limit the scope of the present invention.

Example

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was four Methylsilane (TMS).

An Agilent 1200 Infinity Series mass spectrometer was used for LC-MS measurements. The HPLC measurement was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini _C18 150×4.6mm column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications used for TLC are 0.15mm~0.20mm, and the specifications used for TLC separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

Example 1

4-((5aS,6S,7S,8R,8aR)-7-((dimethylamino)methyl)-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6 Preparation of ,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

The first step: the preparation of 4-(benzyloxy)-2,6-dichloropyridine

Under an ice-water bath, NaH (7.59 g, 60 wt%, 190 mmol) was added in portions to the DMF solution (300 mL) of 2,4,6-trichloropyridine (30.0 g, 165 mmol). After stirring for 15 minutes, benzyl alcohol (17.9 mL, 173 mmol) was added dropwise, and the addition was complete, followed by stirring under an ice-water bath for 1 hour. The reaction solution was poured into ice water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine for several times, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and separated by column chromatography. The title compound 4-(benzyloxy)-2,6-dichloropyridine (30.4 g, 73%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.11 (s, 2H), 6.86 (s, 2H), 7.37-7.42 (m, 5H);

MS m/z(ESI): 254.0[M+H] ⁺ .

The second step: the preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine

To a solution of 4-(benzyloxy)-2,6-dichloropyridine (27.0 g, 106 mmol) in toluene (400 mL) was added a methanol solution of sodium methoxide (30 wt%, 36.4 g, 202 mmol), and then at 60°C Stir for 5 hours. The reaction was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound, 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.6 g, 74%), was isolated.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.81(s, 3H), 5.20(s, 2H), 6.46(d, J =1.9Hz, 1H), 6.81(d, J =1.9Hz, 1H), 7.32-7.47(m,5H);

MS m/z(ESI): 250.2[M+H] ⁺ .

The third step: preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol

Under a dry ice-acetone bath, to a solution of 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.5 g, 78.1 mmol) in THF (200 mL), a solution of n-BuLi in n-hexane was added dropwise (41.0 mL, 2.4 M, 97.6 mmol), stirred at this temperature for 30 minutes, then added acetaldehyde (6.88 g, 156 mmol) dropwise to the reaction system, the dropwise addition was completed, continued stirring for 10 minutes, and added saturated aqueous ammonium chloride solution The reaction was quenched, the reaction solution was extracted several times with ethyl acetate, the organic phases were combined, washed with saturated brine, and the organic phase was separated for Dry over anhydrous sodium sulfate, filter and concentrate the organic solvent under reduced pressure, and separate the title compound by column chromatography to obtain the title compound 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane- 1-ol (16 g, 70%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 1.39(d, J =6.6Hz, 3H), 3.84(s, 3H), 4.60(d, J =6.6Hz, 1H), 5.09-5.14(m, 1H) ), 5.25(s, 2H), 6.93(s, 1H), 7.32-7.49(m, 5H);

MS m/z(ESI): 294.1[M+H] ⁺ .

The fourth step: the preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-one

To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol (16.0 g, 54.6 mmol) in dichloromethane (320 mL) was divided DMP (30.1 g, 71.0 mmol) was added in batches and the addition was complete and stirring was continued at room temperature for 2 hours. Then, a saturated aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution were sequentially added, followed by stirring for an additional 15 minutes. The organic phase was separated and the aqueous phase was extracted twice more with dichloromethane. After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound was separated by column chromatography to obtain the title compound 1-(4-(benzyloxy)-6-chloro-2-methoxypyridine-3). -yl)ethan-1-one (8.10 g, 51%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 2.37(s,3H), 3.84(s,3H), 4.60(d, J =6.1Hz,1H), 5.28(s,2H), 7.10(s,1H) ),7.32-7.47(m,5H);

MS m/z(ESI): 292.2[M+H] ⁺ .

The fifth step: the preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) ethane-1-one

To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one (4.67 g, 16.0 mmol) in ethyl acetate (120 mL), Add Pd/C (140mg, 10wt%), under hydrogen atmosphere, normal temperature and pressure, stir for 3 hours, filter out insolubles with diatomaceous earth, the filtrate is concentrated under reduced pressure and then column chromatography The title compound 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.30 g, 71%) was isolated.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 2.50(s, 3H), 3.90(s, 3H), 6.70(s, 1H), 13.00(s, 1H);

MS m/z(ESI): 202.2[M+H] ⁺ .

The sixth step: (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) prop-2-en-1-one preparation

To 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.00 g, 9.92 mmol), 4-bromobenzaldehyde (1.65 g, 8.93 mmol) To the DMF solution (31 mL), a MeOH solution of MeONa (5.36 g, 30 wt%, 29.8 mmol) was added, vigorously stirred at 50 °C for 30 minutes, cooled, and then poured into dilute hydrochloric acid (0.3 M, 200 mL) under an ice-water bath, The precipitated solid was collected by filtration and dried, and then purified by slurrying with EtOAc/n-heptane mixed solvent (mixed solvent ratio 1:10) to obtain the title compound (E)-3-(4-bromophenyl)-1-(6- Chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one (1.87 g, 57%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.80(s, 3H), 6.60(s, 1H), 7.20(d, J =16.0Hz, 1H), 7.40(d, J =16.0Hz, 1H), 7.56-7.73(m,4H);

MS m/z(ESI): 368.0[M+H] ⁺ .

The seventh step: preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one

Under a water bath, add (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one ( 1.40 g, 3.80 mmol) of a mixed solution of EtOH (27 mL) and DCM (6.8 mL) were successively added dropwise with NaOH aqueous solution (3.36 g, 10 wt%, 8.39 mmol) and H ₂ O ₂ aqueous solution (3.03 g, 30 wt %, 26.7 mmol), and then stirred under a water bath for 1 hour. Saturated aqueous ammonium chloride solution was added, extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain crude 2-(4-bromophenyl)-7-chloro-3-hydroxy-5 -Methoxy-4H-pyrano[3,2-c]pyridin-4-one (700 mg) was used directly in the next step without further purification.

MS m/z(ESI): 381.9[M+H] ⁺ .

The eighth step: preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one

To 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (crude from previous step, 700 mg) DME solution (30 mL) was added with methanol solution of sodium methoxide (15 mL, 30 wt%), then stirred at 80°C for 1 hour, cooled, poured into ice water, and adjusted pH to weakly acidic with hydrochloric acid (6M), The precipitated solid was filtered, the filter cake was washed with water, the solid compound was collected and dried, and separated and purified by column chromatography to obtain the title compound 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H- Pyrano[3,2-c]pyridin-4-one (180 mg, two-step yield: 13%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.95(s, 3H), 4.00(s, 3H), 6.60(s, 1H), 7.75(d, J =9.6Hz, 2H), 8.10(d, J =8.0Hz,2H),9.65(br s,1H);

MS m/z(ESI): 378.0[M+H] ⁺ .

Step 9: Racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl- Preparation of 2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate

2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (160 mg, 0.424 mmol) and cinnamic acid Methyl ester (686 mg, 4.24 mmol) was dissolved in chloroform (7 mL) and trifluoroethanol (5.6 mL) at 0°C with vigorous stirring under 450 W UV light irradiation for 5 hours. Concentrate the organic solvent under reduced pressure to remove excess methyl cinnamate by column chromatography to obtain the crude product racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8 -Dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate (250 mg), which was directly used in the next reaction.

MS m/z(ESI): 540.1[M+H] ⁺ .

Step 10: Racemic-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate

to rac-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3, 4,5-Tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate (250 mg, crude, about 0.424 mmol) in methanol (8 mL) was added dropwise methanol A methanol solution of sodium (30 wt%, 252 mg, 1.40 mmol) was then stirred at 60° C. for 45 minutes, the reaction was cooled to room temperature, the organic solvent was concentrated under reduced pressure, and the residue was layered with dichloromethane and saturated aqueous ammonium chloride solution, The organic phase was separated and dried with anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure to obtain the crude product racemic-methyl(5aR,6S,7R,8aR)-5a- (4-Bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4 ,5]furo[3,2-c]pyridine-7-carboxylate (250 mg) was used directly in the next reaction.

MS m/z(ESI): 540.1[M+H] ⁺ .

Step 11: Racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6- Preparation of phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

The crude product of the previous step was rac-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene yl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate (250 mg, about 0.424 mmol) was dissolved in MeOH ( ₈ mL), then NaBH4 (81 mg, 2.12 mmol) was added portionwise and stirred at room temperature for 75 minutes. Then MeOH was concentrated under reduced pressure, the residue was layered with dichloromethane and water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and the title compound was separated by column chromatography to obtain the title compound racemic-(5aR,6S ,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro -8aH-Cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol (70 mg, three steps yield: 32%).

MS m/z(ESI): 514.1[M+H] ⁺ .

Step 12: Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carbaldehyde

Ice water bath, to racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl -5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol (70 mg, 0.136 mmol) in dichloro To the methane solution (10 mL), DMP (60 mg, 0.143 mmol) was added, followed by stirring at this temperature for 2 hours. Add a mixed aqueous solution of sodium thiosulfate and sodium bicarbonate, stir for 10 minutes, extract twice with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate the organic solvent under reduced pressure, and separate by column chromatography to obtain the title compound Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7 ,8,8a-Tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carbaldehyde (58 mg, 83%).

MS m/z(ESI): 512.1[M+H] ⁺ .

The Thirteenth Step: Racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethyl Preparation of oxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7 ,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carbaldehyde (58 mg, 0.114 mmol), dimethylamine hydrochloride (9.2 mg, 0.228 mmol) in DCE and stirred for 30 minutes, then sodium borohydride acetate (48 mg, 0.228 mmol) was added and stirred at room temperature overnight. use two Diluted with methyl chloride, washed with saturated aqueous sodium bicarbonate solution and saturated brine successively, separated the organic phase and dried with anhydrous sodium sulfate, filtered and concentrated the organic solvent under reduced pressure, and separated by column chromatography to obtain the title compound racemic-(5aR, 6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6, 7,8-Tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol (45 mg, 73%).

MS m/z(ESI): 541.1[M+H] ⁺ .

Step Fourteen: Racemic-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1,3- Preparation of dimethoxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopentadieno[4,5]furo[3,2-c]pyridin-8-one

Under ice-water bath, to racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy yl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol (45mg, DMP (70 mg, 0.166 mmol) was added dropwise to a solution of 0.083 mmol) in DCM (2 mL), followed by stirring at room temperature overnight. Add a mixed aqueous solution of sodium thiosulfate and sodium bicarbonate, stir for 10 minutes, extract twice with dichloromethane, combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate the organic solvent under reduced pressure, prepare thin layer separation and purification to obtain the title Compound Racemic-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy -6-Phenyl-5a,6,7,8a-tetrahydro-8H-cyclopentadieno[4,5]furo[3,2-c]pyridin-8-one (33 mg, 74%).

MS m/z(ESI): 539.2[M+H] ⁺ .

Step 15: Racemic-4-((5aR,6S,7S,8aR)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8- Preparation of carbonyl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

Racemic-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy- 6-Phenyl-5a,6,7,8a-tetrahydro-8H-cyclopentadieno[4,5]furo[3,2-c]pyridin-8-one (33 mg, 0.061 mmol), Zn (CN) ₂ (30 mg, 0.26 mmol), zinc powder (6 mg, 0.083 mmol) were mixed with DMF (1 mL), water (0.1 mL), deoxygenated with nitrogen for 5 minutes, and then Pd ₂ (dba) ₃ (7.5 mg) was added successively , 0.0082 mmol) and dppf (9 mg, 0.017 mmol), heated and stirred at 120° C. for 90 minutes under microwave conditions. The reaction solution was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, the filtrate was concentrated under reduced pressure and purified by preparative thin layer to obtain the title compound racemic-4-((5aR,6S,7S,8aR)-7-((bis Methylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4 ,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (20 mg, 68%).

MS(ESI) m/z: 486.2[M+H] ⁺ .

The sixteenth step: 4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethyl Oxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile preparation

Racemic-4-((5aR,6S,7S,8aR)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl at room temperature -6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (20 mg, 0.041 mmol), hydroxylamine hydrochloride (8.6 mg, 0.123 mmol) was mixed in To DCE (2 mL) was added a drop of acetic acid and stirred for 30 minutes, then sodium borohydride acetate (17 mg, 0.082 mmol) was added and stirred for an additional 5 hours. Saturated aqueous sodium bicarbonate solution and DCM were added, the organic phase was separated and dried over anhydrous sodium sulfate, after filtration, the organic solvent was concentrated under reduced pressure, and rac-4-((5aR,6S,7S,8R,8aS) was obtained by preparative thin layer separation. -7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro- 5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (racemate of Example 1), followed by chiral column resolution to give optical Pure title compound 4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy -6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (3.3 mg ).

MS(ESI) m/z: 503.2[M+H] ⁺ .

Example 2

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxylamino)-1,3-dimethoxy-N,N-dimethyl Preparation of -6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxylamino)-1,3-dimethoxy-N,N-dimethyl -6-Phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide example 1.

MS m/z(ESI): 517.2[M+H] ⁺ .

Example 3

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-N-methyl-6- Preparation of phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-N-methyl-6- Refer to Example 1 for the preparation method of phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide.

MS m/z(ESI): 503.2[M+H] ⁺ .

Example 4

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-7-((methylamino)methyl)-6- Preparation of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-7-((methylamino)methyl)-6- Reference Example for the preparation method of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile 1.

MS m/z(ESI): 489.2[M+H] ⁺ .

Example 5

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1-methyl Preparation of oxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1-methyl Refer to the preparation method of oxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile Example 1.

MS m/z(ESI): 498.2[M+H] ⁺ .

Example 6

4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6- Preparation of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6- Reference Example for the preparation method of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile 1.

MS m/z(ESI): 531.2[M+H] ⁺ .

Example 7

4-((5aR,6S,7S,8R,8aS)-8a-Hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-7-(piperidin-1-ylmethyl yl)-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8a-Hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-7-(piperidin-1-ylmethyl Base)-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile The preparation method of benzonitrile refers to the example 1.

MS m/z(ESI): 543.2[M+H] ⁺ .

Example 8

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxylamino)-1,3-dimethoxy-7-(4-morpholinylmethyl)-6-benzene Preparation of yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxylamino)-1,3-dimethoxy-7-(4-morpholinylmethyl)-6-benzene Reference Example 1 .

MS m/z(ESI): 545.2[M+H] ⁺ .

Example 9

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-7-((4-methylpiperazin-1-yl) Methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile preparation

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-7-((4-methylpiperazin-1-yl) Methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile Refer to Example 1 for the preparation method.

MS m/z(ESI): 558.3[M+H] ⁺ .

Example 10

4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8a-hydroxy-8-(hydroxylamino)- 1,3-Dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-5a- Preparation of benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8a-hydroxy-8-(hydroxylamino)- 1,3-Dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-5a- For the preparation method of benzonitrile, refer to Example 1.

MS m/z(ESI): 565.2[M+H] ⁺ .

Example 11

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-7-(((2-hydroxy-2-methylpropyl)(methyl)amino) Methyl)-8-(Hydroxyamino)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3, Preparation of 2-c]pyridine-3-carbonitrile

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-7-(((2-hydroxy-2-methylpropyl)(methyl)amino) Methyl)-8-(Hydroxyamino)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3, Refer to Example 1 for the preparation method of 2-c]pyridine-3-carbonitrile.

MS m/z(ESI): 556.3[M+H] ⁺ .

Example 12

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxylamino)-1-methoxy-7-(((2-methoxy Ethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c Preparation of ]pyridine-3-carbonitrile

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxylamino)-1-methoxy-7-(((2-methoxy Ethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c ] The preparation method of pyridine-3-carbonitrile refers to Example 1.

MS m/z(ESI): 542.2[M+H] ⁺ .

Example 13

(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1-methoxy-6-phenyl-7-(pyrrolidine Preparation of -1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile

(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1-methoxy-6-phenyl-7-(pyrrolidine Preparation method of -1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile Refer to Example 1.

MS m/z(ESI): 574.2[M+H] ⁺ .

Example 14

4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-8a-hydroxy-8-( Hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c] Preparation of pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-8a-hydroxy-8-( Hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c] Refer to Example 1 for the preparation method of pyridin-5a-yl)benzonitrile.

MS m/z(ESI): 557.2[M+H] ⁺ .

Example 15

4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-8a-hydroxy -8-(Hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3, Preparation of 2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-8a-hydroxy -8-(Hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3, Refer to Example 1 for the preparation method of 2-c]pyridin-5a-yl)benzonitrile.

MS m/z(ESI): 569.3[M+H] ⁺ .

Example 16

4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl )-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5] Preparation of furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl )-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5] Refer to Example 1 for the preparation method of furo[3,2-c]pyridin-5a-yl)benzonitrile.

MS m/z(ESI): 571.3[M+H] ⁺ .

Example 17

4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino) Preparation of -6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino) Preparation method of -6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile Refer to Example 1.

MS m/z(ESI): 517.2[M+H] ⁺ .

Example 18

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-N,N- Preparation of dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-N,N- Preparation of dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide Refer to Example 1 for the method.

MS m/z(ESI): 531.2[M+H] ⁺ .

Example 19

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-N-methyl Preparation of -6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-N-methyl -6-Phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide example 1.

MS m/z(ESI): 517.2[M+H] ⁺ .

Example 20

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-((methylamino)methyl) Preparation of -6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-((methylamino)methyl) Preparation method of -6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile Refer to Example 1.

MS m/z(ESI): 503.2[M+H] ⁺ .

Example 21

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1-methoxy-8-(methyl) oxyamino)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile preparation

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1-methoxy-8-(methyl) oxyamino)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile For the preparation method, refer to Example 1.

MS m/z(ESI): 512.2[M+H] ⁺ .

Example 22

4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino) Preparation of -6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino) Preparation method of -6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile Refer to Example 1.

MS m/z(ESI): 545.3[M+H] ⁺ .

Example 23

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-7-(piperidine-1 -ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-7-(piperidine-1 -ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile preparation method Refer to Example 1.

MS m/z(ESI): 557.3[M+H] ⁺ .

Example 24

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-(4-morpholinylmethyl)- Preparation of 6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-(4-morpholinylmethyl)- Refer to the preparation method of 6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile Example 1.

MS m/z(ESI): 559.3[M+H] ⁺ .

Example 25

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-((4-methylpiperazine-1 -yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl) Preparation of benzonitrile

4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-((4-methylpiperazine-1 -yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl) The preparation method of benzonitrile refers to Example 1.

MS m/z(ESI): 572.3[M+H] ⁺ .

Example 26

4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8a-hydroxy-1,3-dimethoxy yl-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine Preparation of -5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8a-hydroxy-1,3-dimethoxy yl-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine The preparation method of -5a-yl) benzonitrile refers to Example 1.

MS m/z(ESI): 579.2[M+H] ⁺ .

Example 27

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-7-(((2-hydroxy-2-methylpropyl)(methyl)amino) Methyl)-1-methoxy-8-(methoxyamino)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo Preparation of [3,2-c]pyridine-3-carbonitrile

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-7-(((2-hydroxy-2-methylpropyl)(methyl)amino) Methyl)-1-methoxy-8-(methoxyamino)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo For the preparation method of [3,2-c]pyridine-3-carbonitrile, refer to Example 1.

MS m/z(ESI): 570.3[M+H] ⁺ .

Example 28

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1-methoxy-8-(methoxyamino)-7-(((2- Methoxyethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3, Preparation of 2-c]pyridine-3-carbonitrile

(5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1-methoxy-8-(methoxyamino)-7-(((2- Methoxyethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3, Refer to Example 1 for the preparation method of 2-c]pyridine-3-carbonitrile.

MS m/z(ESI): 556.3[M+H] ⁺ .

Example 29

(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1-methoxy-8-(methoxyamino)-6-phenyl-7- (Pyrrolidin-1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile preparation

(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1-methoxy-8-(methoxyamino)-6-phenyl-7- (Pyrrolidin-1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile Refer to Example 1 for the preparation method.

MS m/z(ESI): 588.2[M+H] ⁺ .

Example 30

4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-8a-hydroxy-1,3 -Dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2 Preparation of -c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-8a-hydroxy-1,3 -Dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2 The preparation method of -c]pyridin-5a-yl)benzonitrile refers to Example 1.

MS m/z(ESI): 571.3[M+H] ⁺ .

Example 31

4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-8a-hydroxy -1,3-Dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo Preparation of [3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-8a-hydroxy -1,3-Dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo Refer to Example 1 for the preparation method of [3,2-c]pyridin-5a-yl)benzonitrile.

MS m/z(ESI): 583.3[M+H] ⁺ .

Example 32

4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl )-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4 Preparation of ,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl )-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4 ,5] Furo[3,2-c]pyridin-5a-yl)benzonitrile The preparation method of benzonitrile refers to Example 1.

MS m/z(ESI): 585.3[M+H] ⁺ .

Example 33

4-((8aR,9S,10S,11R,11aS)-9-((dimethylamino)methyl)-11a-hydroxy-3-methoxy-10-phenyl-6,7,8a,9 ,10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzene Preparation of formonitrile

4-((8aR,9S,10S,11R,11aS)-9-((dimethylamino)methyl)-11a-hydroxy-3-methoxy-10-phenyl-6,7,8a,9 ,10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzene Refer to Example 1 for the preparation method of formonitrile.

MS m/z(ESI): 500.2[M+H] ⁺ .

Example 34

(8aR,9R,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-3-methoxy-N,N-dimethyl-10-phenyl-6,7, 8a,10,11,11a-hexahydro-9H-1,11-oxolano[7,8][1,4]dioxino[5,6-b]pyridine-9- Preparation of formamide

(8aR,9R,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-3-methoxy-N,N-dimethyl-10-phenyl-6,7, 8a,10,11,11a-hexahydro-9H-1,11-oxolano[7,8][1,4]dioxino[5,6-b]pyridine-9- For the preparation method of formamide, refer to Example 1.

MS m/z(ESI): 514.2[M+H] ⁺ .

Example 35

(8aR,9R,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-3-methoxy-N-methyl-10-phenyl-6,7,8a,10 ,11,11a-Hexahydro-9H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridine-9-carboxamide preparation

(8aR,9R,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-3-methoxy-N-methyl-10-phenyl-6,7,8a,10 ,11,11a-Hexahydro-9H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridine-9-carboxamide Refer to Example 1 for the preparation method.

MS m/z(ESI): 500.2[M+H] ⁺ .

Example 36

4-((8aR,9S,10S,11R,11aS)-11a-hydroxy-3-methoxy-9-((methylamino)methyl)-10-phenyl-6,7,8a,9 ,10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzene Preparation of formonitrile

4-((8aR,9S,10S,11R,11aS)-11a-hydroxy-3-methoxy-9-((methylamino)methyl)-10-phenyl-6,7,8a,9 ,10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzene Refer to Example 1 for the preparation method of formonitrile.

MS m/z(ESI): 486.2[M+H] ⁺ .

Example 37

(8aR,9S,10S,11R,11aS)-11-(4-cyanophenyl)-9-((dimethylamino)methyl)-11a-hydroxy-10-phenyl-6,7,8a ,10,11,11a-Hexahydro-9H-1,11-oxolano[7,8][1,4]dioxino[5,6-b]pyridine-3-methyl Preparation of Nitriles

(8aR,9S,10S,11R,11aS)-11-(4-cyanophenyl)-9-((dimethylamino)methyl)-11a-hydroxy-10-phenyl-6,7,8a ,10,11,11a-Hexahydro-9H-1,11-oxolano[7,8][1,4]dioxino[5,6-b]pyridine-3-methyl The preparation method of nitrile refers to Example 1.

MS m/z(ESI): 495.2[M+H] ⁺ .

Example 38

4-((8aR,9S,10S,11R,11aS)-9-((diethylamino)methyl)-11a-hydroxy-3-methoxy-10-phenyl-6,7,8a,9 ,10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzene Preparation of formonitrile

4-((8aR,9S,10S,11R,11aS)-9-((diethylamino)methyl)-11a-hydroxy-3-methoxy-10-phenyl-6,7,8a,9 ,10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzene Refer to Example 1 for the preparation method of formonitrile.

MS m/z(ESI): 528.2[M+H] ⁺ .

Example 39

4-((8aR,9S,10S,11R,11aS)-11a-Hydroxy-3-methoxy-10-phenyl-9-(piperidin-1-ylmethyl)-6,7,8a,9 ,10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzene Preparation of formonitrile

4-((8aR,9S,10S,11R,11aS)-11a-Hydroxy-3-methoxy-10-phenyl-9-(piperidin-1-ylmethyl)-6,7,8a,9 ,10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzene Refer to Example 1 for the preparation method of formonitrile.

MS m/z(ESI): 540.2[M+H] ⁺ .

Example 40

4-((8aR,9S,10S,11R,11aS)-11a-hydroxy-3-methoxy-9-(4-morpholinylmethyl)-10-phenyl-6,7,8a,9, 10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzyl Preparation of Nitriles

4-((8aR,9S,10S,11R,11aS)-11a-hydroxy-3-methoxy-9-(4-morpholinylmethyl)-10-phenyl-6,7,8a,9, 10,11a-Hexahydro-11H-1,11-oxolano[7,8][1,4]dioxocino[5,6-b]pyridin-11-yl)benzyl The preparation method of nitrile refers to Example 1.

MS m/z(ESI): 542.2[M+H] ⁺ .

Example 41

4-((8aR,9S,10S,11R,11aS)-11a-hydroxy-3-methoxy-9-((4-methylpiperazin-1-yl)methyl)-10-phenyl-6 ,7,8a,9,10,11a-hexahydro-11H-1,11-oxolano[7,8][1,4]dioxino[5,6-b]pyridine Preparation of -11-yl)benzonitrile

4-((8aR,9S,10S,11R,11aS)-11a-hydroxy-3-methoxy-9-((4-methylpiperazin-1-yl)methyl)-10-phenyl-6 ,7,8a,9,10,11a-hexahydro-11H-1,11-oxolano[7,8][1,4]dioxino[5,6-b]pyridine The preparation method of -11-yl)benzonitrile refers to Example 1.

MS m/z(ESI): 555.3[M+H] ⁺ .

Example 42

4-((8aR,9S,10S,11R,11aS)-9-((3-(difluoromethyl)azetidin-1-yl)methyl)-11a-hydroxy-3-methoxy-10 -Phenyl-6,7,8a,9,10,11a-hexahydro-11H-1,11-oxolano[7,8][1,4]dioxino[5, Preparation of 6-b]pyridin-11-yl)benzonitrile

4-((8aR,9S,10S,11R,11aS)-9-((3-(difluoromethyl)azetidin-1-yl)methyl)-11a-hydroxy-3-methoxy-10 -Phenyl-6,7,8a,9,10,11a-hexahydro-11H-1,11-oxolano[7,8][1,4]dioxino[5, Refer to Example 1 for the preparation method of 6-b]pyridin-11-yl)benzonitrile.

MS m/z(ESI): 552.2[M+H] ⁺ .

Example 43

(8aR,9S,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-9-(((2-hydroxy-2-methylpropyl)(methyl)amino) Methyl)-10-phenyl-6,7,8a,10,11,11a-hexahydro-9H-1,11-oxolano[7,8][1,4]dioxoctane Preparation of Ino[5,6-b]pyridine-3-carbonitrile

(8aR,9S,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-9-(((2-hydroxy-2-methylpropyl)(methyl)amino) Methyl)-10-phenyl-6,7,8a,10,11,11a-hexahydro-9H-1,11-oxolano[7,8][1,4]dioxoctane Refer to Example 1 for the preparation method of ino[5,6-b]pyridine-3-carbonitrile.

MS m/z(ESI): 553.2[M+H] ⁺ .

Example 44

(8aR,9S,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-9-(((2-methoxyethyl)(methyl)amino)methyl) -10-Phenyl-6,7,8a,10,11,11a-hexahydro-9H-1,11-oxolano[7,8][1,4]dioxino[ Preparation of 5,6-b]pyridine-3-carbonitrile

(8aR,9S,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-9-(((2-methoxyethyl)(methyl)amino)methyl) -10-Phenyl-6,7,8a,10,11,11a-hexahydro-9H-1,11-oxolano[7,8][1,4]dioxino[ Refer to Example 1 for the preparation method of 5,6-b]pyridine-3-carbonitrile.

MS m/z(ESI): 539.2[M+H] ⁺ .

Example 45

(8aS,9R,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-10-phenyl-9-(pyrrolidin-1-ylsulfonyl)-6,7, 8a,10,11,11a-hexahydro-9H-1,11-oxolano[7,8][1,4]dioxino[5,6-b]pyridine-3- Preparation of formonitrile

(8aS,9R,10S,11R,11aS)-11-(4-cyanophenyl)-11a-hydroxy-10-phenyl-9-(pyrrolidin-1-ylsulfonyl)-6,7, 8a,10,11,11a-hexahydro-9H-1,11-oxolano[7,8][1,4]dioxino[5,6-b]pyridine-3- Refer to Example 1 for the preparation method of formonitrile.

MS m/z(ESI): 571.2[M+H] ⁺ .

Example 46

4-((8aR,9S,10S,11R,11aS)-9-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-11a-hydroxy-3-methyl Oxy-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-[1,11]oxolano[7,8][1,4]dioxoctane Preparation of Ino[5,6-b]pyridin-11-yl)benzonitrile

4-((8aR,9S,10S,11R,11aS)-9-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-11a-hydroxy-3-methyl Oxy-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-[1,11]oxolano[7,8][1,4]dioxoctane Refer to Example 1 for the preparation method of ino[5,6-b]pyridin-11-yl)benzonitrile.

MS m/z(ESI): 554.2[M+H] ⁺ .

Example 47

4-((8aR,9S,10S,11R,11aS)-9-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-11a-hydroxy -3-Methoxy-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-1,11-oxolano[7,8][1,4] Preparation of Dioxino[5,6-b]pyridin-11-yl)benzonitrile

4-((8aR,9S,10S,11R,11aS)-9-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-11a-hydroxy -3-Methoxy-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-1,11-oxolano[7,8][1,4] Refer to Example 1 for the preparation method of dioxino[5,6-b]pyridin-11-yl)benzonitrile.

MS m/z(ESI): 566.3[M+H] ⁺ .

Example 48

4-((8aR,9S,10S,11R,11aS)-9-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl )-11a-Hydroxy-3-methoxy-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-1,11-oxolano[7,8] Preparation of [1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

4-((8aR,9S,10S,11R,11aS)-9-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl )-11a-Hydroxy-3-methoxy-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-1,11-oxolano[7,8] Refer to Example 1 for the preparation method of [1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile.

MS m/z(ESI): 568.2[M+H] ⁺ .

Example 49

4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-2-phenyl-1,2,2a1,9a - Preparation of tetrahydro-2aH-3,7,9-trioxa-6-azabenzo[cd]cyclopentadieno[ij]azulene-2a-yl)benzonitrile

4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-2-phenyl-1,2,2a1,9a -The preparation method of tetrahydro-2aH-3,7,9-trioxa-6-azabenzo[cd]cyclopentadieno[ij]azulene-2a-yl)benzonitrile refers to Example 1.

MS m/z(ESI): 486.2[M+H] ⁺ .

Example 50

4-((9aR,10S,11S,12R,12aS)-10-((dimethylamino)methyl)-12a-hydroxy-3-methoxy-11-phenyl-7,8,9a,10 ,11,12a-Hexahydro-6H,12H-1,12-oxolano[8,9][1,5]dioxino[6,7-b]pyridin-12-yl ) Preparation of benzonitrile

4-((9aR,10S,11S,12R,12aS)-10-((dimethylamino)methyl)-12a-hydroxy-3-methoxy-11-phenyl-7,8,9a,10 ,11,12a-Hexahydro-6H,12H-1,12-oxolano[8,9][1,5]dioxino[6,7-b]pyridin-12-yl ) The preparation method of benzonitrile refers to Example 1.

MS m/z(ESI): 514.2[M+H] ⁺ .

Example 51

4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-1'-methyl-2-phenyl-1 ,2,2a1,9a-tetrahydro-2aH-3,7,9-trioxa-6-azaspiro[benzo[cd]cyclopentadieno[ij]azulene-8,4'-piperidine Preparation of ]-3a,3a1(6a),5-trien-2a-yl)benzonitrile

4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-1'-methyl-2-phenyl-1 ,2,2a1,9a-tetrahydro-2aH-3,7,9-trioxa-6-azaspiro[benzo[cd]cyclopentadieno[ij]azulene-8,4'-piperidine ]-3a, 3a1 (6a), 5-trien-2a-yl) benzonitrile preparation method with reference to Example 1.

MS m/z(ESI): 569.3[M+H] ⁺ .

Example 52

4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-7-methyl-8-carbonyl-2-benzene base-1,2,2a1,7,8,9a-hexahydro-2aH-3,9-dioxa-6,7-diazabenzo[cd]cyclopentadieno[ij]azulene-2a -Preparation of benzonitrile

4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-7-methyl-8-carbonyl-2-benzene base-1,2,2a1,7,8,9a-hexahydro-2aH-3,9-dioxa-6,7-diazabenzo[cd]cyclopentadieno[ij]azulene-2a -Base) The preparation method of benzonitrile refers to Example 1.

MS m/z(ESI): 513.2[M+H] ⁺ .

Example 53

4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-8-carbonyl-2-phenyl-1,2 ,2a1,7,8,9a-hexahydro-2aH-3,9-dioxa-6,7-diazabenzo[cd]cyclopentadieno[ij]azul-2a-yl)benzyl Preparation of Nitriles

4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-8-carbonyl-2-phenyl-1,2 ,2a1,7,8,9a-hexahydro-2aH-3,9-dioxa-6,7-diazabenzo[cd]cyclopentadieno[ij]azul-2a-yl)benzyl The preparation method of nitrile refers to Example 1.

MS m/z(ESI): 499.2[M+H] ⁺ .

Example 54

(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8, Preparation of 8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-sulfonic acid fluorination

(5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8, Refer to Example 1 for the preparation method of 8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-sulfonyl fluoride.

MS m/z(ESI): 513.1[M+H] ⁺ .

Example 55

4-((5aR,6R,7S,8R,8aS)-7-((dimethylamino)methyl)-6-fluoro-8,8a-dihydroxy-1,3-dimethoxy-6- Preparation of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6R,7S,8R,8aS)-7-((dimethylamino)methyl)-6-fluoro-8,8a-dihydroxy-1,3-dimethoxy-6- Reference Example for the preparation method of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile 1.

MS m/z(ESI): 506.2[M+H] ⁺ .

Example 56

4-((5aS,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-methyl-6 - Preparation of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aS,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-methyl-6 -The preparation method of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was implemented with reference to example 1.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.21(s,3H), 1.87-1.98(m,1H), 2.02-2.09(m,1H), 2.24(s,6H), 2.68-2.76(m, 1H),3.78(s,3H),3.82(s,3H),,4.52-4.59(m,1H),4.88-4.96(m,1H),5.09(s,1H),6.04(s,1H), 6.81-6.88(m,1H),6.91-7.02(m,4H),7.18-7.24(m,2H),7.30-7.36(m,2H);

MS m/z(ESI): 502.2[M+H] ⁺ .

Example 57

4-((5aR,6S,7S,8R,8aS)-6-(bicyclo[1.1.1]pentan-1-yl)-8,8a-dihydroxy-1,3-dimethoxy-7 -((Methoxy(methyl)amino)methyl)-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine Preparation of -5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-6-(bicyclo[1.1.1]pentan-1-yl)-8,8a-dihydroxy-1,3-dimethoxy-7 -((Methoxy(methyl)amino)methyl)-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine The preparation method of -5a-yl) benzonitrile refers to Example 1.

MS m/z(ESI): 494.2[M+H] ⁺ .

Example 58

3-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6 -Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)bicyclo[1.1.1]pentane Preparation of alkane-1-carbonitrile

3-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6 -Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)bicyclo[1.1.1]pentane Refer to Example 1 for the preparation method of alkane-1-carbonitrile.

MS m/z(ESI): 494.2[M+H] ⁺ .

Example 59

4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6 - Preparation of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6 -The preparation method of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was implemented with reference to example 1.

MS m/z(ESI): 504.2[M+H] ⁺ .

Example 60

4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxyamino)methyl)-6-phenyl- Preparation of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxyamino)methyl)-6-phenyl- Refer to Example 1 for the preparation method of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile.

MS m/z(ESI): 490.2[M+H] ⁺ .

Example 61

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,1,3-trimethoxy-N-methyl-6-phenyl- Preparation of 5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide

(5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,1,3-trimethoxy-N-methyl-6-phenyl- Refer to Example 1 for the preparation method of 5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide.

MS m/z(ESI): 518.2[M+H] ⁺ .

Example 62

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)- 6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine Preparation of oxidation

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)- 6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine Refer to Example 1 for the preparation method of oxidation.

MS m/z(ESI): 555.2[M+H] ⁺ .

Example 63

(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxidation

(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Refer to the preparation method of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxidation Example 1.

MS m/z(ESI): 539.2[M+H] ⁺ .

Example 64

(5aR,6S,7R,8R,8aS)-5a-(4-(dimethylphosphoryl)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl Preparation of yl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide

(5aR,6S,7R,8R,8aS)-5a-(4-(dimethylphosphoryl)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl Refer to the preparation method of yl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide Example 1.

MS m/z(ESI): 553.2[M+H] ⁺ .

Example 65

(5aR,6S,7R,8R,8aS)-5a-(4-(dimethylphosphoryl)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N-methyl-6 - Preparation of phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide

(5aR,6S,7R,8R,8aS)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N-methyl- Reference Example for the preparation of 6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide 1.

MS m/z(ESI): 539.2[M+H] ⁺ .

Example 66

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methylamino)methyl)-6-phenyl- Preparation of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methylamino)methyl)-6-phenyl- Preparation method of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide Refer to Example 1.

MS m/z(ESI): 525.2[M+H] ⁺ .

Example 67

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-1 Preparation of -methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-1 Preparation of -methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile Refer to Example 1 for the method.

MS m/z(ESI): 534.2[M+H] ⁺ .

Example 68

(4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

(4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation method of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide Refer to Example 1.

MS m/z(ESI): 567.3[M+H] ⁺ .

Example 69

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-7-(piperidin-1-ylmethyl)- Preparation of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-7-(piperidin-1-ylmethyl)- Preparation method of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide Refer to Example 1.

MS m/z(ESI): 579.3[M+H] ⁺ .

Example 70

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-(4-morpholinylmethyl)-6-phenyl-6 Preparation of ,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-(4-morpholinylmethyl)-6-phenyl-6 , The preparation method of 7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide is referred to Example 1.

MS m/z(ESI): 581.2[M+H] ⁺ .

Example 71

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((4-methylpiperazin-1-yl)methyl) -6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethyl Preparation of Phosphine Oxidation

(4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((4-methylpiperazin-1-yl)methyl) -6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethyl For the preparation method of phosphine oxide, refer to Example 1.

MS m/z(ESI): 594.3[M+H] ⁺ .

Example 72

(4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1,3 -Dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzene base) preparation of dimethyl phosphine oxide

(4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8,8a-dihydroxy-1,3 -Dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzene For the preparation method of dimethyl phosphine oxide, refer to Example 1.

MS m/z(ESI): 601.2[M+H] ⁺ .

Example 73

(5aR,6S,7S,8R,8aS)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-7-((((2-hydroxy-2-methylpropane) (methyl)amino)methyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[ Preparation of 3,2-c]pyridine-3-carbonitrile

(5aR,6S,7S,8R,8aS)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-7-((((2-hydroxy-2-methylpropane) (methyl)amino)methyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[ Refer to Example 1 for the preparation method of 3,2-c]pyridine-3-carbonitrile.

MS m/z(ESI): 592.3[M+H] ⁺ .

Example 74

(5aR,6S,7S,8R,8aS)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-1-methoxy-7-(((2-methyl oxyethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2 Preparation of -c]pyridine-3-carbonitrile

(5aR,6S,7S,8R,8aS)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-1-methoxy-7-(((2-methyl oxyethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2 -c] The preparation method of pyridine-3-carbonitrile refers to Example 1.

MS m/z(ESI): 578.2[M+H] ⁺ .

Example 75

(5aR,6S,7R,8S,8aS)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-( Pyrrolidin-1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile preparation

(5aR,6S,7R,8S,8aS)-5a-(4-(dimethylphosphinooxy)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-( Pyrrolidin-1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-3-carbonitrile For the preparation method, refer to Example 1.

MS m/z(ESI): 610.2[M+H] ⁺ .

Example 76

(4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-8,8a-dihydroxy -1,3-Dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-5a Preparation of -yl)phenyl)dimethylphosphine oxide

(4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-8,8a-dihydroxy -1,3-Dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-5a Refer to Example 1 for the preparation method of -yl)phenyl)dimethylphosphine oxide.

MS m/z(ESI): 593.2[M+H] ⁺ .

Example 77

(4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-8, 8a-Dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c ] Preparation of pyridin-5a-yl)phenyl)dimethylphosphine oxide

(4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-8, 8a-Dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c ] The preparation method of pyridin-5a-yl)phenyl)dimethylphosphine oxide refers to Example 1.

MS m/z(ESI): 605.3[M+H] ⁺ .

Example 78

(4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methane yl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[ Preparation of 3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

(4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methane base)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[ Refer to Example 1 for the preparation method of 3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide.

MS m/z(ESI): 607.3[M+H] ⁺ .

Example 79

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl- Preparation of 5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl- Refer to Example 1 for the preparation method of 5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol.

MS m/z(ESI): 504.2[M+H] ⁺ .

Example 80

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-((trifluoromethyl) )thio)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-((trifluoromethyl) )thio)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation Refer to Example 1 for the method.

MS m/z(ESI): 563.2[M+H] ⁺ .

Example 81

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-thiocyanatophenyl) Preparation of -5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-thiocyanatophenyl) For the preparation method of -5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol, refer to Example 1.

MS m/z(ESI): 520.2[M+H] ⁺ .

Example 82

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl )-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl )-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation method Refer to Example 1.

MS m/z(ESI): 519.2[M+H] ⁺ .

Example 83

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl Preparation of -5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

The first step: the preparation of 4-(benzyloxy)-2,6-dichloropyridine

Under an ice-water bath, NaH (7.59 g, 60 wt%, 190 mmol) was added in portions to the DMF solution (300 mL) of 2,4,6-trichloropyridine (30.0 g, 165 mmol). After stirring for 15 minutes, benzyl alcohol (17.9 mL, 173 mmol) was added dropwise, and the addition was complete, followed by stirring under an ice-water bath for 1 hour. The reaction solution was poured into ice water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine for several times, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and separated by column chromatography. The title compound 4-(benzyloxy)-2,6-dichloropyridine (30.4 g, 73%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.11 (s, 2H), 6.86 (s, 2H), 7.37-7.42 (m, 5H);

MS m/z(ESI): 254.0[M+H] ⁺ .

The second step: the preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine

To a solution of 4-(benzyloxy)-2,6-dichloropyridine (27.0 g, 106 mmol) in toluene (400 mL) was added a methanol solution of sodium methoxide (30 wt%, 36.4 g, 202 mmol), and then at 60°C Stir for 5 hours. The reaction was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound, 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.6 g, 74%), was isolated.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.81(s, 3H), 5.20(s, 2H), 6.46(d, J =1.9Hz, 1H), 6.81(d, J =1.9Hz, 1H), 7.32-7.47(m,5H);

MS m/z(ESI): 250.2[M+H] ⁺ .

The third step: preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol

Under a dry ice-acetone bath, to a solution of 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.5 g, 78.1 mmol) in THF (200 mL), a solution of n-BuLi in n-hexane was added dropwise (41.0 mL, 2.4 M, 97.6 mmol), stirred at this temperature for 30 minutes, then added acetaldehyde (6.88 g, 156 mmol) dropwise to the reaction system, the dropwise addition was completed, continued stirring for 10 minutes, and added saturated aqueous ammonium chloride solution The reaction was quenched, the reaction solution was extracted several times with ethyl acetate, the organic phases were combined, washed with saturated brine, and the organic phase was separated for Dry over anhydrous sodium sulfate, filter and concentrate the organic solvent under reduced pressure, and separate the title compound by column chromatography to obtain the title compound 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane- 1-ol (16 g, 70%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 1.39(d, J =6.6Hz, 3H), 3.84(s, 3H), 4.60(d, J =6.6Hz, 1H), 5.09-5.14(m, 1H) ), 5.25(s, 2H), 6.93(s, 1H), 7.32-7.49(m, 5H);

MS m/z(ESI): 294.1[M+H] ⁺ .

The fourth step: the preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-one

To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol (16.0 g, 54.6 mmol) in dichloromethane (320 mL) was divided DMP (30.1 g, 71.0 mmol) was added in batches and the addition was complete and stirring was continued at room temperature for 2 hours. Then, a saturated aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution were sequentially added, followed by stirring for an additional 15 minutes. The organic phase was separated and the aqueous phase was extracted twice more with dichloromethane. After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound was separated by column chromatography to obtain the title compound 1-(4-(benzyloxy)-6-chloro-2-methoxypyridine-3). -yl)ethan-1-one (8.10 g, 51%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 2.37(s,3H), 3.84(s,3H), 4.60(d, J =6.1Hz,1H), 5.28(s,2H), 7.10(s,1H) ),7.32-7.47(m,5H);

MS m/z(ESI): 292.2[M+H] ⁺ .

The fifth step: the preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) ethane-1-one

To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one (4.67 g, 16.0 mmol) in ethyl acetate (120 mL), Add Pd/C (140mg, 10wt%), under hydrogen atmosphere, normal temperature and pressure, stir for 3 hours, filter out insolubles with diatomaceous earth, the filtrate is concentrated under reduced pressure and then column chromatography The title compound 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.30 g, 71%) was isolated.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 2.50(s, 3H), 3.90(s, 3H), 6.70(s, 1H), 13.00(s, 1H);

MS m/z(ESI): 202.2[M+H] ⁺ .

The sixth step: (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) prop-2-en-1-one preparation

To 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.00 g, 9.92 mmol), 4-bromobenzaldehyde (1.65 g, 8.93 mmol) MeONa in MeOH solution (5.36g, 30wt%, 29.8mmol) was added to the DMF solution (31mL), vigorously stirred at 50°C for 30 minutes, cooled, and then poured into dilute hydrochloric acid (0.3M, 200mL) under an ice-water bath, The precipitated solid was collected by filtration and dried, then purified by slurrying with EtOAc/n-heptane mixed solvent (mixed solvent ratio 1:10) to obtain the title compound (E)-3-(4-bromophenyl)-1-(6- Chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one (1.87 g, 57%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.80(s, 3H), 6.60(s, 1H), 7.20(d, J =16.0Hz, 1H), 7.40(d, J =16.0Hz, 1H), 7.56-7.73(m,4H);

MS m/z(ESI): 368.0[M+H] ⁺ .

The seventh step: preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one

Under a water bath, add (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one ( 1.40 g, 3.80 mmol) of a mixed solution of EtOH (27 mL) and DCM (6.8 mL) were successively added dropwise with NaOH aqueous solution (3.36 g, 10 wt%, 8.39 mmol) and H ₂ O ₂ aqueous solution (3.03 g, 30 wt %, 26.7 mmol), then stirred in a water bath for 1 hour. Saturated aqueous ammonium chloride solution was added, extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain crude 2-(4-bromophenyl)-7-chloro-3-hydroxy-5 -Methoxy-4H-pyrano[3,2-c]pyridin-4-one (700 mg) was used directly in the next step without further purification.

MS m/z(ESI): 381.9[M+H] ⁺ .

The eighth step: preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one

To 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (crude from previous step, 700 mg) In the DMF solution (30 mL), a methanol solution of sodium methoxide (15 mL, 30 wt%) was added, then stirred at 80 °C for 1 hour, cooled, and the reaction solution was poured into ice water, and then the pH was adjusted to weakly acidic with hydrochloric acid (6 M), The precipitated solid was filtered, the filter cake was washed with water, the solid compound was collected and dried, and separated and purified by column chromatography to obtain the title compound 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H- Pyrano[3,2-c]pyridin-4-one (180 mg, two-step yield: 13%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.95(s, 3H), 4.00(s, 3H), 6.60(s, 1H), 7.75(d, J =9.6Hz, 2H), 8.10(d, J =8.0Hz,2H),9.65(br s,1H);

MS m/z(ESI): 378.0[M+H] ⁺ .

Step 9: Racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl- Preparation of 2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate

2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (160 mg, 0.424 mmol) and cinnamic acid Methyl ester (686 mg, 4.24 mmol) was dissolved in chloroform (7 mL) and trifluoroethanol (5.6 mL) at 0°C with vigorous stirring under 450 W UV light irradiation for 5 hours. Concentrate the organic solvent under reduced pressure to remove excess methyl cinnamate by column chromatography to obtain the crude product racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8 -Dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate (250 mg), which was directly used in the next reaction.

MS m/z(ESI): 540.1[M+H] ⁺ .

Step 10: Racemic-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate

to rac-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3, 4,5-Tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate (250 mg, crude, about 0.424 mmol) in methanol (8 mL) was added dropwise methanol A methanol solution of sodium (30wt%, 252mg, 1.40mmol) was then stirred at 60°C for 45 minutes, the reaction was cooled to room temperature, the organic solvent was concentrated under reduced pressure, the residue was separated with dichloromethane and saturated aqueous ammonium chloride solution, The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure to obtain the crude product racemic-methyl(5aR,6S,7R,8aR)-5a- (4-Bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4 ,5]furo[3,2-c]pyridine-7-carboxylate (250 mg) was used directly in the next reaction.

MS m/z(ESI): 540.1[M+H] ⁺ .

Step 11: Racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation of 5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylic acid

Under ice bath, racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-benzene yl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- 8,8a -diol (0.26 g, 479.37 μmol) Dissolved in MeOH (3 mL), THF (1.5 mL) and H ₂ O (1.5 mL), lithium hydroxide hydrate (201.16 mg, 4.79 mmol) was added, the reaction solution was stirred under ice bath for 10 minutes, slowly warmed to 25 °C and stirred for 3 Hour. The pH of the reaction solution was adjusted to 6 with 1N HCl, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the title compound racemic-(5aR,7R,8R,8aS)-5a-(4-bromo) Phenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo [3,2-c]pyridine-7-carboxylic acid (206 mg, 81%).

MS m/z(ESI): 528.1[M+H] ⁺ .

Step 12: Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N -Dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide preparation

Under ice bath, (5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8 ,8a-Tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylic acid (0.23 g, 435.32 μmol) was dissolved in DCM (1.51 mL), DIPEA (365.70mg, 2.83mmol) was added, HATU (246.35mg, 652.98 μmol) was added in batches, the reaction solution was stirred under ice bath for 10 minutes, dimethylamine hydrochloride (177.7mg, 2.18mmol) was added, slowly liters Warm to room temperature and stir for an additional 2 hours. The reaction solution was diluted with DCM, washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the title compound racemic-(5aR,6S,7R,8R,8aS)-5a-( 4-Bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-ring Pentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (215 mg, 89%).

MS m/z(ESI): 555.1[M+H] ⁺ .

The Thirteenth Step: Racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethyl Preparation of oxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

Under ice bath, racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N- Dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (0.215 g, 387.10 μmol) was dissolved in THF (6 mL), borane (3.87 mmol, 1.9 mL, 2M solution in THF) was slowly added, and the reaction solution was stirred under ice bath for 10 minutes and at room temperature for 12 hours. The reaction was quenched by adding methanol solution and stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methane yl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine -8,8a-Diol (120 mg, 57%).

MS m/z(ESI): 541.1[M+H] ⁺ .

The fourteenth step: (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy Preparation of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6- at room temperature Phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- 8,8a -diol (100 mg, 180.47 μmol) Dissolved in 1'4-Dioxane (5 mL) and H ₂ O (1 mL), nitrogen was bubbled for 5 min, Pd(PPh ₃ ) ₄ (64 mg, 55.4 μmol) and K ₃ PO ₄ (117.6 mg, 554.1 μmol ) were added mol), the reaction was heated to 100 °C for 12 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with DCM, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by reverse-phase preparation, and then resolved on a chiral column to obtain the optically pure title compound (5aR,6S ,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6 ,7,8-Tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol (8 mg, 8.6%).

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 0.43-0.53 (m, 2H), 0.78-0.87 (m, 2H), 1.67-1.78 (m, 1H), 1.85-1.91 (m, 1H), 2.18 ( s, 6H), 2.54-2.61(m, 1H), 2.96-3.04(m, 1H), 3.57(d, J = 14.0Hz, 1H), 3.81-3.84(m, 6H), 4.42(d, J = 4.6Hz, 1H), 4.82(s, 1H), 5.14(s, 1H), 6.00(s, 1H), 6.71-6.74(m, 2H), 6.87-6.91(m, 2H), 6.97-7.07(m ,5H);

MS m/z(ESI): 503.3[M+H] ⁺ .

Example 84

N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)-N-methylacetyl Preparation of amines

N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)-N-methylacetyl Refer to Example 1 for the preparation method of the amine.

MS m/z(ESI): 534.3[M+H] ⁺ .

Example 85

4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6 Preparation of ,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)-N,N-dimethylbenzamide

4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6 Preparation of ,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)-N,N-dimethylbenzamide Refer to Example 1 for the method.

MS m/z(ESI): 534.3[M+H] ⁺ .

Example 86

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-nitrophenyl)-6-phenyl- Preparation of 5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

The first step: the preparation of 4-(benzyloxy)-2,6-dichloropyridine

Under an ice-water bath, NaH (7.59 g, 60 wt%, 190 mmol) was added in portions to the DMF solution (300 mL) of 2,4,6-trichloropyridine (30.0 g, 165 mmol). After stirring for 15 minutes, benzyl alcohol (17.9 mL, 173 mmol) was added dropwise, and the addition was complete, followed by stirring under an ice-water bath for 1 hour. The reaction solution was poured into ice water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine several times, the organic phase was separated and dried over anhydrous sodium sulfate, filtered and then reduced in pressure. The organic solvent was concentrated and separated by column chromatography to give the title compound 4-(benzyloxy)-2,6-dichloropyridine (30.4 g, 73%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.11 (s, 2H), 6.86 (s, 2H), 7.37-7.42 (m, 5H);

MS m/z(ESI): 254.0[M+H] ⁺ .

The second step: the preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine

To a solution of 4-(benzyloxy)-2,6-dichloropyridine (27.0 g, 106 mmol) in toluene (400 mL) was added a methanol solution of sodium methoxide (30 wt%, 36.4 g, 202 mmol), and then at 60°C Stir for 5 hours. The reaction was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound, 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.6 g, 74%), was isolated.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.81(s, 3H), 5.20(s, 2H), 6.46(d, J =1.9Hz, 1H), 6.81(d, J =1.9Hz, 1H), 7.32-7.47(m,5H);

MS m/z(ESI): 250.2[M+H] ⁺ .

The third step: preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol

Under a dry ice-acetone bath, to a solution of 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.5 g, 78.1 mmol) in THF (200 mL), a solution of n-BuLi in n-hexane was added dropwise (41.0 mL, 2.4 M, 97.6 mmol), stirred at this temperature for 30 minutes, then added acetaldehyde (6.88 g, 156 mmol) dropwise to the reaction system, the dropwise addition was completed, continued stirring for 10 minutes, and added saturated aqueous ammonium chloride solution quench the reaction, The reaction solution was extracted several times with ethyl acetate, the organic phases were combined, washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound 1-(4- (Benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol (16 g, 70%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 1.39(d, J =6.6Hz, 3H), 3.84(s, 3H), 4.60(d, J =6.6Hz, 1H), 5.09-5.14(m, 1H) ), 5.25(s, 2H), 6.93(s, 1H), 7.32-7.49(m, 5H);

MS m/z(ESI): 294.1[M+H] ⁺ .

The fourth step: the preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-one

To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol (16.0 g, 54.6 mmol) in dichloromethane (320 mL) was divided DMP (30.1 g, 71.0 mmol) was added in batches and the addition was complete and stirring was continued at room temperature for 2 hours. Then, a saturated aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution were sequentially added, followed by stirring for an additional 15 minutes. The organic phase was separated and the aqueous phase was extracted twice more with dichloromethane. After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound was separated by column chromatography to obtain the title compound 1-(4-(benzyloxy)-6-chloro-2-methoxypyridine-3). -yl)ethan-1-one (8.10 g, 51%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 2.37(s,3H), 3.84(s,3H), 4.60(d, J =6.1Hz,1H), 5.28(s,2H), 7.10(s,1H) ),7.32-7.47(m,5H);

MS m/z(ESI): 292.2[M+H] ⁺ .

The fifth step: the preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) ethane-1-one

To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one (4.67 g, 16.0 mmol) in ethyl acetate (120 mL), Add Pd/C (140mg, 10wt%), under hydrogen atmosphere, normal temperature and pressure, stir for 3 hours, filter out insolubles with diatomaceous earth, the filtrate is concentrated under reduced pressure and then column chromatography The title compound 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.30 g, 71%) was isolated.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 2.50(s, 3H), 3.90(s, 3H), 6.70(s, 1H), 13.00(s, 1H);

MS m/z(ESI): 202.2[M+H] ⁺ .

The sixth step: (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) prop-2-en-1-one preparation

To 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.00 g, 9.92 mmol), 4-bromobenzaldehyde (1.65 g, 8.93 mmol) MeONa in MeOH solution (5.36g, 30wt%, 29.8mmol) was added to the DMF solution (31mL), vigorously stirred at 50°C for 30 minutes, cooled, and then poured into dilute hydrochloric acid (0.3M, 200mL) under an ice-water bath, The precipitated solid was collected by filtration and dried, then purified by slurrying with EtOAc/n-heptane mixed solvent (mixed solvent ratio 1:10) to obtain the title compound (E)-3-(4-bromophenyl)-1-(6- Chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one (1.87 g, 57%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.80(s, 3H), 6.60(s, 1H), 7.20(d, J =16.0Hz, 1H), 7.40(d, J =16.0Hz, 1H), 7.56-7.73(m,4H);

MS m/z(ESI): 368.0[M+H] ⁺ .

The seventh step: preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one

Under a water bath, add (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one ( 1.40 g, 3.80 mmol) of a mixed solution of EtOH (27 mL) and DCM (6.8 mL), were successively added dropwise NaOH aqueous solution (3.36 g, 10 wt %, 8.39 mmol) and H ₂ O ₂ aqueous solution (3.03 g, 30 wt %, 26.7 mmol), and then stirred under a water bath for 1 hour. Saturated aqueous ammonium chloride solution was added, extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain crude 2-(4-bromophenyl)-7-chloro-3-hydroxy-5 -Methoxy-4H-pyrano[3,2-c]pyridin-4-one (700 mg) was used directly in the next step without further purification.

MS m/z(ESI): 381.9[M+H] ⁺ .

The eighth step: preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one

To 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (crude from previous step, 700 mg) In the DMF solution (30 mL), a methanol solution of sodium methoxide (15 mL, 30 wt%) was added, then stirred at 80 °C for 1 hour, cooled, and the reaction solution was poured into ice water, and then the pH was adjusted to weakly acidic with hydrochloric acid (6 M), The precipitated solid was filtered, the filter cake was washed with water, the solid compound was collected and dried, and separated and purified by column chromatography to obtain the title compound 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H- Pyrano[3,2-c]pyridin-4-one (180 mg, two-step yield: 13%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.95(s, 3H), 4.00(s, 3H), 6.60(s, 1H), 7.75(d, J =9.6Hz, 2H), 8.10(d, J =8.0Hz,2H),9.65(br s,1H);

MS m/z(ESI): 378.0[M+H] ⁺ .

Step 9: Racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl- Preparation of 2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate

2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (160 mg, 0.424 mmol) and cinnamic acid Methyl ester (686 mg, 4.24 mmol) was dissolved in chloroform (7 mL) and trifluoroethanol (5.6 mL) at 0°C with vigorous stirring under 450 W UV light irradiation for 5 hours. Concentrate the organic solvent under reduced pressure to remove excess methyl cinnamate by column chromatography to obtain the crude product racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8 -Dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate (250 mg), which was directly used in the next reaction.

MS m/z(ESI): 540.1[M+H] ⁺ .

Step 10: Racemic-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate

to rac-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3, 4,5-Tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate (250 mg, crude, about 0.424 mmol) in methanol (8 mL) was added dropwise methanol A methanol solution of sodium (30wt%, 252mg, 1.40mmol) was then stirred at 60°C for 45 minutes, the reaction was cooled to room temperature, the organic solvent was concentrated under reduced pressure, the residue was separated with dichloromethane and saturated aqueous ammonium chloride solution, The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure to obtain the crude product racemic-methyl(5aR,6S,7R,8aR)-5a- (4-Bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4 ,5]furo[3,2-c]pyridine-7-carboxylate (250 mg) was used directly in the next reaction.

MS m/z(ESI): 540.1[M+H] ⁺ .

Step 11: Racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation of 5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylic acid

Under ice bath, racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-benzene yl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- 8,8a -diol (0.26 g, 479.37 μmol) Dissolved in MeOH (3 mL), THF (1.5 mL) and H ₂ O (1.5 mL), lithium hydroxide hydrate (201.16 mg, 4.79 mmol) was added, the reaction solution was stirred under ice bath for 10 minutes, slowly raised to 25 °C and stirred for 3 Hour. The pH of the reaction solution was adjusted to 6 with 1N HCl, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the title compound racemic-(5aR,7R,8R,8aS)-5a-(4-bromo) Phenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo [3,2-c]pyridine-7-carboxylic acid (206 mg, 81%). .

MS m/z(ESI): 528.1[M+H] ⁺ .

Step 12: Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N -Dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide preparation

Under ice bath, (5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8 ,8a-Tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylic acid (0.23 g, 435.32 μmol) was dissolved in DCM (1.51 mL), DIPEA (365.70mg, 2.83mmol) was added, HATU (246.35mg, 652.98 μmol) was added in batches, the reaction solution was stirred under ice bath for 10 minutes, dimethylamine hydrochloride (177.7mg, 2.18mmol) was added, slowly liters Warm to room temperature and stir for an additional 2 hours. The reaction solution was diluted with DCM, washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the title compound racemic-(5aR,6S,7R,8R,8aS)-5a-( 4-Bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-ring Pentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (215 mg, 89%).

MS m/z(ESI): 555.1[M+H] ⁺ .

The thirteenth step: Racemic-(5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-5a-(4- Nitrophenyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide preparation

At room temperature, (5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl- 6-Phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (0.3 g, 540.14 μg mol) was dissolved in t-BuOH (4.5 mL), sodium nitrite (74.54 mg, 1.08 mmol), Pd2(dba) ₃ (148.38 mg, 162.04 μmol), _tBuBrettPhos ( ^157.08 mg, 324.08 μmol ) were added and tris(3,6- dioxepeptyl )amine (8.73 mg, 27.01 μmol), the reaction solution was heated to 130°C and stirred for 16 hours. The reaction solution was cooled to room temperature, diluted with DCM, washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the title compound racemic-(5aR,6S,7R,8R ,8aS)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-5a-(4-nitrophenyl)-6-phenyl-5a,7,8, 8a-Tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (237 mg, 84%).

MS m/z(ESI): 522.1[M+H] ⁺ .

Step Fourteen: (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-nitrophenyl)- Preparation of 6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

Under ice bath, (5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-5a-(4-nitrophenyl) -6-Phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (0.237g, 454.44 g μmol ) was dissolved in THF (10 mL), borane (7.27 mmol, 3.6 mL, 2M THF solution) was slowly added, the reaction solution was stirred under ice bath for 10 minutes, raised to 25° C., and stirred for 12 hours. The reaction was quenched by adding methanol solution and stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure, separated by reverse-phase preparation, and then resolved on a chiral column to obtain the optically pure title compound (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)- 1,3-Dimethoxy-5a-(4-nitrophenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo [3,2-c]pyridine-8,8a-diol (27 mg, 11.7%).

¹ H NMR (400MHz, DMSO-- d ⁶ ) δ 1.95-2.01(m,1H), 2.22(s,6H), 2.53-2.61(m,1H), 3.11-3.21(m,1H), 3.77(d , J =14.0Hz,1H),3.81-3.85(m,6H),4.11-4.45(m,1H),5.03(s,1H),5.45(s,1H),6.07(s,1H),6.96- 7.11(m, 5H), 7.42-7.46(m, 2H), 7.88-7.93(m, 2H);

MS m/z(ESI): 508.3[M+H] ⁺ .

Example 87

N-cyano-N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy yl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyano Preparation of amides

N-cyano-N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy yl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyano Refer to Example 1 for the preparation method of amide.

MS m/z(ESI): 528.2[M+H] ⁺ .

Example 88

2-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Preparation of yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)malononitrile

2-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Refer to the preparation method of base-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)malononitrile Example 1.

MS m/z(ESI): 527.2[M+H] ⁺ .

Example 89

(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)methanetricarbonitrile

(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Reference Example for the preparation of 6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)methanetricarbonitrile 1.

MS m/z(ESI): 552.2[M+H] ⁺ .

Example 90

3-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Preparation of yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)propynonitrile

3-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Refer to the preparation method of base-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)propynonitrile Example 1.

MS m/z(ESI): 512.2[M+H] ⁺ .

Example 91

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoroazetidin-1-yl)phenyl)-1,3- Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoroazetidin-1-yl)phenyl)-1,3- Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1 for the preparation method.

MS m/z(ESI): 536.3[M+H] ⁺ .

Example 92

1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidin-3-one preparation

1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidin-3-one Refer to Example 1 for the preparation method.

MS m/z(ESI): 532.2[M+H] ⁺ .

Example 93

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-hydroxyazetidin-1-yl)phenyl)-1,3- Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-hydroxyazetidin-1-yl)phenyl)-1,3- Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1 for the preparation method.

MS m/z(ESI): 534.3[M+H] ⁺ .

Example 94

(5aR,6S,7S,8R,8aS)-5a-(4-(3,3-difluoroazetidin-1-yl)phenyl)-7-((dimethylamino)methyl)-1 ,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a - Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-(3,3-difluoroazetidin-1-yl)phenyl)-7-((dimethylamino)methyl)-1 ,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a -For the preparation method of the diol, refer to Example 1.

MS m/z(ESI): 554.2[M+H] ⁺ .

Example 95

((5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8 Preparation of ,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridin-7-yl)methylcarbamate

((5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8 Refer to Example 1 for the preparation method of ,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridin-7-yl)methylcarbamate.

MS m/z(ESI): 504.2[M+H] ⁺ .

Example 96

(5aR,6S,7S,8R,8aS)-5a-(4-(2H-tetrazol-5-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethyl Preparation of oxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-(2H-tetrazol-5-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethyl Preparation of oxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1 for the method.

MS m/z(ESI): 531.2[M+H] ⁺ .

Example 97

(5aR,6S,7R,8R,8aS)-8,8a-Dihydroxy-1,3-dimethoxy-N,N-dimethyl-5a-(4-nitrophenyl)-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide

(5aR,6S,7R,8R,8aS)-8,8a-Dihydroxy-1,3-dimethoxy-N,N-dimethyl-5a-(4-nitrophenyl)-6-benzene For the preparation method of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide, refer to Example 1.

MS m/z(ESI): 522.2[M+H] ⁺ .

Example 98

(5aR,6S,7S,8R,8aS)-5a-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-7-((dimethylamino) )methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c ] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-7-((dimethylamino) )methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c ] For the preparation method of pyridine-8,8a-diol, refer to Example 1.

MS m/z(ESI): 560.3[M+H] ⁺ .

Example 99

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-((3aR,6aS) -Tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5 ] Preparation of furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-((3aR,6aS) -Tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5 ] The preparation method of furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

MS m/z(ESI): 574.3[M+H] ⁺ .

Example 100

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-methoxyazetidine-1 -yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Preparation of diols

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-methoxyazetidine-1 -yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Refer to Example 1 for the preparation method of the diol.

MS m/z(ESI): 548.3[M+H] ⁺ .

Example 101

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-(methoxymethyl)acridine) Butperidin-1-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- Preparation of 8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-(methoxymethyl)acridine) Butperidin-1-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- Refer to Example 1 for the preparation method of 8,8a-diol.

MS m/z(ESI): 562.3[M+H] ⁺ .

Example 102

1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidine-3-methyl Preparation of Nitriles

1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidine-3-methyl The preparation method of nitrile refers to Example 1.

MS m/z(ESI): 543.3[M+H] ⁺ .

Example 103

2-(1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy- 6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidine- Preparation of 3-yl)acetonitrile

2-(1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy- 6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidine- For the preparation method of 3-yl)acetonitrile, refer to Example 1.

MS m/z(ESI): 557.3[M+H] ⁺ .

Example 104

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-(fluoromethyl)-3-hydroxyazetidin-1-yl) Phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-(fluoromethyl)-3-hydroxyazetidin-1-yl) Phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Refer to Example 1 for the preparation method of pyridine-8,8a-diol.

MS m/z(ESI): 566.3[M+H] ⁺ .

Example 105

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl) Phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl) Phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Refer to Example 1 for the preparation method of pyridine-8,8a-diol.

MS m/z(ESI): 566.3[M+H] ⁺ .

Example 106

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidine) -1-yl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3 Preparation of ,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidine) -1-yl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3 ,2-c] The preparation method of pyridine-8,8a-diol refers to Example 1.

MS m/z(ESI): 594.3[M+H] ⁺ .

Example 107

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-hydroxy-3-methylazetidin-1-yl)phenyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 Preparation of ,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-hydroxy-3-methylazetidin-1-yl)phenyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 , The preparation method of 8a-diol refers to Example 1.

MS m/z(ESI): 548.3[M+H] ⁺ .

Example 108

(5aR,6S,7S,8R,8aS)-5a-(4-((3S,4R)-3,4-difluoropyrrolidin-1-yl)phenyl)-7-((dimethylamino) Methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-((3S,4R)-3,4-difluoropyrrolidin-1-yl)phenyl)-7-((dimethylamino) Methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Refer to Example 1 for the preparation method of pyridine-8,8a-diol.

MS m/z(ESI): 568.3[M+H] ⁺ .

Example 109

(5aR,6S,7S,8R,8aS)-5a-(4-((3R,4R)-3,4-difluoropyrrolidin-1-yl)phenyl)-7-((dimethylamino) Methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-((3R,4R)-3,4-difluoropyrrolidin-1-yl)phenyl)-7-((dimethylamino) Methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Refer to Example 1 for the preparation method of pyridine-8,8a-diol.

MS m/z(ESI): 568.3[M+H] ⁺ .

Example 110

(5aR,6S,7S,8R,8aS)-5a-(4-((3S,4S)-3,4-difluoropyrrolidin-1-yl)phenyl)-7-((dimethylamino) Methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-((3S,4S)-3,4-difluoropyrrolidin-1-yl)phenyl)-7-((dimethylamino) Methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c] Refer to Example 1 for the preparation method of pyridine-8,8a-diol.

MS m/z(ESI): 568.3[M+H] ⁺ .

Example 111

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(1-fluorocyclopropyl)phenyl)-1,3-dimethoxy Preparation of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(1-fluorocyclopropyl)phenyl)-1,3-dimethoxy Refer to the preparation method of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Example 1.

MS m/z(ESI): 521.2[M+H] ⁺ .

Example 112

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(1-hydroxycyclopropyl)phenyl)-1,3-dimethoxy Preparation of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(1-hydroxycyclopropyl)phenyl)-1,3-dimethoxy Refer to the preparation method of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Example 1.

MS m/z(ESI): 519.2[M+H] ⁺ .

Example 113

(5aR,6S,7S,8R,8aS)-5a-(4-(1-aminocyclopropyl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy Preparation of yl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-(1-aminocyclopropyl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy Preparation method of yl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1.

MS m/z(ESI): 518.3[M+H] ⁺ .

Example 114

1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyclopropane-1-carbonitrile preparation

1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyclopropane-1-carbonitrile Refer to Example 1 for the preparation method.

MS m/z(ESI): 528.2[M+H] ⁺ .

Example 115

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-methyloxetan-3- yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Preparation of alcohol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-methyloxetan-3- yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Refer to Example 1 for the preparation method of alcohol.

MS m/z(ESI): 533.3[M+H] ⁺ .

Example 116

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-6 - Preparation of phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-6 -The preparation method of phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol refers to the examples 1.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 0.85-0.93(m,3H), 1.94-2.02(m,1H), 2.14(s,3H), 2.18-2.28(m,1H), 2.34-2.40( m,1H),2.48-2.55(m,2H),3.97-3.05(m,1H),3.55-3.61(m,1H),3.76(s,3H),3.80(s,3H),4.32-4.37( m,1H),5.20(s,1H),5.96(s,1H),6.71-6.77(m,2H),6.85-6.89(m,2H),6.90-6.96(m,1H),6.97-7.04( m,2H),7.08-7.16(m,2H);

MS m/z(ESI): 518.2[M+H] ⁺ .

Example 117

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl- Preparation of 5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl- Refer to Example 1 for the preparation method of 5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 0.82-0.88(m,6H), 2.08-2.16(m,1H), 2.31-2.39(m,2H), 2.46-2.60(m,4H), 2.96- 3.04(m, 1H), 3.56-3.64(m, 1H), 3.76(s, 3H), 3.78(s, 3H), 4.33-4.38(m, 1H), 5.20(s, 1H), 5.96(s, 1H), 6.72-6.78(m, 2H), 6.86-6.89(m, 2H), 6.91-6.96(m, 1H), 6.97-7.03(m, 2H), 7.10-7.15(m, 2H);

MS m/z(ESI): 532.3[M+H] ⁺ .

Example 118

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((methyl(2,2,2-trifluoroethyl) Amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((methyl(2,2,2-trifluoroethyl) Amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Refer to Example 1 for the preparation method of the diol.

MS m/z(ESI): 572.2[M+H] ⁺ .

Example 119

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-(((methoxymethyl)(methyl)amino) Methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-(((methoxymethyl)(methyl)amino) Methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol For the preparation method, refer to Example 1.

MS m/z(ESI): 534.2[M+H] ⁺ .

Example 120

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol For the preparation method, refer to Example 1.

MS m/z(ESI): 552.2[M+H] ⁺ .

Example 121

(5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-5a-(4-azidophenyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 Preparation of ,8a-diol

(5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-5a-(4-azidophenyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 , The preparation method of 8a-diol refers to Example 1.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 2.15-2.21(m,1H), 2.53-2.61(m,2H), 2.79-2.88(m,2H), 3.27(s,3H), 3.59-3.65( m, 1H), 3.83(s, 3H), 3.85(s, 3H), 4.34-4.37(m, 1H), 4.55-4.61(m, 4H), 5.24(s, 1H), 6.01(s, 1H) ,6.77-6.81(m,2H),6.88-6.93(m,2H),6.98-7.03(m,1H),7.05-7.11(m,2H),7.15-7.19(m,2H);

MS m/z(ESI): 558.2[M+H] ⁺ .

Example 122

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-dimethyl Preparation of oxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-dimethyl Preparation of oxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1 for the method.

MS m/z(ESI): 580.2[M+H] ⁺ .

Example 123

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-(4-morpholinylmethyl)-6-phenyl-5a Preparation of ,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-(4-morpholinylmethyl)-6-phenyl-5a For the preparation method of ,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol, refer to Example 1.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.98-2.05(m,1H), 2.6-2.35(m,2H), 2.52-2.62(m,3H), 3.09-3.18(m,1H), 3.56- 3.68(m, 5H), 3.84(s, 3H), 3.86(s, 3H), 4.40-4.45(m, 1H), 4.80-4.86(m, 1H), 5.27(s, 1H), 6.03(s, 1H), 6.76-6.82(m, 2H), 6.92-6.96(m, 2H), 6.98-7.02(m, 1H), 7.04-7.10(m, 2H), 7.16-7.24(m, 2H);

MS m/z(ESI): 546.2[M+H] ⁺ .

Example 124

(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5a-(4-azide Nitrophenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c ] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5a-(4-azide Nitrophenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c ] For the preparation method of pyridine-8,8a-diol, refer to Example 1.

MS m/z(ESI): 570.3[M+H] ⁺ .

Example 125

(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5a -(4-Azidophenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[ Preparation of 3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5a -(4-Azidophenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[ Refer to Example 1 for the preparation method of 3,2-c]pyridine-8,8a-diol.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 0.84-0.89 (m, 1H), 1.40-1.46 (m, 1H), 1.59-1.69 (m, 4H), 1.97-2.03 (m, 2H), 2.13- 2.20(m, 2H), 2.32-2.36(m, 1H), 2.67-2.69(m, 1H), 2.92-2.98(m, 1H), 3.03-3.07(m, 1H), 3.66-3.71(m, 1H) ),3.82(s,3H),3.86(s,3H),4.51-4.54(m,1H),5.25(s,1H),6.03(s,1H),6.76-6.80(m,2H),6.93- 6.98(m,2H),6.98-7.03(m,1H),7.04-7.10(m,2H),7.18-7.22(m,2H);

MS m/z(ESI): 572.2[M+H] ⁺ .

Example 126

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy- Preparation of 6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy- The preparation method of 6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol is implemented by reference example 1.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 0.39-0.44 (m, 2H), 0.75-0.79 (m, 2H), 0.86-0.91 (m, 3H), 1.62-1.69 (m, 1H), 1.92- 1.98(m,1H), 2.12(s,3H), 2.17-2.24(m,1H), 2.34-2.41(m,1H), 2.46-2.54(m,2H), 2.94-3.03(m,1H), 3.49-3.56(m,1H),3.76(s,3H),3.78(s,3H),4.33-4.38(m,1H),5.08(s,1H),5.94(s,1H),6.65-6.70( m,2H),6.81-6.85(m,2H),6.91-7.00(m,5H);

MS m/z(ESI): 517.3[M+H] ⁺ .

Example 127

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl Preparation of -5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl For the preparation method of -5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol, refer to Example 1.

¹ H NMR (400 MHz, DMSO- d ⁶ ) δ 0.39-0.45 (m, 2H), 0.72-0.80 (m, 2H), 0.82-0.89 (m, 6H), 1.62-1.70 (m, 1H), 2.06- 2.13(m, 1H), 2.30-2.38(m, 2H), 2.46-2.57(m, 4H), 2.92-3.01(m, 1H), 3.51-3.58(m, 1H), 3.75(s, 3H), 3.78(s,3H),4.32-4.38(m,1H),5.08(s,1H),5.94(s,1H),6.65-6.70(m,2H),6.79-6.85(m,2H),6.91- 7.01(m, 5H);

MS m/z(ESI): 531.3[M+H] ⁺ .

Example 128

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((methyl(2,2,2-trifluoroethyl) )amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a - Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((methyl(2,2,2-trifluoroethyl) )amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a -For the preparation method of the diol, refer to Example 1.

MS m/z(ESI): 571.2[M+H] ⁺ .

Example 129

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol For the preparation method, refer to Example 1.

MS m/z(ESI): 579.3[M+H] ⁺ .

Example 130

(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5a -(4-Cyclopropylphenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo Preparation of [3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5a -(4-Cyclopropylphenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo For the preparation method of [3,2-c]pyridine-8,8a-diol, refer to Example 1.

¹ H NMR (400 MHz, DMSO- d ⁶ ) δ 0.44-0.51 (m, 2H), 0.80-0.87 (m, 2H), 1.58-1.74 (m, 5H), 2.10-2.18 (m, 1H), 2.39- 2.44(m, 1H), 2.92-3.06(m, 2H), 3.18-3.22(m, 1H), 3.44-3.46(m, 2H), 3.52-3.58(m, 2H), 3.60-3.66(m, 1H ),3.77(s,3H),3.78(s,3H),4.50-4.54(m,1H),5.08-5.12(m,1H),5.13(s,1H),6.01(s,1H),6.70- 6.76(m,2H),6.89-6.93(m,2H),6.96-7.00(m,1H),7.01-7.08(m,4H);

MS m/z(ESI): 571.3[M+H] ⁺ .

Example 131

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-(4-morpholinylmethyl)-6-phenyl- Preparation of 5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-(4-morpholinylmethyl)-6-phenyl- Refer to Example 1 for the preparation method of 5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 0.45-0.51 (m, 2H), 0.81-0.85 (m, 2H), 1.68-1.75 (m, 1H), 1.96-2.02 (m, 1H), 2.26- 2.34(m, 2H), 2.54-2.60(m, 2H), 3.08-3.15(m, 1H), 3.54-3.67(m, 6H), 3.84(s, 3H), 3.86(s, 3H), 4.40- 4.45(m,1H),4.74-4.78(m,1H),5.15(s,1H),6.00(s,1H),6.71-6.76(m,2H),6.86-6.92(m,2H),6.97- 7.06(m,5H);

MS m/z(ESI): 545.3[M+H] ⁺ .

Example 132

(5aR,6S,7S,8R,8aS)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-5a-(4-(oxetane-3- yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Preparation of alcohol

(5aR,6S,7S,8R,8aS)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-5a-(4-(oxetane-3- yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Refer to Example 1 for the preparation method of alcohol.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 0.85-0.92(m,3H), 1.30-1.35(m,1H), 1.93-1.99(m,1H), 2.13(s,3H), 2.18-2.26( m,1H),2.33-2.40(m,1H),2.47-2.54(m,1H),2.95-3.05(m,1H),3.52-3.58(m,1H),3.76(s,3H),3.78( s,3H),3.96-4.06(m,1H),4.33-4.44(m,3H),4.73-4.79(m,2H),5.13(s,1H),5.95(s,1H),6.80-6.86( m, 2H), 6.88-6.93 (m, 1H), 6.94-7.03 (m, 4H), 7.06-7.12 (m, 2H);

MS m/z(ESI): 533.3[M+H] ⁺ .

Example 133

(5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl )-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl )-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation method Refer to Example 1.

¹ H NMR (400 MHz, DMSO- d ⁶ ) δ 0.81-0.90 (m, 6H), 2.06-2.13 (m, 1H), 2.30-2.37 (m, 2H), 2.48-2.54 (m, 3H), 2.95- 3.02(m,1H),3.54-3.60(m,1H),3.76(s,3H),3.79(s,3H),3.97-4.05(m,1H),4.34-4.42(m,3H),4.73- 4.80(m,2H),4.82-4.88(m,1H),5.12(s,1H),5.96(s,1H),6.82-6.86(m,2H),6.88-6.93(m,1H),6.94- 7.02(m, 4H), 7.07-7.11(m, 2H);

MS m/z(ESI): 547.3[M+H] ⁺ .

Example 134

(5aR,6S,7S,8R,8aS)-1,3-dimethoxy-7-((methyl(2,2,2-trifluoroethyl)amino)methyl)-5a-(4 -(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c ] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-1,3-dimethoxy-7-((methyl(2,2,2-trifluoroethyl)amino)methyl)-5a-(4 -(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c ] For the preparation method of pyridine-8,8a-diol, refer to Example 1.

MS m/z(ESI): 587.2[M+H] ⁺ .

Example 135

(5aR,6S,7S,8R,8aS)-7-((4,4-Difluoropiperidin-1-yl)methyl)-1,3-dimethoxy-5a-(4-(oxabutine) Cyclo-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 Preparation of ,8a-diol

(5aR,6S,7S,8R,8aS)-7-((4,4-Difluoropiperidin-1-yl)methyl)-1,3-dimethoxy-5a-(4-(oxabutine) Cyclo-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 , The preparation method of 8a-diol refers to Example 1.

MS m/z(ESI): 595.3[M+H] ⁺ .

Example 136

(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-1 ,3-Dimethoxy-5a-(4-(oxabutan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[ Preparation of 4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-1 ,3-Dimethoxy-5a-(4-(oxabutan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[ Refer to Example 1 for the preparation method of 4,5]furo[3,2-c]pyridine-8,8a-diol.

MS m/z(ESI): 587.3[M+H] ⁺ .

Example 137

(5aR,6S,7S,8R,8aS)-1,3-dimethoxy-7-(4-morpholinylmethyl)-5a-(4-(oxetan-3-yl)phenyl) Preparation of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-1,3-dimethoxy-7-(4-morpholinylmethyl)-5a-(4-(oxetan-3-yl)phenyl) Refer to the preparation method of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Example 1.

MS m/z(ESI): 561.3[M+H] ⁺ .

Example 138

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoro-3-methylazetidin-1-yl)phenyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 Preparation of ,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoro-3-methylazetidin-1-yl)phenyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 , The preparation method of 8a-diol refers to Example 1.

MS m/z(ESI): 550.3[M+H] ⁺ .

Example 139

(5aR,6S,7S,8R,8aS)-5a-(4-(3,3-difluorocyclobutyl)phenyl)-7-((dimethylamino)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-(3,3-difluorocyclobutyl)phenyl)-7-((dimethylamino)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol For the preparation method, refer to Example 1.

MS m/z(ESI): 553.3[M+H] ⁺ .

Example 140

(5aR,6S,7S,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-7-((dimethylamino)methyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 Preparation of ,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-7-((dimethylamino)methyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 , The preparation method of 8a-diol refers to Example 1.

MS m/z(ESI): 561.3[M+H] ⁺ .

Example 141

(5aR,6S,7R,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-8,8a-dihydroxy-1,3-di Methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine Preparation of -7-formamide

(5aR,6S,7R,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-8,8a-dihydroxy-1,3-di Methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine The preparation method of -7-formamide refers to Example 1.

MS m/z(ESI): 575.3[M+H] ⁺ .

Example 142

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl) )phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c ] Preparation of pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl) )phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c ] For the preparation method of pyridine-8,8a-diol, refer to Example 1.

MS m/z(ESI): 602.2[M+H] ⁺ .

Example 143

(5aR,6S,7S,8R,8aS)-5a-(4-(azetidin-1-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy Preparation of yl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-(azetidin-1-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy Preparation method of yl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1.

MS m/z(ESI): 518.3[M+H] ⁺ .

Example 144

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-nitroazetidine-1- yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Preparation of alcohol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-nitroazetidine-1- yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Refer to Example 1 for the preparation method of alcohol.

MS m/z(ESI): 563.2[M+H] ⁺ .

Example 145

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-hydroxyethyl)(methyl)amino)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-hydroxyethyl)(methyl)amino)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol For the preparation method, refer to Example 1.

¹ H NMR (400 MHz, DMSO- d ⁶ ) δ 1.98-2.05 (m, 1H), 2.16-2.28 (m, 5H), 2.47-2.58 (m, 3H), 3.01-3.08 (m, 2H), 3.54- 3.59(m, 1H), 3.76(s, 3H), 3.80(s, 3H), 4.37-4.41(m, 1H), 4.43-4.48(m, 1H), 5.18(s, 1H), 5.96(s, 1H), 6.71-6.76(m, 2H), 6.85-6.90(m, 2H), 6.92-6.97(m, 1H), 6.98-7.04(m, 2H), 7.10-7.17(m, 2H);

MS m/z(ESI): 534.2[M+H] ⁺ .

Example 146

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-fluoroazetidin-1-yl)methyl)-1,3-dimethoxy Preparation of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-fluoroazetidin-1-yl)methyl)-1,3-dimethoxy Refer to the preparation method of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Example 1.

¹ H NMR (400 MHz, DMSO- d ⁶ ) δ 2.19-2.27 (m, 1H), 2.52-2.69 (m, 2H), 2.77-2.88 (m, 1H), 2.96-3.08 (m, 2H), 3.46 -3.60(m,3H),3.76(s,3H),3.80(s,3H),4.27-4.32(m,1H),4.93-5.02(m,1H),5.19(s,1H),5.95(s ,1H),6.70-6.76(m,2H),6.83-6.88(m,2H),6.91-6.97(m,1H),6.99-7.04(m,2H),7.08-7.14(m,2H);

MS m/z(ESI): 534.2[M+H] ⁺ .

Example 147

2-(1-(((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl -5a,7,8,8a-Tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridin-7-yl)methyl)azetidin-3-yl) Preparation of Acetonitrile

2-(1-(((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl -5a,7,8,8a-Tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridin-7-yl)methyl)azetidin-3-yl) The preparation method of acetonitrile refers to Example 1.

MS m/z(ESI): 555.3[M+H] ⁺ .

Example 148

1-(((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a, Preparation of 7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridin-7-yl)methyl)azetidine-3-carbonitrile

1-(((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a, Preparation method of 7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridin-7-yl)methyl)azetidine-3-carbonitrile Refer to Example 1.

MS m/z(ESI): 541.2[M+H] ⁺ .

Example 149

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-fluoroethyl)(methyl)amino)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-fluoroethyl)(methyl)amino)methyl)-1,3-di Methoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol For the preparation method, refer to Example 1.

MS m/z(ESI): 536.2[M+H] ⁺ .

Example 150

3-((((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a ,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridin-7-yl)methyl)(methyl)amino)propionitrile preparation

3-((((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a ,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridin-7-yl)methyl)(methyl)amino)propionitrile For the preparation method, refer to Example 1.

MS m/z(ESI): 543.2[M+H] ⁺ .

Example 151

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)- 1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8, Preparation of 8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)- 1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8, Refer to Example 1 for the preparation method of 8a-diol.

MS m/z(ESI): 561.3[M+H] ⁺ .

Example 152

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-(((2-methoxyethyl)(methyl) Amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-(((2-methoxyethyl)(methyl) Amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Refer to Example 1 for the preparation method of the diol.

MS m/z(ESI): 547.3[M+H] ⁺ .

Example 153

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-(((2-hydroxyethyl)(methyl)amino)methyl)-1,3- Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-(((2-hydroxyethyl)(methyl)amino)methyl)-1,3- Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1 for the preparation method.

MS m/z(ESI): 533.3[M+H] ⁺ .

Example 154

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((3-methoxyazetidin-1-yl) Methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((3-methoxyazetidin-1-yl) Methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol For the preparation method, refer to Example 1.

¹ H NMR (400 MHz, DMSO- d ⁶ ) δ 0.38-0.47 (m, 2H), 0.72-0.81 (m, 2H), 1.60-1.70 (m, 1H), 2.13-2.19 (m, 1H), 2.54- 2.61(m,1H),2.63-2.72(m,2H),2.74-2.82(m,1H),3.05(s,3H),3.44-3.56(m,3H),3.76(s,3H),3.78( s,3H),3.82-3.88(m,1H),4.27-4.33(m,1H),5.00-5.08(m,2H),5.93(s,1H),6.64-6.70(m,2H),6.78- 6.84(m, 2H), 6.92-7.01(m, 5H);

MS m/z(ESI): 545.2[M+H] ⁺ .

Example 155

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((3-(methoxymethyl)azetidine- 1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a - Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((3-(methoxymethyl)azetidine- 1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a -For the preparation method of the diol, refer to Example 1.

¹ H NMR (400 MHz, DMSO- d ⁶ ) δ 0.37-0.44 (m, 2H), 0.73-0.79 (m, 2H), 1.60-1.68 (m, 1H), 2.16-2.22 (m, 1H), 2.47- 2.58(m, 2H), 2.68-2.81(m, 3H), 3.09-3.16(m, 5H), 3.37-3.42(m, 2H), 3.49-3.56(m, 1H), 3.74(s, 3H), 3.76(s,3H),4.28-4.33(m,1H),5.04(s,1H),5.17-5.25(m,1H),5.92(s,1H),6.64-6.69(m,2H),6.78- 6.83(m, 2H), 6.91-7.01(m, 5H);

MS m/z(ESI): 559.2[M+H] ⁺ .

Example 156

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)-1, 3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)-1, 3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Refer to Example 1 for the preparation method of the diol.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 0.37-0.48 (m, 2H), 0.72-0.81 (m, 2H), 1.24 (s, 3H), 1.62-1.68 (m, 1H), 2.26-2.31 ( m,1H), 2.56-2.63(m,2H), 2.72-2.82(m,2H), 3.04-3.09(m,1H), 3.14-3.22(m,2H), 3.52-3.60(m,1H), 3.75(s,3H),3.78(s,3H),4.29-4.34(m,1H),4.97-5.06(m,1H),5.24-5.32(m,1H),5.93(s,1H),6.63- 6.70(m, 2H), 6.79-6.85(m, 2H), 6.92-7.01(m, 5H);

MS m/z(ESI): 545.2[M+H] ⁺ .

Example 157

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((3-hydroxyazetidin-1-yl)methyl)-1,3-dimethoxy Preparation of yl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((3-hydroxyazetidin-1-yl)methyl)-1,3-dimethoxy Preparation method of yl-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1.

MS m/z(ESI): 531.3[M+H] ⁺ .

Example 158

(4a'S,5'S,5a'R,10b'S,10c'R)-5a'-(4-cyclopropylphenyl)-8',10'-dimethoxy-3'-methyl-5'-benzene base-3',4',4a',5',5a',10c'-hexahydro-10b'H-spiro[oxetane-3,2'-pyrido[3",4":4', Preparation of 5']furo[3',2':3,4]cyclopentadieno[1,2-e][1,3]oxazine]-10b'-ol

(4a'S,5'S,5a'R,10b'S,10c'R)-5a'-(4-cyclopropylphenyl)-8',10'-dimethoxy-3'-methyl-5'-benzene base-3',4',4a',5',5a',10c'-hexahydro-10b'H-spiro[oxetane-3,2'-pyrido[3",4":4', Refer to Example 1 for the preparation method of 5']furo[3',2':3,4]cyclopentadieno[1,2-e][1,3]oxazine]-10b'-ol.

MS m/z(ESI): 543.3[M+H] ⁺ .

Example 159

(4aS,5S,5aR,10bS,10cR)-5a-(4-cyclopropylphenyl)-10b-hydroxy-8,10-dimethoxy-3-methyl-5-phenyl-4,4a ,5,5a,10b,10c-hexahydropyrido[3",4":4',5']furo[3',2':3,4]cyclopentadieno[1,2-e Preparation of ][1,3]oxazin-2(3H)-one

(4aS,5S,5aR,10bS,10cR)-5a-(4-cyclopropylphenyl)-10b-hydroxy-8,10-dimethoxy-3-methyl-5-phenyl-4,4a ,5,5a,10b,10c-hexahydropyrido[3",4":4',5']furo[3',2':3,4]cyclopentadieno[1,2-e For the preparation method of ][1,3]oxazin-2(3H)-one, refer to Example 1.

MS m/z(ESI): 515.2[M+H] ⁺ .

Example 160

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((methyl(oxetan-3-ylmethyl) Amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((methyl(oxetan-3-ylmethyl) Amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Refer to Example 1 for the preparation method of the diol.

MS m/z(ESI): 559.3[M+H] ⁺ .

Example 161

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((methyl(oxetan-3-yl)amino) )methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((methyl(oxetan-3-yl)amino) )methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1 for the preparation method.

MS m/z(ESI): 545.3[M+H] ⁺ .

Example 162

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 Preparation of ,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((3-(fluoromethyl)-3-hydroxyazetidin-1-yl)methyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 , The preparation method of 8a-diol refers to Example 1.

MS m/z(ESI): 563.3[M+H] ⁺ .

Example 163

(5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-5a-(4-cyclopropylphenyl )-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- Preparation of 8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-5a-(4-cyclopropylphenyl )-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- Refer to Example 1 for the preparation method of 8,8a-diol.

MS m/z(ESI): 557.3[M+H] ⁺ .

Example 164

N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Preparation of yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyanoamide

N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Preparation method of base-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyanoamide Refer to Example 1.

MS m/z(ESI): 503.2[M+H] ⁺ .

Example 165

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-morpholinylphenyl)-6-phenyl Preparation of -5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-morpholinylphenyl)-6-phenyl For the preparation method of -5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol, refer to Example 1.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.02-2.00 (d, J =7.2 Hz, 2H), 2.90-2.50 (m, 7H), 3.08-3.05 (m, 4H), 3.83-3.80 (m, 4H) ,3.93(s,3H),4.03(s,3H),5.10(s,1H),5.35(s,1H),6.02(s,1H),6.70(d, J =8.0Hz,2H),6.88- 6.83(m, 2H), 7.15-7.10(m, 5H);

MS m/z(ESI): 548.3[M+H] ⁺ .

Example 166

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(4-methylpiperazin-1-yl) )phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol preparation

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(4-methylpiperazin-1-yl) )phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1 for the preparation method.

MS m/z(ESI): 561.3[M+H] ⁺ .

Example 167

(E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6- Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzene(carboxaldehyde) O-methyl Preparation of oximes

(E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6- Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzene(carboxaldehyde) O-methyl The preparation method of oxime refers to Example 1.

MS m/z(ESI): 520.3[M+H] ⁺ .

Example 168

(E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6- Preparation of Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzene(carboxyl)aldoxime

The first step: the preparation of 4-(benzyloxy)-2,6-dichloropyridine

Under an ice-water bath, NaH (7.59 g, 60 wt%, 190 mmol) was added in portions to the DMF solution (300 mL) of 2,4,6-trichloropyridine (30.0 g, 165 mmol). After stirring for 15 minutes, benzyl alcohol (17.9 mL, 173 mmol) was added dropwise, and the addition was complete, followed by stirring under an ice-water bath for 1 hour. The reaction solution was poured into ice water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine for several times, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and separated by column chromatography. The title compound 4-(benzyloxy)-2,6-dichloropyridine (30.4 g, 73%) was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.11 (s, 2H), 6.86 (s, 2H), 7.37-7.42 (m, 5H);

MS m/z(ESI): 254.0[M+H] ⁺ .

The second step: the preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine

To a toluene solution (400 mL) of 4-(benzyloxy)-2,6-dichloropyridine (27.0 g, 106 mmol) was added a methanol solution of sodium methoxide (30 wt%, 36.4 g, 202 mmol), and then the solution was heated at 60 °C. Stir for 5 hours. The reaction was cooled to room temperature, the reaction solution was poured into water, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound, 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.6 g, 74%), was isolated.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.81(s, 3H), 5.20(s, 2H), 6.46(d, J =1.9Hz, 1H), 6.81(d, J =1.9Hz, 1H), 7.32-7.47(m,5H);

MS m/z(ESI): 250.2[M+H] ⁺ .

The third step: preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol

Under a dry ice-acetone bath, to a solution of 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.5 g, 78.1 mmol) in THF (200 mL), a solution of n-BuLi in n-hexane was added dropwise (41.0 mL, 2.4 M, 97.6 mmol), stirred at this temperature for 30 minutes, then added acetaldehyde (6.88 g, 156 mmol) dropwise to the reaction system, the dropwise addition was completed, continued stirring for 10 minutes, and added saturated aqueous ammonium chloride solution The reaction was quenched, the reaction solution was extracted several times with ethyl acetate, the organic phases were combined, washed with saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure, and the title compound 1 was isolated by column chromatography. -(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol (16 g, 70%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 1.39(d, J =6.6Hz, 3H), 3.84(s, 3H), 4.60(d, J =6.6Hz, 1H), 5.09-5.14(m, 1H) ), 5.25(s, 2H), 6.93(s, 1H), 7.32-7.49(m, 5H);

MS m/z(ESI): 294.1[M+H] ⁺ .

The fourth step: the preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-one

To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol (16.0 g, 54.6 mmol) in dichloromethane (320 mL) was divided DMP (30.1 g, 71.0 mmol) was added in batches and the addition was complete and stirring was continued at room temperature for 2 hours. Then, a saturated aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution were sequentially added, followed by stirring for an additional 15 minutes. The organic phase was separated and the aqueous phase was extracted twice more with dichloromethane. After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound was separated by column chromatography to obtain the title compound 1-(4-(benzyloxy)-6-chloro-2-methoxypyridine-3). -yl)ethan-1-one (8.10 g, 51%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 2.37(s,3H), 3.84(s,3H), 4.60(d, J =6.1Hz,1H), 5.28(s,2H), 7.10(s,1H) ),7.32-7.47(m,5H);

MS m/z(ESI): 292.2[M+H] ⁺ .

The fifth step: the preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) ethane-1-one

To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one (4.67 g, 16.0 mmol) in ethyl acetate (120 mL), Pd/C (140 mg, 10 wt%) was added, and under a hydrogen atmosphere at room temperature and pressure, stirred for 3 hours, filtered off with celite, and the filtrate was concentrated under reduced pressure and separated by column chromatography to obtain the title compound 1-(6 -Chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.30 g, 71%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 2.50(s, 3H), 3.90(s, 3H), 6.70(s, 1H), 13.00(s, 1H);

MS m/z(ESI): 202.2[M+H] ⁺ .

The sixth step: (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl) prop-2-en-1-one preparation

To 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.00 g, 9.92 mmol), 4-bromobenzaldehyde (1.65 g, 8.93 mmol) MeONa in MeOH solution (5.36g, 30wt%, 29.8mmol) was added to the DMF solution (31mL), vigorously stirred at 50°C for 30 minutes, cooled, and then poured into dilute hydrochloric acid (0.3M, 200mL) under an ice-water bath, The precipitated solid was collected by filtration and dried, then purified by slurrying with EtOAc/n-heptane mixed solvent (mixed solvent ratio 1:10) to obtain the title compound (E)-3-(4-bromophenyl)-1-(6- Chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one (1.87 g, 57%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.80(s, 3H), 6.60(s, 1H), 7.20(d, J =16.0Hz, 1H), 7.40(d, J =16.0Hz, 1H), 7.56-7.73(m,4H);

MS m/z(ESI): 368.0[M+H] ⁺ .

The seventh step: preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one

Under a water bath, add (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one ( 1.40 g, 3.80 mmol) of a mixed solution of EtOH (27 mL) and DCM (6.8 mL) were successively added dropwise with NaOH aqueous solution (3.36 g, 10 wt%, 8.39 mmol) and H ₂ O ₂ aqueous solution (3.03 g, 30 wt %, 26.7 mmol), and then stirred under a water bath for 1 hour. Saturated aqueous ammonium chloride solution was added, extracted three times with DCM, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain crude 2-(4-bromophenyl)-7-chloro-3-hydroxy-5 -Methoxy-4H-pyrano[3,2-c]pyridin-4-one (700 mg) was used directly in the next step without further purification.

MS m/z(ESI): 381.9[M+H] ⁺ .

The eighth step: preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one

To 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (crude from previous step, 700 mg) In the DMF solution (30 mL), a methanol solution of sodium methoxide (15 mL, 30 wt%) was added, then stirred at 80 °C for 1 hour, cooled, and the reaction solution was poured into ice water, The pH was adjusted to weakly acidic with hydrochloric acid (6M), the precipitated solid was filtered, the filter cake was washed with water, the solid compound was collected and dried, separated and purified by column chromatography to obtain the title compound 2-(4-bromophenyl)-3-hydroxyl -5,7-Dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (180 mg, yield for two steps: 13%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 3.95(s, 3H), 4.00(s, 3H), 6.60(s, 1H), 7.75(d, J =9.6Hz, 2H), 8.10(d, J =8.0Hz,2H),9.65(br s,1H);

MS m/z(ESI): 378.0[M+H] ⁺ .

Step 9: Racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl- Preparation of 2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate

2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (160 mg, 0.424 mmol) and cinnamic acid Methyl ester (686 mg, 4.24 mmol) was dissolved in chloroform (7 mL) and trifluoroethanol (5.6 mL) at 0°C with vigorous stirring under 450 W UV light irradiation for 5 hours. Concentrate the organic solvent under reduced pressure to remove excess methyl cinnamate by column chromatography to obtain the crude product racemic-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8 -Dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate (250 mg), which was directly used in the next reaction.

MS m/z(ESI): 540.1[M+H] ⁺ .

Step 10: Racemic-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-benzene Preparation of base-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylate

to rac-methyl(3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3, 4,5-Tetrahydro-2,5-methyleneoxhepto[3,2-c]pyridine-4-carboxylate (250 mg, crude, about 0.424 mmol) in methanol (8 mL) was added dropwise methanol A methanol solution of sodium (30wt%, 252mg, 1.40mmol) was then stirred at 60°C for 45 minutes, the reaction was cooled to room temperature, the organic solvent was concentrated under reduced pressure, the residue was separated with dichloromethane and saturated aqueous ammonium chloride solution, The organic phase was separated and dried with anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure to obtain the crude product racemic-methyl(5aR,6S,7R,8aR)-5a-(4-bromophenyl)-8a-hydroxyl-1, 3-Dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine- 7-Carboxylic acid ester (250 mg) was used directly in the next reaction.

MS m/z(ESI): 540.1[M+H] ⁺ .

Step 11: Racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- Preparation of 5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylic acid

Under ice bath, racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-benzene yl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- 8,8a -diol (0.26 g, 479.37 μmol) Dissolved in MeOH (3 mL), THF (1.5 mL) and H ₂ O (1.5 mL), lithium hydroxide hydrate (201.16 mg, 4.79 mmol) was added, the reaction solution was stirred under ice bath for 10 minutes, slowly raised to 25 °C and stirred for 3 Hour. The pH of the reaction solution was adjusted to 6 with 1N HCl, extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to obtain the title compound racemic-(5aR,7R,8R,8aS)-5a-(4-bromo) Phenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo [3,2-c]pyridine-7-carboxylic acid (206 mg, 81%). .

MS m/z(ESI): 528.1[M+H] ⁺ .

Step 12: Racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N -Dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide preparation

Under ice bath, (5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8 ,8a-Tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxylic acid (0.23 g, 435.32 μmol) was dissolved in DCM (1.51 mL), DIPEA (365.70mg, 2.83mmol) was added, HATU (246.35mg, 652.98 μmol) was added in batches, the reaction solution was stirred under ice bath for 10 minutes, dimethylamine hydrochloride (177.7mg, 2.18mmol) was added, slowly liters Warm to room temperature and stir for an additional 2 hours. The reaction solution was diluted with DCM, washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the title compound racemic-(5aR,6S,7R,8R,8aS)-5a-( 4-Bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-ring Pentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (215 mg, 89%).

MS m/z(ESI): 555.1[M+H] ⁺ .

The thirteenth step: racemic-methyl 4-((5aR,6S,7R,8R,8aS)-7-(dimethylaminoformamide)-8,8a-dihydroxy-1,3-di Methoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzoate preparation

At room temperature, racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N- Dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine-7-carboxamide (0.356 g, 640.96 μmol) was dissolved in MeOH (20 mL) and MeCN (7 mL), trans-bis(mu-acetoxy)bis[o-(di-o-tolylphosph)benzyl]dipalladium (180.30 mg, 192.29 g) was added μmol) and Mo(CO) ₆ ( 507.64 mg, 1.92 mmol), bubbled with nitrogen for 5 minutes, heated to 135° C. and microwaved for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was separated with dichloromethane and water, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated and separated by column chromatography to obtain the title compound racemic-methyl 4-((5aR,6S ,7R,8R,8aS)-7-(dimethylaminocarboxylate)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetra Hydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzoate (210 mg, 61%).

MS m/z(ESI): 535.2[M+H] ⁺ .

The fourteenth step: racemic-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(hydroxymethyl)phenyl)-1, 3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Preparation of diols

At room temperature, rac-methyl 4-((5aR,6S,7R,8R,8aS)-7-(dimethylaminoformamide)-8,8a-dihydroxy-1,3-dimethyl Oxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzoate ( 0.23 g, 430.3 μmol) was dissolved in THF (5 mL), borane (7.27 mmol, 5.15 mL, 2M in THF) was slowly added, the temperature was raised to 66° C., and stirred for 12 hours. The reaction was quenched by adding methanol solution and stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound racemic (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(hydroxymethyl) yl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2- c] Pyridine-8,8a-diol (110 mg, 51.9%).

MS m/z(ESI): 493.2[M+H] ⁺ .

Step 15: Racemic-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethyl Oxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzene (meth) Preparation of aldehydes

Under ice bath, racemic-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(hydroxymethyl)phenyl)-1,3 -Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di The alcohol (0.09 g, 182.72 μmol) was dissolved in DCM (6.6 mL), DMP (116.25 mg, 274.08 μmol) was added, and the reaction was stirred under an ice bath for 0.5 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography to obtain the title compound racemic-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a- Dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridine -5a-yl)benzene(formaldehyde) (71 mg, 79%).

MS m/z(ESI): 491.2[M+H] ⁺ .

The sixteenth step: (E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethyl Oxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzene (meth) Preparation of aldoximes

At room temperature, racemic-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy yl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzene(methylene)aldehyde (0.071 g, 144.74 μmol) was dissolved in EtOH (2 mL) and H ₂ O (2 mL), hydroxylamine hydrochloride (20.12 mg, 289.47 μmol) and DIPEA (73.23 mg, 723.68 μmol) were added, and nitrogen was bubbled for 5 minutes , and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, separated by reverse-phase preparation, and then resolved on a chiral column to obtain the optically pure title compound (E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethyl Amino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5 ]furo[3,2-c]pyridin-5a-yl)benzene(methyl)aldoxime (26 mg, 36%).

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.96-2.02(m,1H), 2.13-2.28(m,6H), 2.55-2.59(m,1H), 3.11-3.16(m,1H), 3.68( d,J=14.0Hz,1H),3.81-3.85(m,6H),4.43-4.48(m,1H),4.95(s,1H),5.29(s,1H),6.04(s,1H),6.93 -7.01(m,2H),7.03-7.09(m,2H),7.17-7.21(m,2H),7.23-7.28(m,2H),7.35-7.43(m,1H),7.95(s,1H) ,11.09(s,1H);

MS m/z(ESI): 506.3[M+H] ⁺ .

Example 169

N-((E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy -6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzylidene)cyanide Preparation of amides

N-((E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy -6-Phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzylidene)cyanide Refer to Example 1 for the preparation method of amide.

MS m/z(ESI): 515.2[M+H] ⁺ .

Example 170

Cyclopropyl(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6- Preparation of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)methanone

Cyclopropyl(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6- Refer to the preparation method of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)methanone Example 1.

MS m/z(ESI): 531.2[M+H] ⁺ .

Example 171

(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- 6,7,8,8a-Tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)(oxetan-3-yl) Preparation of ketone

(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl- 6,7,8,8a-Tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)(oxetan-3-yl) For the preparation method of ketone, refer to Example 1.

MS m/z(ESI): 547.2[M+H] ⁺ .

Example 172

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-methyloxetan-3- yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Preparation of alcohol

(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-methyloxetan-3- yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Refer to Example 1 for the preparation method of alcohol.

MS m/z(ESI): 533.3[M+H] ⁺ .

Example 173

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-hydroxyazetidin-1-yl)methyl)-1,3-dimethoxy Preparation of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-hydroxyazetidin-1-yl)methyl)-1,3-dimethoxy Refer to the preparation method of -6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Example 1.

¹ H NMR (400 MHz, DMSO- d ⁶ ) δ 1.96-2.04 (m, 2H), 2.30-2.35 (m, 2H), 2.66-2.71 (m, 1H), 2.89-3.01 (m, 2H), 3.49- 3.52(m, 1H), 3.65(d, J =14.2Hz, 2H), 3.82(s, 3H), 3.85(s, 3H), 4.35-4.42(m, 2H), 5.25-5.31(m, 1H) ,6.03(s,1H),6.78-6.83(m,2H),6.89-6.95(m,2H),7.01-7.05(m,1H),7.06-7.11(m,2H),7.14-7.20(m, 2H);

MS m/z(ESI): 532.2[M+H] ⁺ .

Example 174

4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-6,7,8, Preparation of 8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-6,7,8, Refer to Example 1 for the preparation method of 8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile.

MS m/z(ESI): 461.2[M+H] ⁺ .

Example 175

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((methyl(2,2,2-trifluoroethyl) Amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((methyl(2,2,2-trifluoroethyl) Amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Refer to Example 1 for the preparation method of the diol.

MS m/z(ESI): 572.2[M+H] ⁺ .

Example 176

1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Preparation of yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)propan-1-one

1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-benzene Preparation of yl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)propan-1-one Refer to Example 1 for the method.

MS m/z(ESI): 519.2[M+H] ⁺ .

Example 177

(5aR,6S,7R,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-8,8a-dihydroxy-1,3-di Methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine Preparation of -7-formamide

(5aR,6S,7R,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-8,8a-dihydroxy-1,3-di Methoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopentadieno[4,5]furo[3,2-c]pyridine The preparation method of -7-formamide refers to Example 1.

MS m/z(ESI): 575.2[M+H] ⁺ .

Example 178

(5aR,6S,7S,8R,8aS)-5a-(4-(3-fluoroazetidin-1-yl)phenyl)-7-((3-hydroxyazetidin-1-yl)methyl )-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- Preparation of 8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-(3-fluoroazetidin-1-yl)phenyl)-7-((3-hydroxyazetidin-1-yl)methyl )-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine- The preparation method of 8,8a-diol refers to Example 1

MS m/z(ESI): 564.2[M+H] ⁺ .

Example 179

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)- 1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8, Preparation of 8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)- 1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8, Refer to Example 1 for the preparation method of 8a-diol.

MS m/z(ESI): 561.2[M+H] ⁺ .

Example 180

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((3-(methoxymethyl)azetidine-1 -yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Preparation of diols

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((3-(methoxymethyl)azetidine-1 -yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a- Refer to Example 1 for the preparation method of the diol.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 2.27-2.33(m,1H), 2.58-2.63(m,1H), 2.77-2.88(m,4H), 3.15-3.19(m,1H), 3.20( s,3H),3.21-3.24(m,1H),3.37-3.39(m,2H),3.62-3.67(m,1H),3.82(s,3H),3.84(s,3H),4.35-4.39( m,1H),5.21-5.24(m,1H),5.31- 5.36(m,1H),6.01(s,1H),6.77-6.81(m,2H),6.89-6.94(m,2H),6.98- 7.03(m,1H),7.04-7.10(m,2H),7.15-7.20(m,2H).

MS m/z(ESI): 560.2[M+H] ⁺ .

Example 181

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((3-methoxyazetidin-1-yl)methan yl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((3-methoxyazetidin-1-yl)methan yl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-diol Refer to Example 1 for the method.

MS m/z(ESI): 546.2[M+H] ⁺ .

Example 182

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)-1,3 -Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Preparation of alcohol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-hydroxy-3-methylazetidin-1-yl)methyl)-1,3 -Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8,8a-di Refer to Example 1 for the preparation method of alcohol.

MS m/z(ESI): 546.2[M+H] ⁺ .

Example 183

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-(hydroxymethyl)-3-methylazetidin-1-yl)methyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 Preparation of ,8a-diol

(5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-(hydroxymethyl)-3-methylazetidin-1-yl)methyl) -1,3-Dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopentadieno[4,5]furo[3,2-c]pyridine-8 , The preparation method of 8a-diol refers to Example 1.

¹ H NMR (400MHz, DMSO- d ⁶ ) δ 1.00(s, 3H), 1.89-1.95(m, 1H), 2.60-2.73(m, 4H), 2.77-2.86(m, 2H), 2.93-3.04( m,3H),3.61-3.65(m,1H),3.76(s,3H),3.78(s,3H),4.30-4.34(m,1H),4.58-4.67(m,1H),5.16-5.19( m,1H),5.95(s,1H),6.70-6.74(m,2H),6.84-6.88(m,2H),6.93-6.97(m,1H),6.99-7.03(m,2H),7.09- 7.13(m,2H).

MS m/z(ESI): 560.2[M+H] ⁺ .

Example 184

4-((5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6 - Preparation of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

4-((5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6 -The preparation method of phenyl-6,7,8,8a-tetrahydro-5aH-cyclopentadieno[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was implemented with reference to example 1.

MS m/z(ESI): 504.2[M+H] ⁺ .

Biological Test Evaluation

The present invention is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

1. Cell function experiments

Test Example 1. Proliferation inhibitory activity of the compounds of the present invention on lymphoma cell lines TMD8 and SU-DHL-2

1.1. Experiment purpose:

The proliferation inhibitory activities of the compounds of the examples against the lymphoma cell lines TMD8 and SU-DHL-2 were determined.

2. Experimental equipment:

2.1 Instruments:

Microplate reader (BioTek Synergy H1);

Pipette (Eppendorf & Rainin).

2.2 Reagents:

TMD8 was purchased from Nanjing Kebai Biotechnology Co., Ltd.;

SU-DHL-2 cells were purchased from ATCC under the catalog number CRL-2956;

Cell Titer-Glo cells were purchased from Promega, the product number is G7573;

RPMI 1640 was purchased from Gibco, part number 22400089;

DMEM was purchased from Gibco, catalog number 11995065;

FBS was purchased from Gibco, item number 10091148;

PBS was purchased from Gibco, catalog number 10010023;

Pancreatin was purchased from Gibco, catalog number 25200056;

Cell culture plates were purchased from Corning Company, Cat. No. 3610.

3. Experimental method:

When TMD8 or SU-DHL-2 cells are cultured to an appropriate degree of confluency, collect TMD8 or SU-DHL-2 cells, use complete medium to adjust the cells to an appropriate cell density, and plate the cell suspension in a 96-well plate, each well 90 μL was placed in a 37°C, 5% CO ₂ incubator overnight, compound solutions of different concentrations were prepared using DMSO and culture medium, a vehicle control was set, and the compound solution was added to a 96-well plate, 10 μL per well, and placed in a 96-well plate. After culturing for about 72 hours in a 37°C, 5% CO ₂ incubator, add CellTiter-Glo solution, shake to mix well, incubate in the dark for 10 minutes, and read with a BioTek Synergy H1 microplate reader.

4. Experimental data processing method:

The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted to a nonlinear regression curve using Graphpad Prism software to obtain the GI ₅₀ value.

5. Experimental results:

The IC ₅₀ of the compounds of the present invention for inhibition of TMD8 and SU-DHL-2 cell proliferation showed biological activities of about 0.01 nM to 500 nM.

In some embodiments, the _IC50 of the compounds of the invention for inhibition of TMD8 and SU-DHL-2 cell proliferation is less than about 100 nM, preferably the compound is less than about 50 nM, more preferably less than about 10 nM, more preferably less than about 5 nM. The best of the listed compounds is less than 1 nM.

Table 1 IC ₅₀ values of compounds on cell proliferation inhibitory activity

"NA" stands for not tested.

6. Experimental conclusion:

The compounds of the examples of the present invention have significant inhibitory effects on the proliferation of TMD8 and SU-DHL-2 cells.

Test Example 2. Determination of the Growth Inhibitory Activity of the Compounds of the Invention on Tumor Cell Lines

1. Experimental purpose:

The proliferation inhibitory activity of the compounds in the examples was determined on 8 tumor cell lines, which were 1 human pancreatic cancer cell line (KRAS G12C mutant cell line Mia PaCa-2) and 1 human lung cancer adenocarcinoma cell line (KRAS G13C mutant cell line NCI- H1792), 3 human breast cancer cells (KRAS G13D mutant cell lines MDA-MB-231, BT474 and MDA-MB-361), 1 human B lymphoma cell SU-DHL-6, 2 human colon cancer cell lines (KRAS G12V mutant cell lines SW620 and NCI-H716).

2. Experimental equipment:

2.1 Instruments:

Microplate reader (BioTek Synergy H1);

Pipette (Eppendorf & Rainin).

2.2 Reagents:

MDA-MB-231, MDA-MB-361, SW620 and BT474 were purchased from Nanjing Kebai Biotechnology Co., Ltd.;

Mia PaCa-2 and SU-DHL-6 were purchased from ATCC; NCI-H1792 and NCI-H716 were purchased from Guangzhou Genio Biotechnology Co., Ltd.;

Cell Titer-Glo cells were purchased from Promega, the product number is G7573;

RPMI 1640 was purchased from Gibco, part number 22400089;

DMEM was purchased from Gibco, catalog number 11995065;

FBS was purchased from Gibco with the item number 10091148; PBS was purchased from Gibco with the item number 10010023;

Pancreatin was purchased from Gibco, catalog number 25200056;

Cell culture plates were purchased from Corning Company, Cat. No. 3610.

3. Experimental method:

Adherent cells: Collect MDA-MB-231, MDA-MB-361, MDA-MB-231, MDA-MB-361, For Mia PaCa-2, SW620, NCI- H1792 and BT474 cells, use complete medium to adjust the cells to an appropriate cell density, and plate the cell suspension in a 96-well plate, 90 μL per well, at 37°C, 5% CO _2. The incubator was adhered to the wall overnight, and DMSO and medium were used to prepare compound solutions of different concentrations, and the vehicle control was set. The compound solution was added to a 96-well plate, 10 μL per well, and placed in a 37 ° C, 5% CO ₂ incubator After culturing for about 72 hours, 50 μL of CellTiter -Glo solution was added to each well, shaken and mixed evenly, incubated in the dark for 10 minutes, and read with a BioTek Synergy H1 microplate reader.

Suspension cells: When SU-DHL-6 and NCI-H716 cells are cultured to an appropriate degree of confluency, collect SU-DHL-6 and NCI-H716 cells, use complete medium to adjust the cells to an appropriate cell density, and plate the cell suspension. In a 96-well plate, 90 μL per well. Compound solutions of different concentrations were prepared using DMSO and culture medium, and a vehicle control was set. Compound solutions were added to a 96-well plate, 10 μL per well, and placed in a 37° C., 5% _CO incubator for about 72 hours. Add 50 μL of CellTiter -Glo solution to each well, shake to mix evenly, incubate in the dark for 10 minutes, and read with a BioTek Synergy H1 microplate reader.

4. Experimental data processing method:

The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted to a nonlinear regression curve using Graphpad Prism software to obtain the _IC50 value.

5. Experimental results:

The experimental results are shown in Table 2. The example compounds have inhibitory activity on the proliferation of MDA-MB-231, MDA-MB-361, Mia PaCa-2, SW620, NCI-H1792, BT474, SU-DHL-6 and NCI-H716 cells The IC ₅₀ values of α show a biological activity of about 0.1 nM to 500 nM.

In some embodiments, the compounds of the invention have ICs for inhibition of proliferation of MDA-MB-231, MDA-MB-361, Mia PaCa-2, SW620, NCI-H1792, BT474, SU-DHL-6 and NCI-H716 cells ₅₀ is less than about 100 nM, preferably less than about 50 nM for compounds, more preferably less than about 20 nM, more preferably less than about 10 nM, and most preferably less than 1 nM in the compounds listed in the present invention.

Table 2 IC ₅₀ values of compounds on cell proliferation inhibitory activity

Table 3 IC ₅₀ values of compounds on cell proliferation inhibitory activity

"NA" stands for not tested.

6. Experimental conclusion:

The compounds of the examples of the present invention have significant proliferation inhibitory effects on MDA-MB-231, MDA-MB-361, Mia PaCa-2, SW620, NCI-H1792, BT474, SU-DHL-6 and NCI-H716 cells.

Test Example 3. In vivo pharmacodynamic study of NCI-H716 in BALB/c nude mice subcutaneous xenograft tumor model

1. Experimental purpose:

The efficacy of the test compounds on human colon adenocarcinoma cell line NCI-H716 in BALB/c nude mouse subcutaneous xenograft tumor model was evaluated.

2. Experimental instruments and reagents:

2.1 Instruments:

Ultra-clean workbench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

_CO2 incubator (Thermo-311, Thermo)

Centrifuge (Centrifuge 5720R, Eppendorf)

Constant temperature water bath (HSW-12, Shanghai Yiheng Scientific Instrument Co., Ltd.)

Electric pipetting aid (Easypet 3, Eppendorf)

Automated cell counter (Countess II, Life Technologies)

Electronic balance (BSA2202S-CW, Sartorius)

Vernier caliper (CD-6"AX, Mitutoyo, Japan)

Cell culture flasks (T25/T75/T225, Corning)

2.2 Reagents:

RPMI-1640 (22400-089, Gibco)

Fetal Bovine Serum FBS (10099-141C, Gibco)

0.25% Trypsin-EDTA (25200-056, Gibco)

Phosphate Buffered Saline PBS (10010-023, Gibco)

Matrigel Matrix Matrigel (356234, Corning)

3. Experimental operation and data processing:

3.1 Experimental operation:

Take out NCI-H716 cells from the cell bank, add them to complete medium (RPMI1640+10%FBS+1% P/S) after recovery and place them in a _CO2 incubator (incubator temperature is 37°C, _CO2 concentration is 5 %), NCI-H716 cells were collected when the number of cells expanded to the number required for in vivo inoculation. The cells were counted with an automatic cell counter, and the cells were resuspended with a mixture of PBS and Matrigel (1:1) according to the counting results to prepare a cell suspension (density 5×10 ⁷ /mL), which was placed in an ice box for use.

6-8 week old female BALB/c nude mice (18-20 g, Laboratory Animal Management Department, Shanghai Institute of Family Planning Science) were used. Mice were housed in SPF-grade animal rooms, and were housed in single cages, with 5 mice per cage. All cages, litter and water were autoclaved before use, and all animals had free access to food and water. Before the start of the experiment, the nude mice ^were marked with a disposable ear tag for rats and mice, and the skin of the inoculation site was disinfected with 75% medical alcohol before inoculation. H716 cells. When the tumor volume reached 60-200mm ³ , group administration was started, with 5 mice in each group. Each test compound was administered by tail vein twice a week for a total of 5 times (respectively on D0, D4, D7, D11, D14). Tumor volume was measured, mice were weighed, and tumor TGI (%) was calculated twice a week, and tumor TGI (%) was calculated.

3.2 Data processing:

Tumor volume (mm ³ ), calculated by the formula: V=0.5*D*d*d, where D and d are the long and short diameters of the tumor, respectively.

Calculation of TGI(%):

When the tumor did not regress, TGI(%)=[(1-(average tumor volume at the end of a certain treatment group-the average tumor volume at the beginning of the treatment group))/(average tumor volume at the end of the treatment in the solvent control group -Mean tumor volume at the start of treatment in the solvent control group)] × 100%;

When the tumor regressed, TGI(%)=[1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/average tumor volume at the beginning of administration of this treatment group]× 100%.

4. Experimental results:

Table 4 Pharmacodynamic parameters

5 Experimental conclusions:

The above data show that the compound of Example 83 of the present invention (1.5mpk, BIW, IV ) showed a relatively significant tumor inhibition at 18 days after administration.

Test Example 4. Pharmacokinetic Evaluation Test in Mice

1. Experimental purpose:

PKPD behavior in mice (tumors) after single tail vein administration of compounds was investigated.

2. Experimental protocol

2.1 Experimental animals:

Species: mouse

Strain: BALB/c nude mice

Age and weight: 8-10 weeks old, weight 17-20 grams

gender: female

Supplier: Shanghai Sipple-Bikai Laboratory Animal Co., Ltd.

2.2 Drug preparation:

Weigh 1 mg of the compound to be tested and add 0.098 mL of DMA to fully dissolve the drug. Take 0.045ml of it and then add 2.55mL of solvent, and vortex to obtain 1.5mg/mL liquid medicine.

2.3 Dosing schedule:

2.3.1. After tumor inoculation, the PDPK experiment was started when the tumor volume was 300-500 mm ³ .

2.3.2. Tumor-bearing mice were fasted overnight and euthanized at time points after administration.

2.4 Sample collection:

2.4.1. After the mice were euthanized, blood was collected from the heart, and the collected blood was added to a centrifuge tube containing EDTA-2K, manually inverted for several times and then placed on ice to stand at 4°C, 8000 rpm, and centrifuged for 5 minutes. After centrifugation, 100 μL of plasma was transferred to a new labeled centrifuge tube, quick-frozen on dry ice and stored in a -80°C refrigerator for PK detection.

2.4.2. After blood collection, the tumor tissue was peeled off, and the peeled tumor tissue was divided into 2 parts (~0.1g each), put into a labeled 2mL centrifuge tube, and then transferred to a -80°C refrigerator for storage. One for PK detection (need to be weighed); 1 for PD detection.

2.5 Liquid phase analysis

Liquid phase conditions: Shimadzu LC-20AD pump

Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

Chromatography column: XBridge ® C18 (50*4.6mm, 5μm particle size)

Mobile phase: A solution is 0.1% formic acid aqueous solution, B solution is methanol

Flow rate: 1.0mL/min

Elution time: 0-4.0 minutes, the eluent is as follows:

2.6 Test results and analysis

The main parameters of pharmacokinetics were calculated with WinNonlin 8.2.

Table 5 Pharmacokinetic parameters of mice tail vein administration of compounds of the present invention

3. Experimental conclusion:

The data in the table shows that in the mouse pharmacokinetic evaluation experiment, the compounds of the examples of the present invention showed higher exposure after tail vein administration, and the distribution in the tumor was more advantageous.

Claims (15)

A compound represented by general formula (II), its stereoisomer or its pharmaceutically acceptable salt,

in, R ₁ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, optionally further substituted by one or more _R8 ; R ₂ and R ₂ ' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 Cycloalkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl substituted by one or more substituents; R ₃ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 Membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, -(CH ₂ ) _n1 R _a , -(CH ₂ ) _n1 NR _a OR _b , -(CH ₂ ) _n1 C(O) NR _a R _b , -(CH ₂ ) _n1 NR _a C(O)R _b , -(CH ₂ ) _n1 S(O) _m1 R _a , -(CH ₂ ) _n1 S(O) _m1 NR _a R _b , -(CH ₂ ) _n1 NR _a S(O) _m1 R _b , -(CH ₂ ) _n1 NR _a R _b or -(CH ₂ ) _n1 NR _a (CH ₂ ) _n2 R _b , the C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1 -6} alkylthio, _C1-6 haloalkoxy, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, _C6-14 membered aryl and 5-14 membered heteroaryl, further if necessary Deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl , C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, substituted by one or more substituents in C _6-14 aryl and 5-14 membered heteroaryl; R ₄ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 Member heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, -(CH ₂ ) _n3 R _c , -(CH ₂ ) _n3 NR _c OR _d , -(CH ₂ ) _n3 C(O) NR _c R _d , -(CH ₂ ) _n3 NR _c C(O)R _d , -(CH ₂ ) _n3 S(O) _m2 R _c , -(CH ₂ ) _n3 S(O) _m2 NR _c R _d , -(CH ₂ ) _n3 NR _c S(O) _m2 R _d , -(CH ₂ ) _n3 NR _c R _d or -(CH ₂ ) _n3 NR _c (CH ₂ ) _n4 R _d , the C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1 -6} alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, if necessary, Further by deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkane base, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl , C _6-14 aryl and 5-14 membered heteroaryl substituted by one or more substituents; R ₆ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, _C6-14 -membered aryl and 5-14-membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, _{C1-6 alkyl} , C2- ₆ alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkyl sulfide One or more substituents in the group, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl replace; Alternatively, R ₆ and R ₄ are linked to the carbon atoms to which they are attached to form C _5-14 cycloalkyl or 5-14 membered heterocyclyl, the C _5-14 cycloalkyl and 5-14 membered heterocyclyl, depending on optionally further deuterium, halogen, amine, hydroxyl, cyano, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 deuterium Substituted alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 ring Substituted by one or more substituents in alkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl; R ₇ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl , C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, _C6-14 -membered aryl and 5-14-membered heteroaryl, optionally further deuterium, halogen, amino, hydroxyl, cyano, _{C1-6 alkyl} , C2- ₆ alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkyl sulfide One or more substituents in the group, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl replace; R ₈ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, oximo, azide, mercapto, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy , C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl, 5-14-membered heteroaryl, -C(O)R _e or -P(O)R _e R _f , The oximo group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 deuterated alkyl group, C _1-6 haloalkyl group, C _1-6 hydroxyalkyl group, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5- 14-membered heteroaryl and -C(O)-, optionally further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, thio, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl substituted by one or more substituents; R _a , R _b , R _c , R _d , _Re and R _f are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkane base, C _1-6 hydroxyalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 Heteroaryl, the amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _{1- 6} -hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl and 5-14 membered heteroaryl groups, optionally further deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, C _1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, One of C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl or more substituents; n1~n4 are 0, 1, 2, 3, 4 or 5; and m1 and m2 are 0, 1 or 2; When R ₁ and R ₂ are phenyl, and R ₈ is halogen, cyano or C _1-6 haloalkyl, R ₄ is not hydroxyl, or R ₂ ' is not hydrogen, or R ₃ is not

. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 Alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the C _1-6 alkane base, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, optionally is further substituted by one or more R ₈ ; R ₈ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, oximo, mercapto, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy , C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -C(O)R _e , -SR _e , -OR _e , -NR _e R _f , -C(O)NR _e R _f , -NR _e C(O)R _f , -OC(O)R _e R _f , -C(O)OR _e , -S(O) ₂ R _e , -S(O)R _e , -S(O) ₂ NR _e R _f , -S(O)NR _e R _f , -NR _e S(O) ₂ R _f , -NR _e S(O)R _f , -P(O)R _e R _f , the amine group, oximo group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 deuterated alkyl group, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 Member heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, Thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5- 14-membered heteroaryl is substituted with one or more substituents; R _e and R _f are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Substituted with one or more substituents of haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl. The compound according to claim 2, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl, optionally further substituted by one or more replaced by R ₈ , Preferably phenyl, the phenyl, optionally further substituted by one or more R ₈ ; R ₈ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oximo, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterium Substituted alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 haloalkoxy, C _3-8 ring Alkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl, 5-10 membered heteroaryl, Preferred are cyclopropyl, nitro or oximo. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl Or 5-10 membered heteroaryl, the C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 membered aryl and 5-10 membered heteroaryl, optionally further substituted by deuterium, halogen, Amine, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 Hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 haloalkoxy, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl substituted with one or more substituents in the 5-10 membered heteroaryl group, Preferably, R ₂ is selected from phenyl or bicyclo[1.1.1]pentane; more preferably, R ₂ is selected from phenyl; R ₂ ' is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy, Preferably, R ₂ ' is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl; and/or, R ₃ is selected from -(CH ₂ ) _n1 R _a , -(CH ₂ ) _n1 NR _a OR _b , -(CH ₂ ) _n1 C(O)NR _a R _b , -(CH ₂ ) _n1 NR _a C(O)R _b , -(CH ₂ ) _n1 S(O) _m1 R _a , -(CH ₂ ) _n1 S(O) _m1 NR _a R _b , -(CH ₂ ) _n1 NR _a S(O) _m1 R _b , -(CH ₂ ) _n1 NR _a R _b or -(CH ₂ ) _n1 NR _a (CH ₂ ) _n2 R _b , Preferably, R ₃ is selected from -CH ₂ R _a , -C(O)NR _a R _b , -S(O) ₂ R _a , -CH ₂ NR _a R _b , -CH ₂ NR _a CH ₂ R _b or -CH ₂ NR _a (CH ₂ ) ₂ R _b ; R _a and R _b are each independently selected from hydrogen, halogen, hydroxy, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl, C _1-3 alkoxy, or 4-8 nitrogen-containing heterocyclic group, the C _1-3 alkyl group, C _1-3 hydroxyalkyl group, C _1-3 haloalkyl group, C _1-3 alkoxy group and 4-8-membered nitrogen-containing heterocyclic group, depending on optionally further substituted with one or more substituents of hydrogen, deuterium, hydroxy, _C1-3 alkyl, _C1-3 hydroxyalkyl, _C1-3 haloalkyl or _C1-3 alkoxy , Preferably, R _a and R _b are each independently hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, 2-hydroxyisopropyl, piperidinyl, piperazinyl, morpholinyl, pyrrole Alkyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, (1R, 5S)-3-oxa-8-azabicyclo[3.2.1]octyl, the methyl, ethyl, methoxy, 2-hydroxyisopropyl, piperidinyl, piperazinyl, morpholine base, pyrrolidinyl, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octyl, optionally further substituted by hydrogen, deuterium, hydroxy, methyl, ethyl, methoxy, difluoromethyl or one or more substituents in trifluoromethyl; And/or, R4 is selected from -OH, _- ( _CH2 ) _n3Rc , -( _{CH2 ) n3NRcORd} , -( _{CH2 )n3C ( O ) NRcRd} , -( _CH2 ) _n3 NR _c C(O)R _d , -(CH ₂ ) _n3 S(O) _m2 R _c , -(CH ₂ ) _n3 S(O) _m2 NR _c R _d , -(CH ₂ ) _n3 NR _c S (O) _m2 R _d , -(CH ₂ ) _n3 NR _c R _d or -(CH ₂ ) _n3 NR _c (CH ₂ ) _n4 R _d, Preferably _-OH , -( _CH2 ) _n3NRcRd or - _{( CH2 ) n3NRcORd ;} R _c and R _d are each independently selected from hydrogen, halogen, hydroxy, C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl or C _1-3 alkoxy, the C _{1-3 -3} alkyl, C _1-3 hydroxyalkyl, C _1-3 haloalkyl and C _1-3 alkoxy, optionally further replaced by hydrogen, deuterium, hydroxyl, C _1-3 alkyl, C _1- substituted by one or more substituents in ₃ hydroxyalkyl, C _1-3 haloalkyl or C _1-3 alkoxy; And/or, R ₆ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl group, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy, More preferably, R ₆ is selected from methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy; more preferably methoxy; And/or, R ₇ is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl group, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy, More preferably, R ₇ is selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy; more preferably methoxy; n3 and n4 are 0, 1, 2, 3, 4, or 5; and m2 is 0, 1 or 2. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the general formula (II) is further represented by the general formula (IV):

The compound of claim 5, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R ₂ ' is selected from hydrogen; R ₃ is selected from -(CH ₂ ) _n1 NR _a C(O)R _b or -(CH ₂ ) _n1 NR _a R _b ; R _a or R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy; Alternatively, R _a and R _b and adjacent nitrogen atoms form a 4-8 membered heterocyclic group containing 1-2 atoms selected from nitrogen or oxygen, optionally further substituted by halogen, C _1-3 alkyl, C _{1 -3} alkoxy, C _1-3 haloalkyl or C _1-3 hydroxyalkyl substituted by one or more substituents; R ₇ is selected from cyano or C _1-3 alkoxy; R ₈ is selected from cyano, azido, oximo, nitro, C _3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4 containing 1 nitrogen or oxygen atom -6-membered heterocyclic group, 7-8-membered spiroheterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, 7-8-membered fused heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen; further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkane substituted with one or more substituents in the C _1-3 alkyl substituted by cyano group or cyano group. The compound of claim 6, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R ₂ ' is selected from hydrogen; R ₃ is selected from -(CH ₂ ) _n1 NR _a R _b ; R _a or R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy; preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl or C _1-3 haloalkyl; more preferably methyl; R ₇ is selected from cyano or C _1-3 alkoxy; more preferably methoxy; R ₈ is selected from cyano, azido, oximo, nitro, C _3-6 cycloalkyl; more preferably oximo, nitro or cyclopropyl; n1 is 1. The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, wherein, general formula (II) is further represented by general formula (V) or general formula (VI):

R ₂ ' is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl; more preferably hydrogen; R ₆ and R ₇ are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 deuterium Substituted alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy, More preferably cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy; R ₈ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, oximo, mercapto, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy , C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl, 5-14 membered heteroaryl, -SR _e , -OR _e , -NR _e R _f , -C(O )NR _e R _f , -NR _e C(O)R _f , -OC(O)R _e R _f , -C(O)OR _e , -S(O) ₂ R _e , -S(O)R _e , -S(O) ₂ NR _e R _f , -S(O)NR _e R _f , -NR _e S(O) ₂ R _f , -NR _e S(O)R _f , -P(O)R _e R _f , the amine group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 deuterated alkyl group, C _1-6 haloalkyl group, C _1-6 hydroxy group Alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl, optionally further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _{1- 6} alkoxyalkyl, cyano-substituted C _1-6 alkyl, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl , C _6-14 aryl and 5-14 membered heteroaryl substituted with one or more substituents, Preferably cyano, azido, oximo, nitro, C _3-6 cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4-membered heteroaryl containing 1 nitrogen or oxygen atom 6-membered heterocyclic group, 7-8-membered spiro heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen, 7-8-membered fused heterocyclic group containing 2-3 atoms selected from nitrogen or oxygen; as required further deuterium, halogen, amine, hydroxyl, cyano, azide, nitro, mercapto, pendant oxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl Or substituted by one or more substituents in C _1-3 alkyl substituted by cyano group; R _a and R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkane Thio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl or 5-14-membered heteroaryl, the amine group, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy , C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 membered aryl and 5-14 membered heteroaryl, depending on Desirably, further by deuterium, halogen, amine, hydroxyl, cyano, nitro, azido, mercapto, pendant oxy, thio, _C1-6 alkyl, _C2-6 alkenyl, _{C2 -6} alkynyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 substituted by one or more substituents in haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl; Alternatively, R _a and R _b and adjacent nitrogen atoms form a 4-10-membered heterocyclic group containing 1-3 atoms selected from nitrogen or oxygen, optionally further deuterium, halogen, amine, hydroxyl, cyano , nitro, azide, mercapto, pendant oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 deuterated alkyl, C _{1 -6} haloalkyl, C _1-6 hydroxyalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 substituted with one or more substituents in membered heterocyclyl, _C6-14 aryl and 5-14 membered heteroaryl; R ₄ , _Re and R _f are as described in claim 1 . The compound of claim 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R ₂ ' is selected from hydrogen; R _a or R _b are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, azide, mercapto, C _1-3 alkyl, C _1-3 deuterated alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _1-3 alkylthio or C _1-3 haloalkoxy; preferably hydrogen, deuterium, C _1-3 alkyl, C _1-3 deuterated alkyl or C _1-3 haloalkyl; more preferably methyl; R ₆ and R ₇ are each independently selected from cyano or C _1-3 alkoxy; more preferably methoxy; R ₈ is selected from cyano, azido, oximo, nitro, C _3-6 cycloalkyl; more preferably oximo, nitro or cyclopropyl. The compound, its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein the specific structure of the compound is as follows:

A compound represented by the general formula (M), its stereoisomer or a pharmaceutically acceptable salt thereof,

_R is selected from -C(O)R _g ; R _g is selected from hydroxyl, C _1-3 alkoxy or -NR _a R _b ; The R ₄ , R ₆ , R ₇ , R ₈ , _Ra or R _b are as described in any one of claims 1 to 9. A method for preparing the compound represented by general formula (VI) as described in claim 8, its stereoisomer or its pharmaceutically acceptable salt, is characterized in that, comprises the following steps:

The general formula (M-2) is obtained by the reaction of the general formula (M-1), the general formula (M-3) is obtained by the reaction of the general formula (M-2), and the general formula (VI) is obtained by reduction of the general formula (M-3); Pg is selected from C _1-3 alkoxy; The R ₄ , R ₆ , R ₇ , R ₈ , _Ra or R _b are as described in any one of claims 1 to 9. A pharmaceutical composition comprising a therapeutically effective dose of a compound as described in any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipient. A compound as described in any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 13 in the treatment and/or prevention of ATP dependence. Use in a medicament for RNA helicase-related diseases, especially in a medicament for the treatment and/or prevention of eukaryotic initiation factor 4A inhibitor-related diseases. A compound as described in any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 13 in the treatment and/or prevention of cancer, bone marrow Use in medicine for dysplasia syndrome, Alzheimer's disease, Parkinson's disease, X-chromosome fragile disorder and autism-related diseases; preferably, the cancer is selected from solid tumors or hematological tumors, more preferably large intestine Rectal cancer, bladder cancer, stomach cancer, thyroid cancer, esophagus cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervix cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.