Polycyclic bioregulators, preparation methods and applications thereof

Abstract

A polycyclic bioregulator, a preparation method and application thereof, in particular, a compound represented by general formula (II) or a stereoisomer thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and application thereof in the preparation of drugs for treating cancer and other related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and in particular relates to a polycyclic bioregulator, a preparation method and application thereof. Background Art

[0002] Aberrant messenger RNA (mRNA) translation is a common feature of malignant tumors, manifested by 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 (eIF4F) complex. eIF4F mediates ribosome recruitment to mRNA, initiating mRNA-to-protein translation. The eIF4F complex consists of three subunits: the mRNA 5′ cap-binding protein eIF4E, the scaffolding protein eIF4G, and the RNA helicase eIF4A. eIF4F recognizes the 5′-mRNA cap structure, and eIF4A unwinds the mRNA 5′-UTR secondary structure in an ATP-dependent manner. It then circularizes the mRNA by binding to poly A binding protein, recruiting the 40S subunit for ribosome scanning and translation initiation. eIF4F subunits are frequently overexpressed in various malignancies; therefore, targeting components of the eIF4F complex to normalize dysregulated translation is an emerging strategy for anticancer drug discovery.

[0003] Overactivation of eIF4A, eIF4E, and eIF4G is associated with poor prognosis in related diseases, including lymphoma, lung cancer, colorectal cancer, liver cancer, breast cancer, and ovarian cancer. eIF4A is divided into free and complexed forms based on whether it is bound to the ribosome. The activity of the free form is 1 / 20 of that of the complex form. The eIF4A family consists of three members: eIF4A1, eIF4A2, and eIF4A3. All belong to a family of helicase proteins called DEAD-box. These family proteins all possess nine conserved motifs, each involved in RNA binding or ATP hydrolysis.

[0004] Natural products have been reported to inhibit eIF4A-mediated translation and exhibit antiproliferative and antitumor phenotypes in vitro and in vivo. Silvestrol and rocaglamide A, for example, have been shown to bind and stabilize untranslated RNA / eIF4A complexes. These stabilized eIF4A·RocA complexes block scanning ribosomes, thereby inhibiting the translation of target mRNAs and regulating the expression of related oncogenic factors through eIF4A-mediated translational inhibition. Currently, many eIF4A inhibitors are being developed as antitumor drugs. The main challenges for this class of drugs are metabolic instability, poor solubility, and the development of robust synthetic methods to produce the desired drug substance to support clinical development. Therefore, the development of an eIF4A inhibitor with improved physicochemical properties, good logP, and aqueous solubility to support clinical control of optimal therapeutic doses for intravenous administration is an urgent issue.

[0005] Currently, eFFECTOR Therapeutics' international application WO 2017091585 discloses the eIF4A inhibitor eFT226. Preclinical studies have shown that eFT226 can inhibit the proliferation of RTK solid tumors and lymphomas, and the translation of oncogenic proteins (FGFR1 / 2, HER2, KRAS), as well as being well tolerated in preclinical models. It has entered Phase I clinical trials. Regulating translation is an emerging strategy for anticancer drug discovery. This application aims to provide a novel anti-tumor drug that inhibits eIF4A activity to meet the huge demand in the oncology market. Summary of the Invention

[0006] The object of the present invention is to provide a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, whose structure is as follows:

[0007]

[0008] in:

[0009] X is selected from O, S, S(O), S(O)2, C(O), NR or CRR';

[0010] Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0011] R and R' are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0012] R1 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0013] R2 and R2' are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0014] R3 and R3' are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 R a 、-(CH2) n1 NR a OR b 、-(CH2) n1 C(O)NR a R b 、-(CH2) n1 NR a C(O)R b 、-(CH2) n1 S(O) m1 R a 、-(CH2) n1 S(O) m1 NR a R b 、-(CH2) n1 NR a S(O) m1 R b 、-(CH2) n1 NR a Rb or -(CH2) n1 NR a (CH2) n2 R b , the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0015] R4 and R4' are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n3 R c 、-(CH2) n3 NR c OR d 、-(CH2) n3 C(O)NR c R d 、-(CH2) n3 NR c C(O)R d 、-(CH2) n3 S(O) m2 R c 、-(CH2) n3 S(O) m2 NR c R d 、-(CH2) n3 NR c S(O) m2 R d 、-(CH2) n3 NR c R d or -(CH2) n3 NR c (CH2) n4 R d , the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0016] R5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0017] Ra is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0018] Or, R a and R4 and the carbon atom or heteroatom to which they are attached link to form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups may be further substituted;

[0019] R a 、R b 、R c and R d each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0020] x is 0, 1, 2, 3, 4, or 5;

[0021] n1-n4 are 0, 1, 2, 3, 4 or 5; and

[0022] m1 and m2 are 0, 1, or 2.

[0023] In a preferred embodiment of the present invention, the ring A is selected from C 3-1２ Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0024] In a further preferred embodiment of the present invention, the ring A is selected from C 6-10 Aryl or 5-10 membered heteroaryl;

[0025] In a further preferred embodiment of the present invention, the ring A is selected from 5-6 membered nitrogen-containing heteroaryl groups;

[0026] In a further preferred embodiment of the present invention, the ring A is selected from pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl or pyrazolyl.

[0027] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is further represented by general formula (II):

[0028]

[0029] in:

[0030] R1 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with one or more R8;

[0031] R ２ and R2' 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 1-6Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0032] R3 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -(CH2) n1 R a 、-(CH2) n1 NR a OR b 、-(CH2) n1 C(O)NR a R b、-(CH2) n1 NR a C(O)R b 、-(CH2) n1 S(O) m1 R a 、-(CH2) n1 S(O) m1 NR a R b 、-(CH2) n1 NR a S(O) m1 R b 、-(CH2) n1 NR a R b or -(CH2) n1 NR a (CH2) n2 R b , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0033] R4 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -(CH2) n3 R c 、-(CH2) n3 NR c OR d 、-(CH2) n3 C(O)NR c R d 、-(CH2) n3 NR c C(O)R d 、-(CH2) n3 S(O) m2 R c 、-(CH2) n3 S(O) m2 NR c R d 、-(CH2) n3 NR c S(O) m2 R d 、-(CH2) n3 NR c R d or -(CH2) n3 NR c (CH2) n4 R d , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0034] R6 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0035] Alternatively, R6 and R4 are linked to the carbon atoms to which they are attached to form a C 5-14 Cycloalkyl or 5-14 membered heterocyclic group, the C 5-14 Cycloalkyl and 5-14 membered heterocyclic groups, optionally further substituted by deuterium, halogen, amino, hydroxy, cyano, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0036] R7 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0037] R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxime, azido, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C(O)R e or -P(O)R e R f , the oxime group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl and -C(O)-, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, mercapto, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0038] R a 、R b 、R c 、R d 、R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0039] n1-n4 are 0, 1, 2, 3, 4 or 5; and

[0040] m1 and m2 are 0, 1, or 2;

[0041] When R1 and R2 are phenyl, and R8 is halogen, cyano or C 1-6 When alkyl halide is present, R4 is not hydroxy, or R2' is not hydrogen, or R3 is not

[0042] In a preferred embodiment of the present invention, the R1 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with one or more R8;

[0043] R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, oxime, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 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)Rf、-OC(O)R e R f 、-C(O)OR e 、-S(O)2R e 、-S(O)R e 、-S(O)2NR e R f 、-S(O)NR e R f 、-NR e S(O)2R f 、-NR e S(O)R f 、-P(O)R e R f , the amino, oxime, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, mercapto, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0044] In a further preferred embodiment of the present invention, the R8 is selected from deuterium, halogen, cyano, azido, oxime, nitro, amino, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 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 amino, oxime, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, cyano, hydroxyl, halogen, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0045] In a further preferred embodiment of the present invention, R8 is selected from cyano, azido, nitro, oxime, amino, thiol, methyl, ethynyl, cyclopropyl, oxetanyl, azetidinyl, 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, ethynyl, cyclopropyl, oxetanyl, azetidinyl and tetrazolyl are optionally further substituted with one or more substituents selected from cyano, hydroxyl, fluorine, chlorine, bromine, oxo, methyl and trifluoromethyl;

[0046] In a further preferred embodiment of the present invention, the R8 is selected from -CN, -P(O)(CH3)2, -N3, -NO2, -SCF3, -SCN, -NCH3C(O)CH3, -C(O)N(CH3)2, -N(CN)2, -CH(CN)2, -C(CN)3, -(C≡C)CN,

[0047] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group and the 5-14 membered heteroaryl group are substituted by one or more substituents.

[0048] In a preferred embodiment of the present invention, the R1 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-1 0-membered aryl and 5-10-membered heteroaryl, optionally further substituted by one or more R8;

[0049] In a further preferred embodiment of the present invention, the R1 is selected from phenyl or bicyclo[1.1.1]pentane, and the phenyl and bicyclo[1.1.1]pentane are optionally further substituted by one or more R8;

[0050] R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C1-3 deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-1 0 aryl, 5-10 membered heteroaryl or -P(O)R e R f ;

[0051] Preferably cyano or -P(O)R e R f ;

[0052] R e and R f 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 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 haloalkoxy;

[0053] Preferred are cyano, trifluoromethyl, methyl, ethyl or propyl.

[0054] In a further preferred embodiment of the present invention, R1 is selected from C3-8 cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with one or more R8,

[0055] Preferably phenyl, said phenyl is optionally further substituted by one or more R8;

[0056] R8 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxime, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl,

[0057] Preferred are cyclopropyl, nitro or oxime.

[0058] In a preferred embodiment of the present invention, the R2 is selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl and 5-10 membered heteroaryl, optionally further substituted with 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 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0059] In a further preferred embodiment of the present invention, said R2 is selected from phenyl or bicyclo[1.1.1]pentane;

[0060] In a further preferred embodiment of the present invention, said R2 is selected from phenyl;

[0061] R2' 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 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 haloalkoxy;

[0062] In a further preferred embodiment of the present invention, the R2' is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl.

[0063] In a preferred embodiment of the present invention, R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-l4 Aryl, 5-14 membered heteroaryl, -(CH2) n1 R a 、-(CH2) n1 NRa OR b 、-(CH2) n1 C(O)NR a R b 、-(CH2) n1 OC(O)R a 、-(CH2) n1 NR a C(O)R b 、-(CH2) n1 S(O) m1 R a 、-(CH2) n1 S(O) m1 NR a R b 、-(CH2) n1 NR a S(O) m1 R b 、-(CH2) n1 NR a R b or -(CH2) n1 NR a (CH2) n2 R b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thioxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0064] R aand R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0065] n1 and n2 are 0, 1, 2, 3, 4 or 5; and

[0066] m1 is 0, 1, or 2.

[0067] In a preferred embodiment of the present invention, the R3 is selected from -(CH2) n1 R a 、-(CH2)n1 NR a OR b 、-(CH2) n1 C(O)NR a R b 、-(CH2) n1 NR a C(O)R b 、-(CH2) n1 S(O) m1 R a 、-(CH2) n1 S(O) m1 NR a R b 、-(CH2) n1 NR a S(O) m1 R b 、-(CH2) n1 NR a R b or -(CH2) n1 NR a (CH2) n2 R b ;

[0068] In a further preferred embodiment of the present invention, the R3 is selected from -CH2R a 、-C(O)NR a R b 、-S(O)2R b 、-CH2NR a Rb d 、-CH2)NR a CH2R b or -CH2NR a (CH2)2R b ;

[0069] R a and R b Each independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or 4-8 membered nitrogen-containing heterocyclic group, the C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy and 4-8 membered nitrogen-containing heterocyclic groups, optionally further substituted with hydrogen, deuterium, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl, C 1-3Alkoxy, halogen, cyano, cyano-substituted C 1-3 Alkyl or C 1-3 Alkoxy-C 1-3 substituted by one or more substituents in the alkylene group;

[0070] Preferred are 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, azetidinyl, 2-oxa-6-azaspiro[3.3]heptyl, (1R,5S)-8-azabicyclo[3.2.1]octanyl, (1R,5S)-3-oxa-8-azabicyclo[3.2.1]octanyl, optionally further substituted with one or more substituents selected from hydrogen, deuterium, hydroxy, methyl, ethyl, methoxy, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, cyano, monofluoromethyl, cyanomethylene, and methoxymethylene;

[0071] n1 and n2 are 0, 1, 2, 3, 4 or 5; and

[0072] m1 is 0, 1, or 2.

[0073] In a preferred embodiment of the present invention, the R4 is selected from -OH, -(CH2) n3 R c 、-(CH2) n3 NR c OR d 、-(CH2) n3 C(O)NR c R d 、-(CH2) n3 NR c C(O)R d 、-(CH2) n3 S(O) m2 R c 、-(CH2) n3 S(O) m2 NR c R d 、-(CH2) n3 NR c S(O) m2 R d 、-(CH2) n3 NR c R d or -(CH2) n3 NRc (CH2) n4 R d

[0074] In a further preferred embodiment of the present invention, the R4 is selected from -OH, -(CH2) n3 NR c R d or -(CH2) n3 NR c OR d ;

[0075] R c and R d Each independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy, the C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl and C 1-3 Alkoxy, optionally further substituted with hydrogen, deuterium, hydroxyl, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 substituted by one or more substituents in the alkoxy group;

[0076] n3 and n4 are 0, 1, 2, 3, 4 or 5; and

[0077] m2 is 0, 1 or 2.

[0078] In a preferred embodiment of the present invention, the R3 and R4, as well as the carbon atoms where they are located, are linked together to form C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C6-14 The aryl group and the 5-14 membered heteroaryl group are substituted by one or more substituents.

[0079] In a preferred embodiment of the present invention, R3 and R4, as well as the carbon atoms where they are located, are linked together to form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents in aryl and 5-10 membered heteroaryl

[0080] In a preferred embodiment of the present invention, R3 and R4, together with the carbon atoms where they are located, are linked to form the following heterocyclic group:

[0081] The heterocyclic group is optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, oxo or cyclopropyl.

[0082] In a preferred embodiment of the present invention, R6 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 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 haloalkoxy;

[0083] In a further preferred embodiment of the present invention, R6 is selected from methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0084] In a preferred embodiment of the present invention, R7 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 Halogenated alkyl, C 1-3Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 haloalkoxy;

[0085] In a further preferred embodiment of the present invention, R7 is selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0086] In a preferred embodiment of the present invention, the R4 and R6 are linked to the carbon atoms to form a C 5-14 Cycloalkyl or 5-14 membered heterocyclic group, the C 5-14 Cycloalkyl and 5-14 membered heterocyclic groups, optionally further substituted 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 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0087] In a further preferred embodiment of the present invention, the R4 and R6 together with the carbon atoms to which they are attached form a 5-12 membered heterocyclic group, wherein the 5-12 membered heterocyclic group is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0088] In a further preferred embodiment of the present invention, R4 and R6 together with the carbon atoms to which they are attached form the following heterocyclic group: The heterocyclic group is optionally further substituted by one or more substituents selected from deuterium, fluorine, chlorine, bromine, methyl, ethyl, oxo or cyclopropyl.

[0089] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is further represented by general formula (III):

[0090]

[0091] The R3, R7 and R d The definition of is as mentioned above.

[0092] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is further represented by general formula (IV):

[0093]

[0094] In a preferred embodiment of the present invention, the R2' 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 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 haloalkoxy;

[0095] In a further preferred embodiment of the present invention, said R2' is selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl;

[0096] In a preferred embodiment of the present invention, R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -(CH2) n1 R a 、-(CH2) n1 NR a OR b 、-(CH2) n1 C(O)NR a R b 、-(CH2)n1 OC(O)R a 、-(CH2) n1 NR a C(O)R b 、-(CH2) n1 S(O) m1 R a 、-(CH2) n1 S(O) m1 NR a R b 、-(CH2) n1 NR a S(O) m1 R b 、-(CH2) n1 NR a R b or -(CH2) n1 NR a (CH2) n2 R b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thioxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0097] R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0098] n1 and n2 are 0, 1, 2, 3, 4 or 5; and

[0099] m1 is 0, 1, or 2.

[0100] In a preferred embodiment of the present invention, R7 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 Halogenated alkyl, C 1-3 Hydroxyalkyl, C1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 haloalkoxy;

[0101] In a further preferred embodiment of the present invention, the R7 is selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

[0102] In a preferred embodiment of the present invention, R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 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 c 、-S(O)2R e 、-S(O)R e 、-S(O)2NR e R f 、-S(O)NR e R f 、-NR e S(O)2R f 、-NR e S(O)R f 、-P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, mercapto, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0103] In a further preferred embodiment of the present invention, the R8 is selected from deuterium, halogen, cyano, azido, nitro, amino, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 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 amino group, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, cyano, hydroxy, amino, halogen, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkoxyalkyl, cyano substituted C 1-3Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0104] In a further preferred embodiment of the present invention, R8 is selected from cyano, azido, nitro, amino, thiol, methyl, ethynyl, cyclopropyl, oxetane, azetidinyl, 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 are optionally further substituted with one or more substituents selected from cyano, hydroxyl, amino, fluorine, chlorine, bromine, oxo, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, methoxymethyl, hydroxymethyl, hydroxyisopropyl and cyanomethyl;

[0105] In a further preferred embodiment of the present invention, the R8 is selected from cyano, azido, nitro, C 3-6 Cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4-6 membered heterocyclic group containing 1 nitrogen or oxygen atom, 7-8 membered spiroheterocyclic group containing 2-3 nitrogen or oxygen atoms, 7-8 membered fused heterocyclic group containing 2-3 nitrogen or oxygen atoms, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, azido, nitro, mercapto, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 C substituted with haloalkyl or cyano 1-3 The alkyl group is substituted by one or more substituents;

[0106] In a further preferred embodiment of the present invention, the R8 is selected from -CN, -P(O)(CH3)2, -N3, -NO2, -SCF3, -SCN, -NCH3C(O)CH3, -C(O)N(CH3)2, -N(CN)2, -CH(CN)2, -C(CN)3, -(C≡C)CN,

[0107] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group and the 5-14 membered heteroaryl group are substituted by one or more substituents.

[0108] In a further preferred embodiment of the present invention, the compound represented by general formula (IV), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:

[0109] R2' is selected from hydrogen;

[0110] R3 is selected from -(CH2) n1 NR a C(O)R b or -(CH2) n1 NR a R b ;

[0111] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 haloalkoxy;

[0112] Or, R a and R b Together with the adjacent nitrogen atom, it forms a 4-8 membered heterocyclic group containing 1-2 atoms selected from nitrogen or oxygen atoms, which is optionally further substituted by halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl or C 1-3 substituted by one or more substituents in the hydroxyalkyl group;

[0113] R7 is selected from cyano or C 1-3 alkoxy;

[0114] R8 is selected from cyano, azido, nitro, C 3-6 Cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4-6 membered heterocyclic group containing 1 nitrogen or oxygen atom, 7-8 membered spiroheterocyclic group containing 2-3 nitrogen or oxygen atoms, 7-8 membered fused heterocyclic group containing 2-3 nitrogen or oxygen atoms, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, azido, nitro, mercapto, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 C substituted with haloalkyl or cyano 1-3 The alkyl group is substituted by one or more substituents.

[0115] In a further preferred embodiment of the present invention, the compound represented by general formula (IV), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:

[0116] R2' is selected from hydrogen;

[0117] R3 is selected from -(CH2) n1 NR a R b;

[0118] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 Halogenated alkoxy; preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl; more preferably methyl;

[0119] R7 is selected from cyano or C 1-3 Alkoxy; more preferably methoxy;

[0120] R8 is selected from cyano, azido, oxime, nitro, C 3-6 Cycloalkyl; more preferably oxime, nitro or cyclopropyl;

[0121] n1 is 1.

[0122] In a further preferred embodiment of the present invention, the compound, its stereoisomer or pharmaceutically acceptable salt thereof is further represented by general formula (V):

[0123]

[0124] R2' 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 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 Haloalkoxy,

[0125] Preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl or propyl; more preferably hydrogen;

[0126] R6 and R7 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 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3Alkoxy, C 1-3 Alkylthio or C 1-3 Haloalkoxy,

[0127] More preferably cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

[0128] R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, oxime, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 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)2R e 、-S(O)R e 、-S(O)2NR e R f 、-S(O)NR e R f 、-NR e S(O)2R f 、-NR e S(O)R f 、-P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, mercapto, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl,

[0129] Preferably, cyano, azido, oxime, nitro, C 3-6 Cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4-6 membered heterocyclic group containing 1 nitrogen or oxygen atom, 7-8 membered spiroheterocyclic group containing 2-3 nitrogen or oxygen atoms, 7-8 membered fused heterocyclic group containing 2-3 nitrogen or oxygen atoms; optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, azido, nitro, thiol, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 C substituted with haloalkyl or cyano 1-3 Alkyl, substituted by one or more substituents;

[0130] R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0131] Or, R a and R b Together with the adjacent nitrogen atom, it forms a 4-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen or oxygen atoms, which is optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0132] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C1-6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0133] n1 and n2 are 0, 1, 2, 3, 4 or 5; and

[0134] m1 is 0, 1, or 2.

[0135] In a preferred embodiment of the present invention, R6 and R7 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 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 haloalkoxy;

[0136] In a further preferred embodiment of the present invention, R6 and R7 are selected from cyano, methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

[0137] In a preferred embodiment of the present invention, R8 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 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)2R e 、-S(O)R e 、-S(O)2NR e R f 、-S(O)NR e R f 、-NR e S(O)2R f 、-NR e S(O)R f 、-P(O)R e R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, mercapto, oxo, thio, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0138] In a further preferred embodiment of the present invention, the R8 is selected from deuterium, halogen, cyano, azido, nitro, amino, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 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 amino group, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with deuterium, cyano, hydroxy, amino, halogen, oxo, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkoxyalkyl, cyano substituted C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0139] In a further preferred embodiment of the present invention, R8 is selected from cyano, azido, nitro, amino, thiol, methyl, ethynyl, cyclopropyl, oxetane, azetidinyl, 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 are optionally further substituted with one or more substituents selected from cyano, hydroxyl, amino, fluorine, chlorine, bromine, oxo, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, methoxymethyl, hydroxymethyl, hydroxyisopropyl and cyanomethyl;

[0140] In a further preferred embodiment of the present invention, the R8 is selected from cyano, azido, nitro, C 3-6 Cycloalkyl, 5-6 membered heteroaryl containing 2-4 nitrogen atoms, 4-6 membered heterocyclic group containing 1 nitrogen or oxygen atom, 7-8 membered spiroheterocyclic group containing 2-3 nitrogen or oxygen atoms, 7-8 membered fused heterocyclic group containing 2-3 nitrogen or oxygen atoms, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, azido, nitro, mercapto, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 C substituted with haloalkyl or cyano 1-3 The alkyl group is substituted by one or more substituents;

[0141] In a further preferred embodiment of the present invention, the R8 is selected from -CN, -P(O)(CH3)2, -N3, -NO2, -SCF3, -SCN, -NCH3C(O)CH3, -C(O)N(CH3)2, -N(CN)2, -CH(CN)2, -C(CN)3, -(C≡C)CN,

[0142] R e and R f are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-6Alkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally, further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group and the 5-14 membered heteroaryl group are substituted by one or more substituents.

[0143] In a further preferred embodiment of the present invention, the compound represented by general formula (V), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:

[0144] R2' is selected from hydrogen;

[0145] R a or R b are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, thiol, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C1-3 Alkylthio or C 1-3 Halogenated alkoxy; preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl; more preferably methyl;

[0146] R6 and R7 are each independently selected from cyano or C 1-3 Alkoxy; more preferably methoxy;

[0147] R8 is selected from cyano, azido, oxime, nitro, C 3-6 cycloalkyl; more preferably oxime, nitro or cyclopropyl.

[0148] The present invention further provides a compound represented by the intermediate general formula (M), its stereoisomers or pharmaceutically acceptable salts thereof:

[0149]

[0150] R3 is selected from -C(O)R g ;

[0151] R g Selected from hydroxyl, C 1-3 Alkoxy or -NR a R b ;

[0152] R4, R6, R7, R8, R a or R b As mentioned above.

[0153] The present invention further provides a method for preparing a compound of formula (VI) or a stereoisomer thereof and a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:

[0154]

[0155] The general formula (M-1) is reacted to obtain the general formula (M-2), the general formula (M-2) is reacted to obtain the general formula (M-3), and the general formula (M-3) is reduced to obtain the general formula (VI);

[0156] Pg is selected from C 1-3 alkoxy;

[0157] R4, R6, R7, R8, R a or R b As mentioned above.

[0158] In one embodiment of the present invention, in the general formulas (M-1), (M-2) and (M-3), R4 is preferably a hydroxyl group.

[0159] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0160] On the other hand, the present invention also aims to provide a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in drugs for treating and / or preventing ATP-dependent RNA helicase-related diseases, particularly for treating and / or preventing eukaryotic initiation factor 4A (eIF4A) inhibitor-related diseases.

[0161] On the other hand, the present invention also aims to provide a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating and / or preventing cancer, myelodysplastic syndrome, Alzheimer's disease, Parkinson's disease, fragile X syndrome, autism and other related diseases.

[0162] The present invention also relates to a method for treating and / or preventing cancer, myelodysplastic syndrome, Alzheimer's disease, Parkinson's disease, fragile X syndrome, autism, and other related diseases. In another aspect, the present invention also provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating and / or preventing cancer, myelodysplastic syndrome, Alzheimer's disease, Parkinson's disease, fragile X syndrome, autism, and other related diseases.

[0163] In the above technical solution, the cancer-related disease is selected from or blood 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 carcinoma, cervical cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.

[0164] Detailed Description of the Invention

[0165] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0166] 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 an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 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, pentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 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 various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which 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, n-heptyl, 4-heptyl, 1-propylbutyl, 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, and the like.The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0167] The term "alkylene" refers to an alkyl group in which one hydrogen atom is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc. 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, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0168] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0169] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiral atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spiroalkyl is divided into a single spiroalkyl, a double spiroalkyl or a multi-spiroalkyl, preferably a single spiroalkyl and a double spiroalkyl. More preferably, it is 3 yuan / 6 yuan, 3 yuan / 5 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0170] wait;

[0171] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0172] wait.

[0173] The term "fused cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0174] wait.

[0175] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0176]

[0177] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group 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, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0178] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O) or S(O). m(wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0179] Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl or tetrahydrothiopyran dioxide, and the like. ; Preferred are oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydrothiopyran dioxide, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azepanyl, 1,4-diazepanyl and piperazinyl; More preferably, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, oxetanyl or azetidinyl. Polycyclic heterocyclic groups include spirocyclic, condensed ring and bridged heterocyclic groups; wherein the spirocyclic, condensed ring and bridged heterocyclic groups are optionally connected to other groups by a single bond, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms on the ring.

[0180] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiral heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0181] wait.

[0182] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being 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 fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0183] wait.

[0184] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0185] wait.

[0186] The heterocyclyl ring may 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:

[0187] wait.

[0188] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0189] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0190] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include:

[0191] wait.

[0192] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0193] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 12-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, 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, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0194] wait.

[0195] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0196] 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, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0197] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0198] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0199] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0200] "Alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0201] "Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0202] The term "alkenylcarbonyl" refers to -C(O)-(alkenyl), wherein the definition of alkenyl is as described above. Non-limiting examples of alkenylcarbonyl include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0203] "Hydroxy" refers to an -OH group.

[0204] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0205] "Amino" refers to -NH2.

[0206] "Cyano" refers to -CN.

[0207] "Nitro" refers to -NO2.

[0208] "Carbonyl" or "oxo" refers to -C(O)-.

[0209] "Carboxyl" refers to -C(O)OH.

[0210] "THF" refers to tetrahydrofuran.

[0211] "Ethyl acetate" means ethyl acetate.

[0212] "MeOH" refers to methanol.

[0213] "DMF" refers to N,N-dimethylformamide.

[0214] "DIPEA" refers to diisopropylethylamine.

[0215] "TFA" refers to trifluoroacetic acid.

[0216] "TEA" refers to triethylamine.

[0217] "MeCN" refers to acetylene glycol.

[0218] "DMA" refers to N,N-dimethylacetamide.

[0219] "Et2O" refers to diethyl ether.

[0220] "DCM" refers to dichloromethane.

[0221] "DMAP" refers to 4-dimethylaminopyridine.

[0222] "DCC" refers to dicyclohexylcarbodiimide.

[0223] "DCE" refers to 1,2-dichloroethane.

[0224] "DIPEA" refers to N,N-diisopropylethylamine.

[0225] "NBS" refers to N-bromosuccinimide.

[0226] "NIS" refers to N-iodosuccinimide.

[0227] "Cbz-Cl" refers to benzyl chloroformate.

[0228] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0229] "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

[0230] "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0231] "KHMDS" refers to potassium hexamethyldisilazide.

[0232] "LiHMDS" refers to lithium bis(trimethylsilylamide).

[0233] "MeLi" refers to methyllithium.

[0234] "n-BuLi" refers to n-butyllithium.

[0235] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0236] "Amino acid residue" refers to a natural amino acid residue or a non-natural amino acid residue.

[0237] “Natural amino acids” refer to the 20 common 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).

[0238] "Unnatural amino acids" refer to amino acids that are not naturally encoded or found in the genetic code of any organism and can be, for example, purely synthetic compounds.

[0239] "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 the oxygen atom in a carbonyl group (C=O) or a hydroxyl group (OH).

[0240] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0241] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0242] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0243] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0244] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0245] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0246] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0247] Example

[0248] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0249] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0250] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography 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.

[0251] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0252] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0253] Example 1

[0254] Preparation of 4-((5aS,6S,7S,8R,8aR)-7-((dimethylamino)methyl)-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0255]

[0256] Step 1: Preparation of 4-(benzyloxy)-2,6-dichloropyridine

[0257]

[0258] To a DMF solution (300 mL) of 2,4,6-trichloropyridine (30.0 g, 165 mmol) was added portionwise NaH (7.59 g, 60 wt%, 190 mmol) under an ice-water bath. After the addition was complete, stirring was continued at the same temperature for 15 minutes. Then, benzyl alcohol (17.9 mL, 173 mmol) was added dropwise. After the addition was complete, stirring was continued under an ice-water bath for 1 hour. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The organic phases were combined and washed several times with saturated brine. The organic phases were separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to give the title compound, 4-(benzyloxy)-2,6-dichloropyridine (30.4 g, 73%).

[0259] 1 H NMR (400MHz, CDCl3) δ5.11 (s, 2H), 6.86 (s, 2H), 7.37-7.42 (m, 5H);

[0260] MS m / z(ESI):254.0[M+H] + .

[0261] Step 2: Preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine

[0262]

[0263] 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), followed by stirring at 60°C for 5 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, separated, 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 obtained by column chromatography.

[0264] 1 H NMR (400MHz, DMSO-d6) δ3.81 (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);

[0265] MS m / z(ESI):250.2[M+H] + .

[0266] Step 3: Preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol

[0267]

[0268] To a THF solution (200 mL) of 4-(benzyloxy)-2-chloro-6-methoxypyridine (195 g, 78.1 mmol) was added dropwise a n-BuLi solution in n-hexane (41.0 mL, 2.4 M, 97.6 mmol) under a dry ice-acetone bath. The mixture was stirred at this temperature for 30 minutes, and then acetaldehyde (6.88 g, 156 mmol) was added dropwise to the reaction system. After the addition was complete, stirring was continued for 10 minutes. The reaction was quenched by adding a saturated aqueous ammonium chloride solution. The reaction solution was extracted several times with ethyl acetate, and the organic phases were combined and 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)ethan-1-ol (16 g, 70%) was separated by column chromatography.

[0269] 1H NMR (400MHz, DMSO-d6) δ1.39 (d, J=6.6Hz, 3H), 3.84 (s, 3H), 4.60 (d, J=6.6Hz, 1H), 5.09-5.14 (m, 1H), 525 (s, 2H), 693 (s, 1H), 7.32-7.49 (m, 5H);

[0270] MS m / z(ESI):294.1[M+H] + .

[0271] Step 4: Preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one

[0272]

[0273] To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-ol (16.0 g, 54.6 mmol) in dichloromethane (320 mL) was added portionwise DMP (30.1 g, 71.0 mmol). After addition, the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate and sodium thiosulfate were then added sequentially, and the mixture was stirred for an additional 15 minutes. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were 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)ethan-1-one (8.10 g, 51%), was obtained by column chromatography.

[0274] 1 H NMR (400MHz, DMSO-d6) δ2.37 (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);

[0275] MS m / z(ESI):292.2[M+H] + .

[0276] Step 5: Preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one

[0277]

[0278] 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) was added Pd / C (140 mg, 10 wt%). The mixture was stirred for 3 hours at room temperature and pressure under a hydrogen atmosphere. The insoluble matter was removed by filtration using celite. The filtrate was concentrated under reduced pressure and separated by column chromatography to give the title compound 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.30 g, 71%).

[0279] 1 H NMR (400MHz, DMSO-d6) δ2.50 (s, 3H), 3.90 (s, 3H), 6.70 (s, 1H), 13.00 (s, 1H);

[0280] MS m / z(ESI):202.2[M+H] + .

[0281] Step 6: Preparation of (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one

[0282]

[0283] To a solution (31 mL) of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.00 g, 9.92 mmol) and 4-bromobenzaldehyde (1.65 g, 8.93 mmol) in DMF was added a solution of MeONa in MeOH (5.36 g, 30 wt %, 29.8 mmol). The mixture was vigorously stirred at 50°C for 30 min, 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 a mixed solvent of EtOAc / n-heptane (mixed solvent ratio of 1:10) to give 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%).

[0284] 1 H NMR (400MHz, DMSO-d6) δ3.80 (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);

[0285] MS m / z(ESI):368.0[M+H] + .

[0286] Step 7: Preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one

[0287]

[0288] To a mixed solution of (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one (1.40 g, 3.80 mmol) in EtOH (27 mL) and DCM (6.8 mL) was added dropwise an aqueous NaOH solution (3.36 g, 10 wt %, 8.39 mmol) and an aqueous H2O2 solution (3.03 g, 30 wt %, 26.7 mmol) in a water bath, followed by stirring for 1 hour in a water bath. Saturated aqueous ammonium chloride was added, and the mixture was 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 give a crude product of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (700 mg), which was used in the next step without further purification.

[0289] MS m / z(ESI):381.9[M+H] + .

[0290] Step 8: Preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one

[0291]

[0292] To a DMF solution (30 mL) of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (crude product from the previous step, 700 mg) was added a methanol solution of sodium methoxide (15 mL, 30 wt%), followed by stirring at 80°C for 1 hour. After cooling, the reaction solution was poured into ice water and the pH was adjusted to weak acidity with hydrochloric acid (6 M). The precipitated solid was filtered and the filter cake was washed with water. The solid compound was collected and dried, and then separated and purified by column chromatography to give 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%).

[0293] 1 H NMR (400MHz, DMSO-d6) δ3.95 (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);

[0294] MS m / z(ESI):378.0[M+H] + .

[0295] Step 9: Preparation of racemic-methyl (3S, 4R, 5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate

[0296]

[0297] 2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (160 mg, 0.424 mmol) and methyl cinnamate (686 mg, 4.24 mmol) were dissolved in chloroform (7 mL) and trifluoroethanol (5.6 mL) and vigorously stirred at 0°C under 450W UV light for 5 hours. The organic solvent was concentrated under reduced pressure and column chromatography was used to remove excess methyl cinnamate to obtain crude racemic-methyl (3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate (250 mg), which was used directly in the next reaction.

[0298] MS m / z(ESI):540.1[M+H] + .

[0299] Step 10: Preparation of racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate

[0300]

[0301] To a methanol solution (8 mL) of racemic methyl (3S, 4R, 5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate (250 mg, crude product, about 0.424 mmol) was added dropwise a methanol solution of sodium methoxide (30 wt%, 252 mg, 1.40 mmol), and then stirred at 60°C for 45 minutes. The reaction mixture was cooled to room temperature and the mixture was desorbed. The organic solvent was concentrated under reduced pressure, and the residue was separated by 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 give crude racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (250 mg), which was used directly in the next reaction.

[0302] MS m / z(ESI):540.1[M+H] + .

[0303] Step 11: Preparation of racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0304]

[0305] The crude product of the previous step, racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (250 mg, about 0.424 mmol), was dissolved in MeOH (8 mL), and NaBH4 (81 mg, 2.12 mmol) was added in portions and stirred at room temperature for 75 minutes. The MeOH was then concentrated under reduced pressure, and the residual liquid was separated between dichloromethane and water. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to give 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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (70 mg, three-step yield: 32%).

[0306] MS m / z(ESI):514.1[M+H] + .

[0307] Step 12: Preparation of racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carbaldehyde

[0308]

[0309] To a dichloromethane solution (10 mL) of racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (70 mg, 0.136 mmol) was added DMP (60 mg, 0.143 mmol) in an ice-water bath, followed by stirring at the same temperature for 2 hours. A mixed aqueous solution of sodium thiosulfate and sodium bicarbonate was added, stirred for 10 minutes, extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound was separated by column chromatography to give racemic-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carbaldehyde (58 mg, 83%).

[0310] MS m / z(ESI):512.1[M+H] + .

[0311] Step 13: Preparation of racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0312]

[0313] Rac-(5aR,6S,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carbaldehyde (58 mg, 0.114 mmol) and dimethylamine hydrochloride (9.2 mg, 0.228 mmol) were mixed in DCE and stirred for 30 minutes. Then, sodium acetate borohydride (48 mg, 0.228 mmol) was added and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The title compound was separated by column chromatography to give racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (45 mg, 73%).

[0314] MS m / z(ESI):541.1[M+H] + .

[0315] Step 14: Preparation of racemic-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[4,5]furo[3,2-c]pyridin-8-one

[0316]

[0317] To a DCM solution (2 mL) of rac-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (45 mg, 0.083 mmol) was added DMP (70 mg, 0.166 mmol) dropwise under ice-water bath, and the mixture was stirred at room temperature overnight. A mixed aqueous solution of sodium thiosulfate and sodium bicarbonate was added, stirred for 10 minutes, extracted twice with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. Preparative thin layer separation and purification gave 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-cyclopenta[4,5]furo[3,2-c]pyridin-8-one (33 mg, 74%).

[0318] MS m / z(ESI):539.2[M+H] + .

[0319] Step 15: Preparation of racemic-4-((5aR,6S,7S,8aR)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0320]

[0321] Racemic-(5aR,6S,7S,8aR)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-6-phenyl-5a,6,7,8a-tetrahydro-8H-cyclopenta[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) and water (0.1 mL), and the mixture was deoxygenated with nitrogen for 5 minutes. Pd2(dba)3 (7.5 mg, 0.0082 mmol) and dppf (9 mg, 0.017 mmol) were then added in sequence. The mixture was stirred and heated at 120°C under microwave conditions for 90 minutes. The reaction solution was cooled to room temperature, and the insoluble matter was removed by filtration through celite. The filtrate was concentrated under reduced pressure and purified by preparative thin-layer chromatography to give the title compound, racemic-4-((5aR,6S,7S,8aR)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (20 mg, 68%).

[0322] MS (ESI) m / z: 486.2 [M+H] + .

[0323] Step 16: Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0324]

[0325] At room temperature, racemic-4-((5aR,6S,7S,8aR)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (20 mg, 0.041 mmol) and hydroxylamine hydrochloride (8.6 mg, 0.123 mmol) were mixed in DCE (2 mL). One drop of acetic acid was added and the mixture was stirred for 30 minutes. Then, sodium acetate borohydride (17 mg, 0.082 mmol) was added and the mixture was stirred for another 5 hours. Saturated aqueous sodium bicarbonate solution and DCM were added, the organic phase was separated and dried over anhydrous sodium sulfate, filtered and the organic solvent was concentrated under reduced pressure, and the product was separated by preparative thin layer chromatography to give racemic-4-((5aR, 6S, 7S, 8R, 8aS)-7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyrrolidone The reaction mixture was stirred for 2 hours, and then the mixture was dried over a medium temperature for 2 hours to obtain the optically 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (racemate of Example 1), followed by chiral column separation to give the optically 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile (3.3 mg).

[0326] MS (ESI) m / z: 503.2 [M+H] + .

[0327] Example 2

[0328] Preparation of (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0329]

[0330] The preparation method of (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[0331] MS m / z(ESI):517.2[M+H]+ .

[0332] Example 3

[0333] Preparation of (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0334]

[0335] The preparation method of (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[0336] MS m / z(ESI):503.2[M+H] + .

[0337] Example 4

[0338] Preparation of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0339]

[0340] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0341] MS m / z(ESI):489.2[M+H] + .

[0342] Example 5

[0343] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0344]

[0345] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1-methoxy-6-phenyl-5a, 7, 8, 8a-tetrahydro-6H-cyclopenta[4, 5] furo[3, 2-c] pyridine-3-carbonitrile refers to Example 1.

[0346] MS m / z(ESI):498.2[M+H] + .

[0347] Example 6

[0348] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0349]

[0350] The preparation method of 4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0351] MS m / z(ESI):531.2[M+H] + .

[0352] Example 7

[0353] Preparation of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-7-(piperidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0354]

[0355] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-7-(piperidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was referred to Example 1.

[0356] MS m / z(ESI):543.2[M+H] + .

[0357] Example 8

[0358] Preparation of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0359]

[0360] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0361] MS m / z(ESI):545.2[M+H] + .

[0362] Example 9

[0363] Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0364]

[0365] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0366] MS m / z(ESI):558.3[M+H] + .

[0367] Example 10

[0368] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0369]

[0370] The preparation method of 4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was described in Example 1.

[0371] MS m / z(ESI):565.2[M+H] + .

[0372] Example 11

[0373] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0374]

[0375] The preparation method of (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-cyclopenta[4, 5] furo[3, 2-c] pyridine-3-carbonitrile refers to Example 1.

[0376] MS m / z(ESI):556.3[M+H] + .

[0377] Example 12

[0378] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1-methoxy-7-(((2-methoxyethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0379]

[0380] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1-methoxy-7-(((2-methoxyethyl)(methyl)amino)methyl)-6-phenyl-5a, 7, 8, 8a-tetrahydro-6H-cyclopenta[4, 5] furo[3, 2-c] pyridine-3-carbonitrile refers to Example 1.

[0381] MS m / z(ESI):542.2[M+H] + .

[0382] Example 13

[0383] Preparation of (5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0384]

[0385] The preparation method of (5aR, 6S, 7R, 8S, 8aS)-5a-(4-cyanophenyl)-8a-hydroxy-8-(hydroxyamino)-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a, 7, 8, 8a-tetrahydro-6H-cyclopenta[4, 5] furo[3, 2-c] pyridine-3-carbonitrile refers to Example 1.

[0386] MS m / z(ESI):574.2[M+H] + .

[0387] Example 14

[0388] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0389]

[0390] The preparation method of 4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0391] MS m / z(ESI):557.2[M+H] + .

[0392] Example 15

[0393] Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0394]

[0395] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0396] MS m / z(ESI):569.3[M+H] + .

[0397] Example 16

[0398] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[32.1]octan-8-yl)methyl)-8a-hydroxy-8-(hydroxyamino)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0399]

[0400] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0401] MS m / z(ESI):571.3[M+H] + .

[0402] Example 17

[0403] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0404]

[0405] The preparation method of 4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0406] MS m / z(ESI):517.2[M+H] + .

[0407] Example 18

[0408] Preparation of (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0409]

[0410] The preparation method of (5aR, 6S, 7R, 8R, 8aS)-5a-(4-cyanophenyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[0411] MS m / z(ESI):531.2[M+H] + .

[0412] Example 19

[0413] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0414]

[0415] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[0416] MS m / z(ESI):517.2[M+H] + .

[0417] Example 20

[0418] Preparation of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0419]

[0420] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0421] MS m / z(ESI):503.2[M+H] + .

[0422] Example 21

[0423] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1-methoxy-8-(methoxyamino)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0424]

[0425] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-5a-(4-cyanophenyl)-7-((dimethylamino)methyl)-8a-hydroxy-1-methoxy-8-(methoxyamino)-6-phenyl-5a, 7, 8, 8a-tetrahydro-6H-cyclopenta[4, 5] furo[3, 2-c] pyridine-3-carbonitrile refers to Example 1.

[0426] MS m / z(ESI):512.2[M+H] + .

[0427] Example 22

[0428] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0429]

[0430] The preparation method of 4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0431] MS m / z(ESI):545.3[M+H] + .

[0432] Example 23

[0433] Preparation of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-7-(piperidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0434]

[0435] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-7-(piperidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was referred to Example 1.

[0436] MS m / z(ESI):557.3[M+H] + .

[0437] Example 24

[0438] Preparation of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0439]

[0440] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0441] MS m / z(ESI):559.3[M+H] + .

[0442] Example 25

[0443] Preparation of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0444]

[0445] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-7-((4-methylpiperazin-1-yl)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0446] MS m / z(ESI):572.3[M+H] + .

[0447] Example 26

[0448] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0449]

[0450] The preparation method of 4-((5aR,6S,7S,8R,8aS)-7-((3-(difluoromethyl)azetidin-1-yl)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0451] MS m / z(ESI):579.2[M+H] + .

[0452] Example 27

[0453] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0454]

[0455] The preparation method of (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-cyclopenta[4, 5] furo[3, 2-c] pyridine-3-carbonitrile refers to Example 1.

[0456] MS m / z(ESI):570.3[M+H] + .

[0457] Example 28

[0458] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0459]

[0460] The preparation method of (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-cyclopenta[4, 5] furo[3, 2-c] pyridine-3-carbonitrile refers to Example 1.

[0461] MS m / z(ESI):556.3[M+H] + .

[0462] Example 29

[0463] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0464]

[0465] The preparation method of (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-cyclopenta[4, 5] furo[3, 2-c] pyridine-3-carbonitrile refers to Example 1.

[0466] MS m / z(ESI):588.2[M+H] + .

[0467] Example 30

[0468] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0469]

[0470] The preparation method of 4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0471] MS m / z(ESI):571.3[M+H] + .

[0472] Example 31

[0473] Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0474]

[0475] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0476] MS m / z(ESI):583.3[M+H] + .

[0477] Example 32

[0478] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[32.1]octan-8-yl)methyl)-8a-hydroxy-1,3-dimethoxy-8-(methoxyamino)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0479]

[0480] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile refers to Example 1.

[0481] MS m / z(ESI):585.3[M+H] + .

[0482] Example 33

[0483] Preparation of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0484]

[0485] The preparation method of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile was referred to Example 1.

[0486] MS m / z(ESI):500.2[M+H] + .

[0487] Example 34

[0488] Preparation of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-9-carboxamide

[0489]

[0490] The preparation method of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-9-carboxamide refers to Example 1.

[0491] MS m / z(ESI):514.2[M+H] + .

[0492] Example 35

[0493] Preparation of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-9-carboxamide

[0494]

[0495] The preparation method of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-9-carboxamide refers to Example 1.

[0496] MS m / z(ESI):500.2[M+H] + .

[0497] Example 36

[0498] Preparation of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0499]

[0500] The preparation method of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile was referred to Example 1.

[0501] MS m / z(ESI):486.2[M+H] + .

[0502] Example 37

[0503] Preparation of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-3-carbonitrile

[0504]

[0505] The preparation method of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-3-carbonitrile refers to Example 1.

[0506] MS m / z(ESI):495.2[M+H] + .

[0507] Example 38

[0508] Preparation of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0509]

[0510] The preparation method of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile was as described in Example 1.

[0511] MS m / z(ESI):528.2[M+H] + .

[0512] Example 39

[0513] Preparation of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0514]

[0515] The preparation method of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile refers to Example 1.

[0516] MS m / z(ESI):540.2[M+H] + .

[0517] Example 40

[0518] Preparation of 4-((8aR,9S,10S,11R,11aS)-11a-hydroxy-3-methoxy-9-(morpholinomethyl)-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-1,11-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0519]

[0520] The preparation method of 4-((8aR,9S,10S,11R,11aS)-11a-hydroxy-3-methoxy-9-(morpholinomethyl)-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-1,11-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile refers to Example 1.

[0521] MS m / z(ESI):542.2[M+H] + .

[0522] Example 41

[0523] Preparation of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0524]

[0525] The preparation method of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile was as described in Example 1.

[0526] MS m / z(ESI):555.3[M+H] + .

[0527] Example 42

[0528] Preparation of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0529]

[0530] The preparation method of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile refers to Example 1.

[0531] MS m / z(ESI):552.2[M+H] + .

[0532] Example 43

[0533] Preparation of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-3-carbonitrile

[0534]

[0535] The preparation method of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-3-carbonitrile refers to Example 1.

[0536] MS m / z(ESI):553.2[M+H] + .

[0537] Example 44

[0538] Preparation of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-3-carbonitrile

[0539]

[0540] The preparation method of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-3-carbonitrile refers to Example 1.

[0541] MS m / z(ESI):539.2[M+H] + .

[0542] Example 45

[0543] Preparation of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-3-carbonitrile

[0544]

[0545] The preparation method of (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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridine-3-carbonitrile refers to Example 1.

[0546] MS m / z(ESI):571.2[M+H] + .

[0547] Example 46

[0548] Preparation of 4-((8aR,9S,10S,11R,11aS)-9-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-11a-hydroxy-3-methoxy-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-[1,11]epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0549]

[0550] The preparation method of 4-((8aR,9S,10S,11R,11aS)-9-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-11a-hydroxy-3-methoxy-10-phenyl-6,7,8a,9,10,11a-hexahydro-11H-[1,11]epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile refers to Example 1.

[0551] MS m / z(ESI):554.2[M+H] + .

[0552] Example 47

[0553] Preparation of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0554]

[0555] The preparation method of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile was as described in Example 1.

[0556] MS m / z(ESI):566.3[M+H] + .

[0557] Example 48

[0558] Preparation of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile

[0559]

[0560] The preparation method of 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-epoxycyclopenta[7,8][1,4]dioxino[5,6-b]pyridin-11-yl)benzonitrile refers to Example 1.

[0561] MS m / z(ESI):568.2[M+H] + .

[0562] Example 49

[0563] Preparation of 4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-2-phenyl-1,2,2a1,9a-tetrahydro-2aH-3,7,9-trioxa-6-azabenzo[cd]cyclopenta[ij]azul-2a-yl)benzonitrile

[0564]

[0565] The preparation method of 4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-2-phenyl-1,2,2a1,9a-tetrahydro-2aH-3,7,9-trioxa-6-azabenzo[cd]cyclopenta[ij]azul-2a-yl)benzonitrile was described in Example 1.

[0566] MS m / z(ESI):486.2[M+H] + .

[0567] Example 50

[0568] Preparation of 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-epoxycyclopenta[8,9][1,5]dioxino[6,7-b]pyridin-12-yl)benzonitrile

[0569]

[0570] The preparation method of 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-epoxycyclopenta[8,9][1,5]dioxino[6,7-b]pyridin-12-yl)benzonitrile was as described in Example 1.

[0571] MS m / z(ESI):514.2[M+H] + .

[0572] Example 51

[0573] Preparation of 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]cyclopenta[ij]azulene-8,4′-piperidinyl]-3a,3a1(6a),5-trien-2a-yl)benzonitrile

[0574]

[0575] The preparation method of 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]cyclopenta[ij]azulene-8,4′-piperidine]-3a,3a1(6a),5-trien-2a-yl)benzonitrile was referred to Example 1.

[0576] MS m / z(ESI):569.3[M+H] + .

[0577] Example 52

[0578] Preparation of 4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-7-methyl-8-carbonyl-2-phenyl-1,2,2a1,7,8,9a-hexahydro-2aH-3,9-dioxa-6,7-diazabenzo[cd]cyclopenta[ij]azul-2a-yl)benzonitrile

[0579]

[0580] The preparation method of 4-((1S,2S,2aR,2a1S,9aR)-1-((dimethylamino)methyl)-2a1-hydroxy-5-methoxy-7-methyl-8-carbonyl-2-phenyl-1,2,2a1,7,8,9a-hexahydro-2aH-3,9-dioxa-6,7-diazabenzo[cd]cyclopenta[ij]azul-2a-yl)benzonitrile was described in Example 1.

[0581] MS m / z(ESI):513.2[M+H] + .

[0582] Example 53

[0583] Preparation of 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]cyclopenta[ij]azul-2a-yl)benzonitrile

[0584]

[0585] The preparation method of 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]cyclopenta[ij]azul-2a-yl)benzonitrile was described in Example 1.

[0586] MS m / z(ESI):499.2[M+H] + .

[0587] Example 54

[0588] Preparation of (5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-sulfonyl fluoride

[0589]

[0590] The preparation method of (5aR,6S,7R,8S,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-sulfonyl fluoride is shown in Example 1.

[0591] MS m / z(ESI):513.1[M+H] + .

[0592] Example 55

[0593] Preparation of 4-((5aR,6R,7S,8R,8aS)-7-((dimethylamino)methyl)-6-fluoro-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0594]

[0595] The preparation method of 4-((5aR,6R,7S,8R,8aS)-7-((dimethylamino)methyl)-6-fluoro-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0596] MS m / z(ESI):506.2[M+H]+ .

[0597] Example 56

[0598] Preparation of 4-((5aS,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-methyl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0599]

[0600] The preparation method of 4-((5aS,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-methyl-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0601] 1 H NMR (400 MHz, DMSO-d 6 )δ1.21(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);

[0602] MS m / z(ESI):502.2[M+H] + .

[0603] Example 57

[0604] Preparation of 4-((5aR,6S,7S,8R,8aS)-6-(bicyclo[11.1]pentan-1-yl)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0605]

[0606] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0607] MS m / z(ESI):494.2[M+H] + .

[0608] Example 58

[0609] Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)bicyclo[1.11]pentane-1-carbonitrile

[0610]

[0611] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)bicyclo[1.1.1]pentane-1-carbonitrile refers to Example 1.

[0612] MS m / z(ESI):494.2[M+H] + .

[0613] Example 59

[0614] Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0615]

[0616] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0617] MS m / z(ESI):504.2[M+H] + .

[0618] Example 60

[0619] Preparation of 4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxyamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[0620]

[0621] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxyamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[0622] MS m / z(ESI):490.2[M+H] + .

[0623] Example 61

[0624] Preparation of (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,1,3-trimethoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0625]

[0626] The preparation method of (5aR,6S,7R,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-N,1,3-trimethoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[0627] MS m / z(ESI):518.2[M+H] + .

[0628] Example 62

[0629] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0630]

[0631] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0632] MS m / z(ESI):555.2[M+H] + .

[0633] Example 63

[0634] Preparation of (4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0635]

[0636] The preparation method of (4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0637] MS m / z(ESI):539.2[M+H] + .

[0638] Example 64

[0639] Preparation of (5aR,6S,7R,8R,8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0640]

[0641] The preparation method of (5aR,6S,7R,8R,8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[0642] MS m / z(ESI):553.2[M+H] + .

[0643] Example 65

[0644] Preparation of (5aR,6S,7R,8R,8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0645]

[0646] The preparation method of (5aR,6S,7R,8R,8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N-methyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[0647] MS m / z(ESI):539.2[M+H] + .

[0648] Example 66

[0649] Preparation of (4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0650]

[0651] The preparation method of (4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methylamino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0652] MS m / z(ESI):5252[M+H] +

[0653] Example 67

[0654] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0655]

[0656] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile refers to Example 1.

[0657] MS m / z(ESI):534.2[M+H] + .

[0658] Example 68

[0659] Preparation of (4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0660]

[0661] The preparation method of (4-((5aR,6S,7S,8R,8aS)-7-((diethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0662] MS m / z(ESI):567.3[M+H] + .

[0663] Example 69

[0664] Preparation of (4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-7-(piperidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0665]

[0666] The preparation method of (4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-7-(piperidin-1-ylmethyl)-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide is shown in Example 1.

[0667] MS m / z(ESI):579.3[M+H] + .

[0668] Example 70

[0669] Preparation of (4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0670]

[0671] The preparation method of (4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-(morpholinomethyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0672] MS m / z(ESI):581.2[M+H] + .

[0673] Example 71

[0674] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0675]

[0676] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0677] MS m / z(ESI):5943[M+H] + .

[0678] Example 72

[0679] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0680]

[0681] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0682] MS m / z(ESI):601.2[M+H] + .

[0683] Example 73

[0684] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-7-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0685]

[0686] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-7-(((2-hydroxy-2-methylpropyl)(methyl)amino)methyl)-1-methoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile refers to Example 1.

[0687] MS m / z(ESI):592.3[M+H] + .

[0688] Example 74

[0689] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1-methoxy-7-(((2-methoxyethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0690]

[0691] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1-methoxy-7-(((2-methoxyethyl)(methyl)amino)methyl)-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile refers to Example 1.

[0692] MS m / z(ESI):578.2[M+H] + .

[0693] Example 75

[0694] Preparation of (5aR,6S,7R,8S,8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile

[0695]

[0696] The preparation method of (5aR, 6S, 7R, 8S, 8aS)-5a-(4-(dimethylphosphino)phenyl)-8,8a-dihydroxy-1-methoxy-6-phenyl-7-(pyrrolidin-1-ylsulfonyl)-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-3-carbonitrile refers to Example 1.

[0697] MS m / z(ESI):610.2[M+H] + .

[0698] Example 76

[0699] Preparation of (4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0700]

[0701] The preparation method of (4-((5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0702] MS m / z(ESI):593.2[M+H] + .

[0703] Example 77

[0704] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0705]

[0706] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0707] MS m / z(ESI):6053[M+H] + .

[0708] Example 78

[0709] Preparation of (4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide

[0710]

[0711] The preparation method of (4-((5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-yl)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)dimethylphosphine oxide was prepared by referring to Example 1.

[0712] MS m / z(ESI):607.3[M+H] + .

[0713] Example 79

[0714] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0715]

[0716] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0717] MS m / z(ESI):504.2[M+H] + .

[0718] Example 80

[0719] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-((trifluoromethyl)thio)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0720]

[0721] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-((trifluoromethyl)thio)phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0722] MS m / z(ESI):563.2[M+H] + .

[0723] Example 81

[0724] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-thiocyanato<thiocyanato>phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0725]

[0726] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a-(4-thiocyanato<thiocyanato>phenyl)-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[0727] MS m / z(ESI):520.2[M+H] + .

[0728] Example 82

[0729] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0730]

[0731] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0732] MS m / z(ESI):519.2[M+H] + .

[0733] Example 83

[0734] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0735]

[0736] Step 1: Preparation of 4-(benzyloxy)-2,6-dichloropyridine

[0737]

[0738] To a DMF solution (300 mL) of 2,4,6-trichloropyridine (30.0 g, 165 mmol) was added portionwise NaH (7.59 g, 60 wt%, 190 mmol) under an ice-water bath. After the addition was complete, stirring was continued at the same temperature for 15 minutes. Then, benzyl alcohol (17.9 mL, 173 mmol) was added dropwise. After the addition was complete, stirring was continued under an ice-water bath for 1 hour. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The organic phases were combined and washed several times with saturated brine. The organic phases were separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to give the title compound, 4-(benzyloxy)-2,6-dichloropyridine (30.4 g, 73%).

[0739] 1 H NMR (400MHz, CDCl3) δ5.11 (s, 2H), 6.86 (s, 2H), 7.37-7.42 (m, 5H);

[0740] MS m / z(ESI):254.0[M+H] + .

[0741] Step 2: Preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine

[0742]

[0743] 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), followed by stirring at 60°C for 5 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, separated, 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 obtained by column chromatography.

[0744] 1 H NMR (400MHz, DMSO-d6) δ3.81 (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);

[0745] MS m / z(ESI):250.2[M+H] + .

[0746] Step 3: Preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol

[0747]

[0748] To a THF solution (200 mL) of 4-(benzyloxy)-2-chloro-6-methoxypyridine (195 g, 78.1 mmol) was added dropwise a n-BuLi solution in n-hexane (41.0 mL, 2.4 M, 97.6 mmol) under a dry ice-acetone bath. The mixture was stirred at this temperature for 30 minutes, and then acetaldehyde (6.88 g, 156 mmol) was added dropwise to the reaction system. After the addition was complete, stirring was continued for 10 minutes. The reaction was quenched by adding a saturated aqueous ammonium chloride solution. The reaction solution was extracted several times with ethyl acetate, and the organic phases were combined and 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)ethan-1-ol (16 g, 70%) was separated by column chromatography.

[0749] 1 H NMR (400MHz, DMSO-d6) δ1.39 (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);

[0750] MS m / z(ESI):294.1[M+H] + .

[0751] Step 4: Preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one

[0752]

[0753] To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-ol (16.0 g, 54.6 mmol) in dichloromethane (320 mL) was added portionwise DMP (30.1 g, 71.0 mmol). After addition, the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate and sodium thiosulfate were then added sequentially, and the mixture was stirred for an additional 15 minutes. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were 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)ethan-1-one (8.10 g, 51%), was obtained by column chromatography.

[0754] 1H NMR (400MHz, DMSO-d6) δ2.37 (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);

[0755] MS m / z(ESI):292.2[M+H] + .

[0756] Step 5: Preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one

[0757]

[0758] To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-one (4.67 g, 16.0 mmol) in ethyl acetate (120 mL) was added Pd / C (140 mg, 10 wt%). The mixture was stirred for 3 hours at room temperature and pressure under a hydrogen atmosphere. The insoluble matter was removed by filtration using celite. The filtrate was concentrated under reduced pressure and separated by column chromatography to give the title compound 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethane-1-one (230 g, 71%).

[0759] 1 H NMR (400MHz, DMSO-d6) δ2.50 (s, 3H), 3.90 (s, 3H), 6.70 (s, 1H), 13.00 (s, 1H);

[0760] MS m / z(ESI):202.2[M+H] + .

[0761] Step 6: Preparation of (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one

[0762]

[0763] To a solution (31 mL) of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.00 g, 9.92 mmol) and 4-bromobenzaldehyde (1.65 g, 8.93 mmol) in DMF was added a solution of MeONa in MeOH (5.36 g, 30 wt %, 29.8 mmol). The mixture was vigorously stirred at 50°C for 30 min, 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 a mixed solvent of EtOAc / n-heptane (mixed solvent ratio of 1:10) to give 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%).

[0764] 1 H NMR (400MHz, DMSO-d6) δ3.80 (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);

[0765] MS m / z(ESI):368.0[M+H] + .

[0766] Step 7: Preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one

[0767]

[0768] To a mixed solution of (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one (1.40 g, 3.80 mmol) in EtOH (27 mL) and DCM (6.8 mL) was added dropwise an aqueous NaOH solution (3.36 g, 10 wt %, 8.39 mmol) and an aqueous H2O2 solution (3.03 g, 30 wt %, 26.7 mmol) in a water bath, followed by stirring for 1 hour in a water bath. Saturated aqueous ammonium chloride was added, and the mixture was 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 give a crude product of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (700 mg), which was used in the next step without further purification.

[0769] MS m / z(ESI):381.9[M+H] + .

[0770] Step 8: Preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one

[0771]

[0772] To a DMF solution (30 mL) of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (crude product from the previous step, 700 mg) was added a methanol solution of sodium methoxide (15 mL, 30 wt%), followed by stirring at 80°C for 1 hour. After cooling, the reaction solution was poured into ice water and the pH was adjusted to weak acidity with hydrochloric acid (6 M). The precipitated solid was filtered and the filter cake was washed with water. The solid compound was collected and dried, and then separated and purified by column chromatography to give 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%).

[0773] 1 H NMR (400MHz, DMSO-d6) δ3.95 (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);

[0774] MS m / z(ESI):378.0[M+H] + .

[0775] Step 9: Preparation of racemic-methyl (3S, 4R, 5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate

[0776]

[0777] 2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (160 mg, 0.424 mmol) and methyl cinnamate (686 mg, 4.24 mmol) were dissolved in chloroform (7 mL) and trifluoroethanol (5.6 mL) and vigorously stirred at 0°C under 450W UV light for 5 hours. The organic solvent was concentrated under reduced pressure and column chromatography was used to remove excess methyl cinnamate to obtain crude racemic-methyl (3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate (250 mg), which was used directly in the next reaction.

[0778] MS m / z(ESI):540.1[M+H] + .

[0779] Step 10: Preparation of racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate

[0780]

[0781] To a methanol solution (8 mL) of racemic methyl (3S, 4R, 5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate (250 mg, crude product, about 0.424 mmol) was added dropwise a methanol solution of sodium methoxide (30 wt%, 252 mg, 1.40 mmol), and then stirred at 60°C for 45 minutes. The reaction mixture was cooled to room temperature and the mixture was desorbed. The organic solvent was concentrated under reduced pressure, and the residue was separated by 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 give crude racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (250 mg), which was used directly in the next reaction.

[0782] MS m / z(ESI):540.1[M+H] + .

[0783] Step 11: Preparation of racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid

[0784]

[0785] Under ice bath, racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (0.26 g, 479.37 μmol) was dissolved in MeOH (3 mL), THF (1.5 mL) and H2O (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, then slowly heated to 25°C and stirred for 3 hours. The reaction solution was adjusted to pH 6 with 1N HCl and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to give the title compound racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid (206 mg, 81%).

[0786] MS m / z(ESI):528.1[M+H] + .

[0787] Step 12: Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0788]

[0789] Under ice bath, (5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid (0.23 g, 435.32 μmol) was dissolved in DCM (1.51 mL). DIPEA (365.70 mg, 2.83 mmol) was added, and HATU (246.35 mg, 652.98 μmol) was added portionwise. The reaction solution was stirred under ice bath for 10 minutes. Dimethylamine hydrochloride (177.7 mg, 2.18 mmol) was added, the temperature was slowly raised to room temperature, and the mixture was stirred for 2 hours. The reaction solution was diluted with DCM, washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide (215 mg, 89%).

[0790] MS m / z(ESI):555.1[M+H] + .

[0791] Step 13: Preparation of racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0792]

[0793] On ice, 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-cyclopenta[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, 2 M THF solution) was slowly added. The reaction mixture was stirred on ice for 10 minutes and then at room temperature for 12 hours. Methanol was added to quench the reaction, and the mixture was stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure and separated by column chromatography to give 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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (120 mg, 57%).

[0794] MS m / z(ESI):541.1[M+H] + .

[0795] Step 14: Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0796]

[0797] At room temperature, (5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (100 mg, 180.47 μmol) was dissolved in 1′4-Dioxane (5 mL) and H2O (1 mL), and nitrogen was bubbled through the mixture for 5 minutes. Pd(PPh3)4 (64 mg, 55.4 μmol) and K3PO4 (117.6 mg, 554.1 μmol) were added, and the reaction was heated to 100°C for 12 hours. The reaction solution was cooled to room temperature, diluted with water, extracted with DCM, and the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to reverse phase preparative separation and chiral column separation to give 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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (8 mg, 8.6%).

[0798] 1 H NMR (400 MHz, DMSO-d 6 )δ0.43-0.53(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=14.0H z, 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] + .

[0799] Example 84

[0800] Preparation of N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)-N-methylacetamide

[0801]

[0802] The preparation method of N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)-N-methylacetamide refers to Example 1.

[0803] MS m / z(ESI):534.3[M+H] + .

[0804] Example 85

[0805] Preparation of 4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)-N,N-dimethylbenzamide

[0806]

[0807] The preparation method of 4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)-N,N-dimethylbenzamide was described in Example 1.

[0808] MS m / z(ESI):534.3[M+H] + .

[0809] Example 86

[0810] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-nitrophenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0811]

[0812] Step 1: Preparation of 4-(benzyloxy)-2,6-dichloropyridine

[0813]

[0814] To a DMF solution (300 mL) of 2,4,6-trichloropyridine (30.0 g, 165 mmol) was added portionwise NaH (7.59 g, 60 wt%, 190 mmol) under an ice-water bath. After the addition was complete, stirring was continued at the same temperature for 15 minutes. Then, benzyl alcohol (17.9 mL, 173 mmol) was added dropwise. After the addition was complete, stirring was continued under an ice-water bath for 1 hour. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The organic phases were combined and washed several times with saturated brine. The organic phases were separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to give the title compound, 4-(benzyloxy)-2,6-dichloropyridine (30.4 g, 73%).

[0815] 1 H NMR (400MHz, CDCl3) δ5.11 (s, 2H), 6.86 (s, 2H), 7.37-7.42 (m, 5H);

[0816] MS m / z(ESI):254.0[M+H] + .

[0817] Step 2: Preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine

[0818]

[0819] 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), followed by stirring at 60°C for 5 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, separated, 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 obtained by column chromatography.

[0820] 1 H NMR (400MHz, DMSO-d6) δ3.81 (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);

[0821] MS m / z(ESI):250.2[M+H] + .

[0822] Step 3: Preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol

[0823]

[0824] To a THF solution (200 mL) of 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.5 g, 78.1 mmol) was added dropwise a n-BuLi solution in n-hexane (41.0 mL, 2.4 M, 97.6 mmol) under a dry ice-acetone bath. The mixture was stirred at this temperature for 30 minutes, and then acetaldehyde (6.88 g, 156 mmol) was added dropwise to the reaction system. After the addition was complete, stirring was continued for 10 minutes. The reaction was quenched by adding a saturated aqueous ammonium chloride solution. The reaction solution was extracted several times with ethyl acetate, and the organic phases were combined and 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)ethan-1-ol (16 g, 70%), was separated by column chromatography.

[0825] 1 H NMR (400MHz, DMSO-d6) δ1.39 (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);

[0826] MS m / z(ESI):294.1[M+H] + .

[0827] Step 4: Preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one

[0828]

[0829] To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-ol (16.0 g, 54.6 mmol) in dichloromethane (320 mL) was added portionwise DMP (30.1 g, 71.0 mmol). After addition, the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate and sodium thiosulfate were then added sequentially, and the mixture was stirred for an additional 15 minutes. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were 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)ethan-1-one (8.10 g, 51%), was obtained by column chromatography.

[0830] 1H NMR (400MHz, DMSO-d6) δ2.37 (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);

[0831] MS m / z(ESI):292.2[M+H] + .

[0832] Step 5: Preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one

[0833]

[0834] 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) was added Pd / C (140 mg, 10 wt%). The mixture was stirred for 3 hours at room temperature and pressure under a hydrogen atmosphere. The insoluble matter was removed by filtration using celite. The filtrate was concentrated under reduced pressure and separated by column chromatography to give the title compound 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.30 g, 71%).

[0835] 1 H NMR (400MHz, DMSO-d6) δ2.50 (s, 3H), 3.90 (s, 3H), 6.70 (s, 1H), 13.00 (s, 1H);

[0836] MS m / z(ESI):202.2[M+H] + .

[0837] Step 6: Preparation of (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one

[0838]

[0839] To a solution (31 mL) of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.00 g, 9.92 mmol) and 4-bromobenzaldehyde (1.65 g, 8.93 mmol) in DMF was added a solution of MeONa in MeOH (5.36 g, 30 wt %, 29.8 mmol). The mixture was vigorously stirred at 50°C for 30 min, 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 a mixed solvent of EtOAc / n-heptane (mixed solvent ratio of 1:10) to give 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%).

[0840] 1 H NMR (400MHz, DMSO-d6) δ3.80 (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);

[0841] MS m / z(ESI):368.0[M+H] + .

[0842] Step 7: Preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one

[0843]

[0844] To a mixed solution of (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one (1.40 g, 3.80 mmol) in EtOH (27 mL) and DCM (6.8 mL) was added dropwise an aqueous NaOH solution (3.36 g, 10 wt %, 8.39 mmol) and an aqueous H2O2 solution (3.03 g, 30 wt %, 26.7 mmol) in a water bath, followed by stirring for 1 hour in a water bath. Saturated aqueous ammonium chloride was added, and the mixture was 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 give a crude product of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (700 mg), which was used in the next step without further purification.

[0845] MS m / z(ESI):381.9[M+H] + .

[0846] Step 8: Preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one

[0847]

[0848] To a DMF solution (30 mL) of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (crude product from the previous step, 700 mg) was added a methanol solution of sodium methoxide (15 mL, 30 wt%), followed by stirring at 80°C for 1 hour. After cooling, the reaction solution was poured into ice water and the pH was adjusted to weak acidity with hydrochloric acid (6 M). The precipitated solid was filtered and the filter cake was washed with water. The solid compound was collected and dried, and then separated and purified by column chromatography to give 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%).

[0849] 1 H NMR (400MHz, DMSO-d6) δ3.95 (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);

[0850] MS m / z(ESI):378.0[M+H] + .

[0851] Step 9: Preparation of racemic-methyl (3S, 4R, 5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate

[0852]

[0853] 2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (160 mg, 0.424 mmol) and methyl cinnamate (686 mg, 4.24 mmol) were dissolved in chloroform (7 mL) and trifluoroethanol (5.6 mL) and vigorously stirred at 0°C under 450W UV light for 5 hours. The organic solvent was concentrated under reduced pressure and column chromatography was used to remove excess methyl cinnamate to obtain crude racemic-methyl (3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate (250 mg), which was used directly in the next reaction.

[0854] MS m / z(ESI):540.1[M+H] + .

[0855] Step 10: Preparation of racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate

[0856]

[0857] To a methanol solution (8 mL) of racemic methyl (3S, 4R, 5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate (250 mg, crude product, about 0.424 mmol) was added dropwise a methanol solution of sodium methoxide (30 wt%, 252 mg, 1.40 mmol), and then stirred at 60°C for 45 minutes. The reaction mixture was cooled to room temperature and the mixture was desorbed. The organic solvent was concentrated under reduced pressure, and the residue was separated by 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 give crude racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (250 mg), which was used directly in the next reaction.

[0858] MS m / z(ESI):540.1[M+H] + .

[0859] Step 11: Preparation of racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid

[0860]

[0861] Under ice bath, racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (0.26 g, 479.37 μmol) was dissolved in MeOH (3 mL), THF (1.5 mL) and H2O (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, then slowly heated to 25°C and stirred for 3 hours. The reaction solution was adjusted to pH 6 with 1N HCl and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to give the title compound racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid (206 mg, 81%).

[0862] MS m / z(ESI):528.1[M+H] + .

[0863] Step 12: Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0864]

[0865] Under ice bath, (5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid (0.23 g, 435.32 μmol) was dissolved in DCM (1.51 mL). DIPEA (365.70 mg, 2.83 mmol) was added, and HATU (246.35 mg, 652.98 μmol) was added portionwise. The reaction solution was stirred under ice bath for 10 minutes. Dimethylamine hydrochloride (177.7 mg, 2.18 mmol) was added, the temperature was slowly raised to room temperature, and the mixture was stirred for 2 hours. The reaction solution was diluted with DCM, washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide (215 mg, 89%).

[0866] MS m / z(ESI):555.1[M+H] + .

[0867] Step 13: Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0868]

[0869] 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide (0.3 g, 540.14 μmol) was dissolved in t-BuOH (4.5 mL), and sodium nitrite (74.54 mg, 1.08 mmol) and Pd2(dba)3 (148.38 mg, 162.04 μmol) were added. tBuBrettPhos (157.08 mg, 324.08 μmol) and tris(3,6-dioxaheptyl)amine (8.73 mg, 27.01 μmol) were added, and the reaction mixture was heated to 130°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with DCM, washed with saturated brine, and 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide (237 mg, 84%).

[0870] MS m / z(ESI):522.1[M+H] + .

[0871] Step 14: Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-nitrophenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0872]

[0873] On ice, (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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide (0.237 g, 454.44 μmol) was dissolved in THF (10 mL). Borane (7.27 mmol, 3.6 mL, 2 M THF solution) was slowly added. The reaction mixture was stirred on ice for 10 minutes, then heated to 25°C and stirred for an additional 12 hours. Methanol was added to quench the reaction, and the mixture was stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure and subjected to reverse phase preparative separation followed by chiral column resolution to give 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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (27 mg, 11.7%).

[0874] 1 H NMR (400 MHz, DMSO-d 6)δ1.95-2.01(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);

[0875] MS m / z(ESI):508.3[M+H] + .

[0876] Example 87

[0877] Preparation of N-cyano-N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyanamide

[0878]

[0879] The preparation method of N-cyano-N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyanamide refers to Example 1.

[0880] MS m / z(ESI):528.2[M+H] + .

[0881] Example 88

[0882] Preparation of 2-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)malononitrile

[0883]

[0884] The preparation method of 2-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)malononitrile was as described in Example 1.

[0885] MS m / z(ESI):527.2[M+H] + .

[0886] Example 89

[0887] Preparation of (4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)methanetricarbonitrile

[0888]

[0889] The preparation method of (4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)methanetricarboxylic acid nitrile refers to Example 1.

[0890] MS m / z(ESI):552.2[M+H] + .

[0891] Example 90

[0892] Preparation of 3-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)propionetonitrile

[0893]

[0894] The preparation method of 3-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)propiolonitrile refers to Example 1.

[0895] MS m / z(ESI):512.2[M+H] + .

[0896] Example 91

[0897] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0898]

[0899] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0900] MS m / z(ESI):536.3[M+H] + .

[0901] Example 92

[0902] Preparation of 1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidin-3-one

[0903]

[0904] The preparation method of 1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidin-3-one was described in Example 1.

[0905] MS m / z(ESI):532.2[M+H] + .

[0906] Example 93

[0907] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0908]

[0909] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0910] MS m / z(ESI):534.3[M+H] + .

[0911] Example 94

[0912] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0913]

[0914] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[0915] MS m / z(ESI):554.2[M+H] + .

[0916] Example 95

[0917] Preparation of ((5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methylcarbamate

[0918]

[0919] The preparation method of ((5aR,6S,7S,8R,8aS)-5a-(4-cyanophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methylcarbamate refers to Example 1.

[0920] MS m / z(ESI):504.2[M+H] + .

[0921] Example 96

[0922] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-(2H-tetrazol-5-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0923]

[0924] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-(2H-tetrazol-5-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0925] MS m / z(ESI):531.2[M+H] + .

[0926] Example 97

[0927] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[0928]

[0929] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[0930] MS m / z(ESI):522.2[M+H] + .

[0931] Example 98

[0932] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0933]

[0934] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-5a-(4-(2-oxa-6-azaspiro[3.3]heptane-6-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0935] MS m / z(ESI):560.3[M+H] + .

[0936] Example 99

[0937] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0938]

[0939] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0940] MS m / z(ESI):574.3[M+H] + .

[0941] Example 100

[0942] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-methoxyazetidin-1-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0943]

[0944] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-methoxyazetidin-1-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0945] MS m / z(ESI):548.3[M+H] + .

[0946] Example 101

[0947] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-(methoxymethyl)azetidin-1-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0948]

[0949] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-(methoxymethyl)azetidin-1-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[0950] MS m / z(ESI):562.3[M+H] + .

[0951] Example 102

[0952] Preparation of 1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidine-3-carbonitrile

[0953]

[0954] The preparation method of 1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidine-3-carbonitrile refers to Example 1.

[0955] MS m / z(ESI):543.3[M+H] + .

[0956] Example 103

[0957] Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidin-3-yl)acetonitrile

[0958]

[0959] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)azetidin-3-yl)acetonitrile was described in Example 1.

[0960] MS m / z(ESI):557.3[M+H] + .

[0961] Example 104

[0962] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0963]

[0964] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[0965] MS m / z(ESI):566.3[M+H] + .

[0966] Example 105

[0967] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0968]

[0969] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was described in Example 1.

[0970] MS m / z(ESI):566.3[M+H] + .

[0971] Example 106

[0972] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0973]

[0974] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(3-fluoro-3-(2-hydroxypropan-2-yl)azetidin-1-yl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was described in Example 1.

[0975] MS m / z(ESI):594.3[M+H] + .

[0976] Example 107

[0977] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0978]

[0979] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was described in Example 1.

[0980] MS m / z(ESI):548.3[M+H] + .

[0981] Example 108

[0982] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0983]

[0984] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0985] MS m / z(ESI):568.3[M+H] + .

[0986] Example 109

[0987] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0988]

[0989] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0990] MS m / z(ESI):568.3[M+H] + .

[0991] Example 110

[0992] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0993]

[0994] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[0995] MS m / z(ESI):568.3[M+H] + .

[0996] Example 111

[0997] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(1-fluorocyclopropyl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[0998]

[0999] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(1-fluorocyclopropyl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1000] MS m / z(ESI):521.2[M+H] + .

[1001] Example 112

[1002] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(1-hydroxycyclopropyl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1003]

[1004] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(1-hydroxycyclopropyl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1005] MS m / z(ESI):519.2[M+H] + .

[1006] Example 113

[1007] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-(1-aminocyclopropyl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1008]

[1009] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-(1-aminocyclopropyl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1010] MS m / z(ESI):518.3[M+H] + .

[1011] Example 114

[1012] Preparation of 1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyclopropane-1-carbonitrile

[1013]

[1014] The preparation method of 1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyclopropane-1-carbonitrile refers to Example 1.

[1015] MS m / z(ESI):528.2[M+H] + .

[1016] Example 115

[1017] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1018]

[1019] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1020] MS m / z(ESI):533.3[M+H] + .

[1021] Example 116

[1022] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1023]

[1024] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1025] 1 H NMR (400 MHz, DMSO-d 6 )δ0.85-0.93(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, 2 H), 6.85-6.89(m, 2H), 6.90-6.96(m, 1H), 6.97-7.04(m, 2H), 7.08-7.16(m, 2H);

[1026] MS m / z(ESI):518.2[M+H] + .

[1027] Example 117

[1028] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1029]

[1030] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1031] 1 H NMR (400 MHz, DMSO-d 6)δ0.82-0.88(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);

[1032] MS m / z(ESI):532.3[M+H] + .

[1033] Example 118

[1034] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1035]

[1036] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1037] MS m / z(ESI):572.2[M+H] + .

[1038] Example 119

[1039] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-(((methoxymethyl)(methyl)amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1040]

[1041] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-(((methoxymethyl)(methyl)amino)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1042] MS m / z(ESI):534.2[M+H] + .

[1043] Example 120

[1044] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1045]

[1046] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3,3-difluoroazetidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1047] MS m / z(ESI):552.2[M+H] + .

[1048] Example 121

[1049] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1050]

[1051] The preparation method of (5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-5a-(4-azidophenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1052] 1 H NMR (400 MHz, DMSO-d 6 )δ2.15-2.21(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);

[1053] MS m / z(ESI):558.2[M+H] + .

[1054] Example 122

[1055] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1056]

[1057] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1058] MS m / z(ESI):580.2[M+H] + .

[1059] Example 123

[1060] (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-(morpholinomethyl)-6-phenyl

[1061] Preparation of 5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1062]

[1063] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was as described in Example 1.

[1064] 1 H NMR (400 MHz, DMSO-d 6 )δ1.98-2.05(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);

[1065] MS m / z(ESI):546.2[M+H] + .

[1066] Example 124

[1067] Preparation of (5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5a-(4-azidophenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1068]

[1069] The preparation method of (5aR,6S,7S,8R,8aS)-7-(((1R,5S)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5a-(4-azidophenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1070] MS m / z(ESI):570.3[M+H] + .

[1071] Example 125

[1072] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1073]

[1074] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1075] 1 H NMR (400 MHz, DMSO-d 6 )δ0.84-0.89(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);

[1076] MS m / z(ESI):572.2[M+H] + .

[1077] Example 126

[1078] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1079]

[1080] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1081] 1 H NMR (400 MHz, DMSO-d 6 )δ0.39-0.44(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);

[1082] MS m / z(ESI):517.3[M+H] + .

[1083] Example 127

[1084] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1085]

[1086] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((diethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1087] 1 H NMR (400 MHz, DMSO-d6 )δ0.39-0.45(m, 2H), 0.72-0.80(m, 2H), 0.82-0.89(m, 6H), 1.62-1.70(m, 1 H), 2.06-2.13(m, 1H), 2.30-2.38(m, 2H), 2.46-2.57(m, 4H), 2.92-3.01(m, 1 H), 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);

[1088] MS m / z(ESI):531.3[M+H] + .

[1089] Example 128

[1090] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1091]

[1092] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1093] MS m / z(ESI):571.2[M+H] + .

[1094] Example 129

[1095] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1096]

[1097] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1098] MS m / z(ESI):579.3[M+H] + .

[1099] Example 130

[1100] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1101]

[1102] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1103] 1 H NMR (400 MHz, DMSO-d 6 )δ0.44-0.51(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);

[1104] MS m / z(ESI):571.3[M+H] + .

[1105] Example 131

[1106] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1107]

[1108] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-(morpholinomethyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1109] 1 H NMR (400 MHz, DMSO-d 6 )δ0.45-0.51(m, 2H), 0.81-0.85(m, 2H), 1.68-1.75(m, 1H), 1.96-2.02(m, 1 H), 2.26-2.34(m, 2H), 2.54-2.60(m, 2H), 3.08-3.15(m, 1H), 3.54-3.67(m, 6 H), 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);

[1110] MS m / z(ESI):545.3[M+H] + .

[1111] Example 132

[1112] Preparation of (5aR,6S,7S,8R,8aS)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1113]

[1114] The preparation method of (5aR,6S,7S,8R,8aS)-7-((ethyl(methyl)amino)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1115] 1 H NMR (400 MHz, DMSO-d 6 )(δ0.85-0.92(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);

[1116] MS m / z(ESI):533.3[M+H] + .

[1117] Example 133

[1118] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1119]

[1120] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1121] 1 H NMR (400 MHz, DMSO-d 6)δ0.81-0.90(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);

[1122] MS m / z(ESI):547.3[M+H] + .

[1123] Example 134

[1124] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1125]

[1126] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1127] MS m / z(ESI):587.2[M+H] + .

[1128] Example 135

[1129] Preparation of (5aR,6S,7S,8R,8aS)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1130]

[1131] The preparation method of (5aR,6S,7S,8R,8aS)-7-((4,4-difluoropiperidin-1-yl)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1132] MS m / z(ESI):595.3[M+H] + .

[1133] Example 136

[1134] Preparation of (5aR,6S,7S,8R,8aS)-7-(((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1135]

[1136] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-7-(((1R, 5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-1,3-dimethoxy-5a-(4-(oxetan-3-yl)phenyl)-6-phenyl-5a, 6, 7, 8-tetrahydro-8aH-cyclopenta[4, 5] furo[3, 2-c] pyridine-8, 8a-diol was referred to Example 1.

[1137] MS m / z(ESI):587.3[M+H] + .

[1138] Example 137

[1139] Preparation of (5aR,6S,7S,8R,8aS)-1,3-dimethoxy-7-(morpholinomethyl)-5a-(4-(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1140]

[1141] The preparation method of (5aR,6S,7S,8R,8aS)-1,3-dimethoxy-7-(morpholinomethyl)-5a-(4-(oxetan-3-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was as described in Example 1.

[1142] MS m / z(ESI):561.3[M+H] + .

[1143] Example 138

[1144] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1145]

[1146] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1147] MS m / z(ESI):550.3[M+H] + .

[1148] Example 139

[1149] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-(3,3-difluorocyclobutyl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1150]

[1151] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-(3,3-difluorocyclobutyl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1152] MS m / z(ESI):553.3[M+H] + .

[1153] Example 140

[1154] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1155]

[1156] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1157] MS m / z(ESI):561.3[M+H] + .

[1158] Example 141

[1159] Preparation of (5aR,6S,7R,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[1160]

[1161] The preparation method of (5aR,6S,7R,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[1162] MS m / z(ESI):575.3[M+H] + .

[1163] Example 142

[1164] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1165]

[1166] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1167] MS m / z(ESI):602.2[M+H] + .

[1168] Example 143

[1169] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-(azetidin-1-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1170]

[1171] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-(azetidin-1-yl)phenyl)-7-((dimethylamino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1172] MS m / z(ESI):518.3[M+H] + .

[1173] Example 144

[1174] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-nitroazetidin-1-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1175]

[1176] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-(3-nitroazetidin-1-yl)phenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1177] MS m / z(ESI):563.2[M+H] + .

[1178] Example 145

[1179] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-hydroxyethyl)(methyl)amino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1180]

[1181] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-hydroxyethyl)(methyl)amino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1182] 1 H NMR (400 MHz, DMSO-d 6 )δ1.98-2.05(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);

[1183] MS m / z(ESI):534.2[M+H] + .

[1184] Example 146

[1185] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-fluoroazetidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1186]

[1187] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-fluoroazetidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1188] 1 H NMR (400 MHz, DMSO-d 6 )δ2.19-2.27(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);

[1189] MS m / z(ESI):534.2[M+H] + .

[1190] Example 147

[1191] Preparation of 2-(1-(((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)azetidin-3-yl)acetonitrile

[1192]

[1193] The preparation method of 2-(1-(((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)azetidin-3-yl)acetonitrile refers to Example 1.

[1194] MS m / z(ESI):555.3[M+H] + .

[1195] Example 148

[1196] Preparation of 1-(((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)azetidine-3-carbonitrile

[1197]

[1198] The preparation method of 1-(((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)azetidine-3-carbonitrile refers to Example 1.

[1199] MS m / z(ESI):541.2[M+H] + .

[1200] Example 149

[1201] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-fluoroethyl)(methyl)amino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1202]

[1203] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-(((2-fluoroethyl)(methyl)amino)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1204] MS m / z(ESI):536.2[M+H] + .

[1205] Example 150

[1206] Preparation of 3-((((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)(methyl)amino)propionitrile

[1207]

[1208] The preparation method of 3-((((5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridin-7-yl)methyl)(methyl)amino)propionitrile refers to Example 1.

[1209] MS m / z(ESI):543.2[M+H] + .

[1210] Example 151

[1211] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1212]

[1213] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1214] MS m / z(ESI):561.3[M+H] + .

[1215] Example 152

[1216] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1217]

[1218] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was described in Example 1.

[1219] MS m / z(ESI):547.3[M+H] + .

[1220] Example 153

[1221] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1222]

[1223] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1224] MS m / z(ESI):533.3[M+H] + .

[1225] Example 154

[1226] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1227]

[1228] The preparation method of (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-cyclopenta[4, 5] furo[3, 2-c] pyridine-8, 8a-diol was as described in Example 1.

[1229] 1 H NMR (400 MHz, DMSO-d 6 )δ0.38-0.47(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);

[1230] MS m / z(ESI):545.2[M+H] + .

[1231] Example 155

[1232] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((3-(methoxymethyl)azetidin-1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1233]

[1234] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-7-((3-(methoxymethyl)azetidin-1-yl)methyl)-6-phenyl-5a, 6, 7, 8-tetrahydro-8aH-cyclopenta[4, 5] furo[3, 2-c] pyridine-8, 8a-diol was referred to Example 1.

[1235] 1H NMR (400 MHz, DMSO-d 6 )δ0.37-0.44(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);

[1236] MS m / z(ESI):559.2[M+H] + .

[1237] Example 156

[1238] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1239]

[1240] The preparation method of (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-cyclopenta[4, 5] furo[3, 2-c] pyridine-8, 8a-diol was referred to Example 1.

[1241] 1 H NMR (400 MHz, DMSO-d 6)δ0.37-0.48(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), 5.2 4-5.32(m, 1H), 5.93(s, 1H), 6.63-6.70(m, 2H), 6.79-6.85(m, 2H), 6.92-7.01(m, 5H);

[1242] MS m / z(ESI):545.2[M+H] + .

[1243] Example 157

[1244] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-cyclopropylphenyl)-7-((3-hydroxyazetidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1245]

[1246] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-5a-(4-cyclopropylphenyl)-7-((3-hydroxyazetidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a, 6, 7, 8-tetrahydro-8aH-cyclopenta[4, 5] furo[3, 2-c] pyridine-8, 8a-diol was as described in Example 1.

[1247] MS m / z(ESI):531.3[M+H] + .

[1248] Example 158

[1249] Preparation of (4a′S,5′S,5a′R,10b′S,10c′R)-5a′-(4-cyclopropylphenyl)-8′,10′-dimethoxy-3′-methyl-5′-phenyl-3′,4′,4a′,5′,5a′,10c′-hexahydro-10b′H-spiro[oxetane-3,2′-pyrido[3″,4″:4′,5′]furo[3′,2′:3,4]cyclopenta[1,2-e][1,3]oxazin]-10b′-ol

[1250]

[1251] The preparation method of (4a′S, 5′S, 5a′R, 10b′S, 10c′R)-5a′-(4-cyclopropylphenyl)-8′, 10′-dimethoxy-3′-methyl-5′-phenyl-3′, 4′, 4a′, 5′, 5a′, 10c′-hexahydro-10b′H-spiro[oxetane-3, 2′-pyrido[3″, 4″: 4′, 5′]furo[3′, 2′: 3, 4]cyclopenta[1, 2-e][1, 3]oxazine]-10b′-ol refers to Example 1.

[1252] MS m / z(ESI):543.3[M+H] + .

[1253] Example 159

[1254] Preparation of (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]cyclopenta[1,2-e][1,3]oxazin-2(3H)-one

[1255]

[1256] The preparation method of (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]cyclopenta[1,2-e][1,3]oxazin-2(3H)-one refers to Example 1.

[1257] MS m / z(ESI):5152[M+H] + .

[1258] Example 160

[1259] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1260]

[1261] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1262] MS m / z(ESI):559.3[M+H] + .

[1263] Example 161

[1264] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1265]

[1266] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1267] MS m / z(ESI):545.3[M+H] + .

[1268] Example 162

[1269] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1270]

[1271] The preparation method of (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-cyclopenta[4, 5] furo[3, 2-c] pyridine-8, 8a-diol was referred to Example 1.

[1272] MS m / z(ESI):563.3[M+H] + .

[1273] Example 163

[1274] Preparation of (5aR,6S,7S,8R,8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1275]

[1276] The preparation method of (5aR, 6S, 7S, 8R, 8aS)-7-((2-oxa-6-azaspiro[3.3]heptane-6-yl)methyl)-5a-(4-cyclopropylphenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is as shown in Example 1.

[1277] MS m / z(ESI):557.3[M+H] + .

[1278] Example 164

[1279] Preparation of N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyanamide

[1280]

[1281] The preparation method of N-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)cyanamide refers to Example 1.

[1282] MS m / z(ESI):503.2[M+H] + .

[1283] Example 165

[1284] Preparation of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-morpholinophenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1285]

[1286] The preparation method of (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-1,3-dimethoxy-5a-(4-morpholinophenyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1287] 1 H NMR (400MHz, CDCl3) δ2.02-2.00 (d, J=7.2Hz, 2H), 2.90-2.50 (m, 7H), 3.08-3.05 (m, 4H), 3.83-3.80 (m, 4H), 3.93 (s, 3 H), 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);

[1288] MS m / z(ESI):548.3[M+H] + .

[1289] Example 166

[1290] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1291]

[1292] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1293] MS m / z(ESI):561.3[M+H] + .

[1294] Example 167

[1295] Preparation of (E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzaldehyde O-methyloxime

[1296]

[1297] The preparation method of (E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzaldehyde O-methyloxime refers to Example 1.

[1298] MS m / z(ESI):520.3[M+H] + .

[1299] Example 168

[1300] Preparation of (E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzaldehyde oxime

[1301]

[1302] Step 1: Preparation of 4-(benzyloxy)-2,6-dichloropyridine

[1303]

[1304] To a DMF solution (300 mL) of 2,4,6-trichloropyridine (30.0 g, 165 mmol) was added portionwise NaH (7.59 g, 60 wt%, 190 mmol) under an ice-water bath. After the addition was complete, stirring was continued at the same temperature for 15 minutes. Then, benzyl alcohol (17.9 mL, 173 mmol) was added dropwise. After the addition was complete, stirring was continued under an ice-water bath for 1 hour. The reaction solution was poured into ice water and extracted three times with ethyl acetate. The organic phases were combined and washed several times with saturated brine. The organic phases were separated and dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and separated by column chromatography to give the title compound, 4-(benzyloxy)-2,6-dichloropyridine (30.4 g, 73%).

[1305] 1 H NMR (400MHz, CDCl3) δ5.11 (s, 2H), 6.86 (s, 2H), 7.37-7.42 (m, 5H);

[1306] MS m / z(ESI):254.0[M+H] + .

[1307] Step 2: Preparation of 4-(benzyloxy)-2-chloro-6-methoxypyridine

[1308]

[1309] 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), followed by stirring at 60°C for 5 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, separated, 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 obtained by column chromatography.

[1310] 1 H NMR (400MHz, DMSO-d6) δ3.81 (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);

[1311] MS m / z(ESI):250.2[M+H] + .

[1312] Step 3: Preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethane-1-ol

[1313]

[1314] To a THF solution (200 mL) of 4-(benzyloxy)-2-chloro-6-methoxypyridine (19.5 g, 78.1 mmol) was added dropwise a n-BuLi solution in n-hexane (41.0 mL, 2.4 M, 97.6 mmol) under a dry ice-acetone bath. The mixture was stirred at this temperature for 30 minutes, and then acetaldehyde (6.88 g, 156 mmol) was added dropwise to the reaction system. After the addition was complete, stirring was continued for 10 minutes. The reaction was quenched by adding a saturated aqueous ammonium chloride solution. The reaction solution was extracted several times with ethyl acetate, and the organic phases were combined and 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)ethan-1-ol (16 g, 70%), was separated by column chromatography.

[1315] 1 H NMR (400MHz, DMSO-d6) δ1.39 (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);

[1316] MS m / z(ESI):294.1[M+H] + .

[1317] Step 4: Preparation of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-one

[1318]

[1319] To a solution of 1-(4-(benzyloxy)-6-chloro-2-methoxypyridin-3-yl)ethan-1-ol (16.0 g, 54.6 mmol) in dichloromethane (320 mL) was added portionwise DMP (30.1 g, 71.0 mmol). After addition, the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate and sodium thiosulfate were then added sequentially, and the mixture was stirred for an additional 15 minutes. The organic phase was separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were 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)ethan-1-one (810 g, 51%), was obtained by column chromatography.

[1320] 1H NMR (400MHz, DMSO-d6) δ2.37 (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);

[1321] MS m / z(ESI):292.2[M+H] + .

[1322] Step 5: Preparation of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one

[1323]

[1324] 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) was added Pd / C (140 mg, 10 wt%). The mixture was stirred for 3 hours at room temperature and pressure under a hydrogen atmosphere. The insoluble matter was removed by filtration using celite. The filtrate was concentrated under reduced pressure and separated by column chromatography to give the title compound 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.30 g, 71%).

[1325] 1 H NMR (400MHz, DMSO-d6) δ2.50 (s, 3H), 3.90 (s, 3H), 6.70 (s, 1H), 13.00 (s, 1H);

[1326] MS m / z(ESI):202.2[M+H] + .

[1327] Step 6: Preparation of (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one

[1328]

[1329] To a solution (31 mL) of 1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)ethan-1-one (2.00 g, 9.92 mmol) and 4-bromobenzaldehyde (1.65 g, 8.93 mmol) in DMF was added a solution of MeONa in MeOH (5.36 g, 30 wt %, 29.8 mmol). The mixture was vigorously stirred at 50°C for 30 min, 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 a mixed solvent of EtOAc / n-heptane (mixed solvent ratio of 1:10) to give 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%).

[1330] 1 H NMR (400MHz, DMSO-d6) δ3.80 (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);

[1331] MS m / z(ESI):368.0[M+H] + .

[1332] Step 7: Preparation of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one

[1333]

[1334] To a mixed solution of (E)-3-(4-bromophenyl)-1-(6-chloro-4-hydroxy-2-methoxypyridin-3-yl)prop-2-en-1-one (1.40 g, 3.80 mmol) in EtOH (27 mL) and DCM (6.8 mL) was added dropwise an aqueous NaOH solution (3.36 g, 10 wt %, 8.39 mmol) and an aqueous H2O2 solution (3.03 g, 30 wt %, 26.7 mmol) in a water bath, followed by stirring for 1 hour in a water bath. Saturated aqueous ammonium chloride was added, and the mixture was 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 give a crude product of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (700 mg), which was used in the next step without further purification.

[1335] MS m / z(ESI):381.9[M+H] + .

[1336] Step 8: Preparation of 2-(4-bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one

[1337]

[1338] To a DMF solution (30 mL) of 2-(4-bromophenyl)-7-chloro-3-hydroxy-5-methoxy-4H-pyrano[3,2-c]pyridin-4-one (crude product from the previous step, 700 mg) was added a methanol solution of sodium methoxide (15 mL, 30 wt%), followed by stirring at 80°C for 1 hour. After cooling, the reaction solution was poured into ice water and the pH was adjusted to weak acidity with hydrochloric acid (6 M). The precipitated solid was filtered and the filter cake was washed with water. The solid compound was collected and dried, and then separated and purified by column chromatography to give 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%).

[1339] 1 H NMR (400MHz, DMSO-d6) δ3.95 (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);

[1340] MS m / z(ESI):378.0[M+H] + .

[1341] Step 9: Preparation of racemic-methyl (3S, 4R, 5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate

[1342]

[1343] 2-(4-Bromophenyl)-3-hydroxy-5,7-dimethoxy-4H-pyrano[3,2-c]pyridin-4-one (160 mg, 0.424 mmol) and methyl cinnamate (686 mg, 4.24 mmol) were dissolved in chloroform (7 mL) and trifluoroethanol (5.6 mL) and vigorously stirred at 0°C under 450W UV light for 5 hours. The organic solvent was concentrated under reduced pressure and column chromatography was used to remove excess methyl cinnamate to obtain crude racemic-methyl (3S,4R,5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate (250 mg), which was used directly in the next reaction.

[1344] MS m / z(ESI):540.1[M+H] + .

[1345] Step 10: Preparation of racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate

[1346]

[1347] To a methanol solution (8 mL) of racemic methyl (3S, 4R, 5R)-2-(4-bromophenyl)-5-hydroxy-6,8-dimethoxy-10-carbonyl-3-phenyl-2,3,4,5-tetrahydro-2,5-methyleneoxepino[3,2-c]pyridine-4-carboxylate (250 mg, crude product, about 0.424 mmol) was added dropwise a methanol solution of sodium methoxide (30 wt%, 252 mg, 1.40 mmol), and then stirred at 60°C for 45 minutes. The reaction mixture was cooled to room temperature and the mixture was desorbed. The organic solvent was concentrated under reduced pressure, and the residue was separated by 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 give crude racemic-methyl (5aR, 6S, 7R, 8aR)-5a-(4-bromophenyl)-8a-hydroxy-1,3-dimethoxy-8-carbonyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylate (250 mg), which was used directly in the next reaction.

[1348] MS m / z(ESI):540.1[M+H] + .

[1349] Step 11: Preparation of racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid

[1350]

[1351] Under ice bath, racemic-(5aR,6S,7S,8R,8aS)-5a-(4-bromophenyl)-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (0.26 g, 479.37 μmol) was dissolved in MeOH (3 mL), THF (1.5 mL) and H2O (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, then slowly heated to 25°C and stirred for 3 hours. The reaction solution was adjusted to pH 6 with 1N HCl and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure to give the title compound racemic-(5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid (206 mg, 81%).

[1352] MS m / z(ESI):528.1[M+H] + .

[1353] Step 12: Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[1354]

[1355] Under ice bath, (5aR,7R,8R,8aS)-5a-(4-bromophenyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxylic acid (0.23 g, 435.32 μmol) was dissolved in DCM (1.51 mL). DIPEA (365.70 mg, 2.83 mmol) was added, and HATU (246.35 mg, 652.98 μmol) was added portionwise. The reaction solution was stirred under ice bath for 10 minutes. Dimethylamine hydrochloride (177.7 mg, 2.18 mmol) was added, the temperature was slowly raised to room temperature, and the mixture was stirred for 2 hours. The reaction solution was diluted with DCM, washed with saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give 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-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide (215 mg, 89%).

[1356] MS m / z(ESI):555.1[M+H] + .

[1357] Step 13: Preparation of racemic-methyl 4-((5aR,6S,7R,8R,8aS)-7-(dimethylcarbamoyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzoate

[1358]

[1359] 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-cyclopenta[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), and trans-bis(mu-acetoxy)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (18030 mg, 192.29 μmol) and Mo(CO)6 (507.64 mg, 1.92 mmol) were added. Nitrogen was bubbled for 5 minutes and the mixture was heated to 135°C and microwaved for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and water. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to give the title compound, racemic-methyl 4-((5aR,6S,7R,8R,8aS)-7-(dimethylcarbamoyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzoate (210 mg, 61%).

[1360] MS m / z(ESI):535.2[M+H] + .

[1361] Step 14: Preparation of rac-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(hydroxymethyl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1362]

[1363] At room temperature, racemic methyl 4-((5aR,6S,7R,8R,8aS)-7-(dimethylcarbamoyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[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, 2 M THF solution) was slowly added, and the mixture was heated 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 give the title compound, racemic (5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(hydroxymethyl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (110 mg, 51.9%).

[1364] MS m / z(ESI):493.2[M+H] + .

[1365] Step 15: Preparation of racemic-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzaldehyde

[1366]

[1367] Under ice-cooling, rac-(5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-5a-(4-(hydroxymethyl)phenyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol (0.09 g, 182.72 μmol) was dissolved in DCM (6.6 mL) and DMP (116.25 mg, 274.08 μmol) was added. The reaction was stirred under ice-cooling for 0.5 h. The reaction solution was concentrated under reduced pressure and separated by column chromatography to give 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzaldehyde (71 mg, 79%).

[1368] MS m / z(ESI):491.2[M+H] + .

[1369] Step 16: Preparation of (E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzaldehyde oxime

[1370]

[1371] At room temperature, racemic-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzaldehyde (0.071 g, 144.74 μmol) was dissolved in EtOH (2 mL) and H2O (2 mL). Hydroxylamine hydrochloride (20.12 mg, 289.47 μmol) and DIPEA (73.23 mg, 723.68 μmol) were added, nitrogen was bubbled through the mixture for 5 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and subjected to reverse phase preparative separation, followed by chiral column resolution to give the optically pure title compound (E)-4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzaldehyde oxime (26 mg, 36%).

[1372] 1 H NMR (400 MHz, DMSO-d 6 )δ1.96-2.02(m, 1H), 2.13-2.28(m, 6H), 2.55-2.59(m, 1H), 3.11-3.16(m, 1 H), 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);

[1373] MS m / z(ESI):506.3[M+H] + .

[1374] Example 169

[1375] Preparation of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzylidene)cyanamide

[1376]

[1377] The preparation method of 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-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzylidene)cyanamide refers to Example 1.

[1378] MS m / z(ESI):515.2[M+H] + .

[1379] Example 170

[1380] Preparation of cyclopropyl(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)methanone

[1381]

[1382] The preparation method of cyclopropyl(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)methanone was prepared by referring to Example 1.

[1383] MS m / z(ESI):531.2[M+H] + .

[1384] Example 171

[1385] Preparation of (4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)(oxetan-3-yl)methanone

[1386]

[1387] The preparation method of (4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)(oxetan-3-yl)methanone refers to Example 1.

[1388] MS m / z(ESI):547.2[M+H] + .

[1389] Example 172

[1390] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1391]

[1392] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1393] MS m / z(ESI):533.3[M+H] + .

[1394] Example 173

[1395] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-hydroxyazetidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1396]

[1397] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-7-((3-hydroxyazetidin-1-yl)methyl)-1,3-dimethoxy-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1398] 1 H NMR (400 MHz, DMSO-d 6 )δ1.96-2.04(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);

[1399] MS m / z(ESI):532.2[M+H] + .

[1400] Example 174

[1401] Preparation of 4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[1402]

[1403] The preparation method of 4-((5aR,6S,7S,8R,8aS)-8,8a-dihydroxy-7-(hydroxymethyl)-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[1404] MS m / z(ESI):461.2[M+H] + .

[1405] Example 175

[1406] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1407]

[1408] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1409] MS m / z(ESI):572.2[M+H] + .

[1410] Example 176

[1411] Preparation of 1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)propan-1-one

[1412]

[1413] The preparation method of 1-(4-((5aR,6S,7S,8R,8aS)-7-((dimethylamino)methyl)-8,8a-dihydroxy-1,3-dimethoxy-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)phenyl)propan-1-one was referred to Example 1.

[1414] MS m / z(ESI):519.2[M+H] + .

[1415] Example 177

[1416] Preparation of (5aR,6S,7R,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide

[1417]

[1418] The preparation method of (5aR,6S,7R,8R,8aS)-5a-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-8,8a-dihydroxy-1,3-dimethoxy-N,N-dimethyl-6-phenyl-5a,7,8,8a-tetrahydro-6H-cyclopenta[4,5]furo[3,2-c]pyridine-7-carboxamide refers to Example 1.

[1419] MS m / z(ESI):575.2[M+H] + .

[1420] Example 178

[1421] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1422]

[1423] The preparation method of (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-cyclopenta[4, 5] furo[3, 2-c] pyridine-8, 8a-diol was as described in Example 1.

[1424] MS m / z(ESI):564.2[M+H] + .

[1425] Example 179

[1426] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1427]

[1428] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol was referred to Example 1.

[1429] MS m / z(ESI):561.2[M+H] + .

[1430] Example 180

[1431] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((3-(methoxymethyl)azetidin-1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1432]

[1433] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((3-(methoxymethyl)azetidin-1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1434] 1 H NMR (400 MHz, DMSO-d 6 )δ2.27-2.33(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), 6.77-6.8 1(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).

[1435] MS m / z(ESI):560.2[M+H] + .

[1436] Example 181

[1437] Preparation of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((3-methoxyazetidin-1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1438]

[1439] The preparation method of (5aR,6S,7S,8R,8aS)-5a-(4-azidophenyl)-1,3-dimethoxy-7-((3-methoxyazetidin-1-yl)methyl)-6-phenyl-5a,6,7,8-tetrahydro-8aH-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol refers to Example 1.

[1440] MS m / z(ESI):546.2[M+H] + .

[1441] Example 182

[1442] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1443]

[1444] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1445] MS m / z(ESI):546.2[M+H] + .

[1446] Example 183

[1447] Preparation of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol

[1448]

[1449] The preparation method of (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-cyclopenta[4,5]furo[3,2-c]pyridine-8,8a-diol is shown in Example 1.

[1450] 1 H NMR (400 MHz, DMSO-d 6 )δ1.00(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).

[1451] MS m / z(ESI):560.2[M+H] + .

[1452] Example 184

[1453] Preparation of 4-((5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile

[1454]

[1455] The preparation method of 4-((5aR,6S,7R,8R,8aS)-8,8a-dihydroxy-1,3-dimethoxy-7-((methoxy(methyl)amino)methyl)-6-phenyl-6,7,8,8a-tetrahydro-5aH-cyclopenta[4,5]furo[3,2-c]pyridin-5a-yl)benzonitrile was as described in Example 1.

[1456] MS m / z(ESI):504.2[M+H] + .

[1457] Biological test evaluation

[1458] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[1459] 1. Cell Function Experiment

[1460] Test Example 1: Inhibitory Effect of the Compounds of the Invention on the Proliferation of Lymphoma Cell Lines TMD8 and SU-DHL-2

[1461] 1.1. Experimental Purpose:

[1462] The proliferation inhibitory activity of the example compounds on lymphoma cell lines TMD8 and SU-DHL-2 was determined.

[1463] 2. Experimental instruments:

[1464] 2.1 Instruments:

[1465] Microplate reader (BioTek Synergy H1);

[1466] Pipette (Eppendorf & Rainin).

[1467] 2.2 Reagents:

[1468] TMD8 was purchased from Nanjing Kebai Biotechnology Co., Ltd.;

[1469] SU-DHL-2 cells were purchased from ATCC with catalog number CRL-2956;

[1470] Cell Titer-Glo cells were purchased from Promega, catalog number G7573;

[1471] RPMI 1640 was purchased from Gibco, catalog number 22400089;

[1472] DMEM was purchased from Gibco, catalog number 11995065;

[1473] FBS was purchased from Gibco, catalog number 10091148;

[1474] PBS was purchased from Gibco, catalog number 10010023;

[1475] Pancreatin was purchased from Gibco, catalog number 25200056;

[1476] Cell culture plates were purchased from Corning, catalog number 3610.

[1477] 3. Experimental methods:

[1478] When TMD8 or SU-DHL-2 cells were cultured to an appropriate degree of confluence, the TMD8 or SU-DHL-2 cells were collected and adjusted to an appropriate cell density using complete culture medium. The cell suspension was plated on a 96-well plate at 90 μL per well and placed in a 37°C, 5% CO2 incubator overnight. Compound solutions of different concentrations were prepared using DMSO and culture medium, and a solvent control was set up. The compound solution was added to a 96-well plate at 10 μL per well and continued to be cultured in a 37°C, 5% CO2 incubator for approximately 72 hours. CellTiter-Glo solution was then added, the plates were shaken to mix evenly, incubated in the dark for 10 minutes, and read using a BioTek Synergy H1 microplate reader.

[1479] 4. Experimental data processing method:

[1480] The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the GI 50 value.

[1481] 5. Experimental results:

[1482] IC of the compounds of the present invention on the inhibition of TMD8 and SU-DHL-2 cell proliferation 50 It exhibits biological activity ranging from about 0.01 nM to 500 nM.

[1483] In some embodiments, the IC values ​​of the compounds of the present invention for inhibition of TMD8 and SU-DHL-2 cell proliferation are 50 Less than about 100 nM, preferably less than about 50 nM for the compounds listed in the present invention, further preferably less than about 10 nM, more preferably less than about 5 nM, and most preferably less than 1 nM for the compounds listed in the present invention.

[1484] Table 1 IC of compounds against cell proliferation inhibition 50 value

[1485]

[1486]

[1487] “NA” stands for not tested.

[1488] 6. Experimental conclusions:

[1489] The compounds of the present invention have significant proliferation inhibitory effects on TMD8 and SU-DHL-2 cells.

[1490] Test Example 2: Determination of the proliferation inhibitory activity of the compounds of the present invention on tumor cell lines

[1491] 1. Experimental purpose:

[1492] The proliferation inhibitory activity of the example compounds against 8 tumor cell lines was determined, including 1 human pancreatic cancer cell line (KRAS G12C mutant cell line Mia PaCa-2), 1 human lung adenocarcinoma cell line (KRAS G13C mutant cell line NCI-H1792), 3 human breast cancer cell lines (KRAS G13D mutant cell lines MDA-MB-231, BT474 and MDA-MB-361), 1 human B lymphoma cell line SU-DHL-6, and 2 human colon cancer cell lines (KRAS G12V mutant cell lines SW620 and NCI-H716).

[1493] 2. Experimental instruments:

[1494] 2.1 Instruments:

[1495] Microplate reader (BioTek Synergy H1);

[1496] Pipette (Eppendorf & Rainin).

[1497] 2.2 Reagents:

[1498] MDA-MB-231, MDA-MB-361, SW620, and BT474 were purchased from Nanjing Kebai Biotechnology Co., Ltd.;

[1499] Mia PaCa-2 and SU-DHL-6 were purchased from ATCC; NCI-H1792 and NCI-H716 were purchased from Guangzhou Geneo Biotechnology Co., Ltd.

[1500] Cell Titer-Glo cells were purchased from Promega, catalog number G7573;

[1501] RPMI 1640 was purchased from Gibco, catalog number 22400089;

[1502] DMEM was purchased from Gibco, catalog number 11995065;

[1503] FBS was purchased from Gibco, catalog number 10091148; PBS was purchased from Gibco, catalog number 10010023;

[1504] Pancreatin was purchased from Gibco, catalog number 25200056;

[1505] Cell culture plates were purchased from Corning, catalog number 3610.

[1506] 3. Experimental methods:

[1507] Adherent cells: When MDA-MB-231, MDA-MB-361, Mia PaCa-2, SW620, NCI-H1792, and BT474 cells were cultured to appropriate confluence, harvested, grown to an appropriate cell density with complete medium, plated into 96-well plates at 90 μL per well, and allowed to adhere overnight in a 37°C, 5% CO2 incubator. Compound solutions of varying concentrations were prepared using DMSO and culture medium. Vehicle controls were set up and compound solutions were added to each well of the 96-well plate at 10 μL. The plates were incubated in a 37°C, 5% CO2 incubator for approximately 72 hours. Then, 50 μL of CellTiter-Glo solution was added to each well, the plates were vortexed to mix, incubated in the dark for 10 minutes, and read using a BioTek Synergy H1 microplate reader.

[1508] Suspension cells: When SU-DHL-6 and NCI-H716 cells are cultured to an appropriate confluency, harvest the cells, adjust the cells to an appropriate cell density using complete medium, and plate the cell suspension in a 96-well plate at 90 μL per well. Prepare compound solutions of varying concentrations using DMSO and culture medium. As a vehicle control, add 10 μL of the compound solution to each well of the 96-well plate. Continue incubating in a 37°C, 5% CO2 incubator for approximately 72 hours. Add 50 μL of CellTiter-Glo solution to each well, shake to mix thoroughly, incubate in the dark for 10 minutes, and read using a BioTek Synergy H1 microplate reader.

[1509] 4. Experimental data processing method:

[1510] The inhibition rate was calculated using the luminescence signal value, and the concentration and inhibition rate were fitted with a nonlinear regression curve using Graphpad Prism software to obtain the IC 50 value.

[1511] 5. Experimental results:

[1512] The experimental results are shown in Table 2. The IC values ​​of the example compounds for the inhibitory activity against MDA-MB-231, MDA-MB-361, Mia PaCa-2, SW620, NCI-H1792, BT474, SU-DHL-6 and NCI-H716 cells are shown in Table 2. 50 The values ​​showed biological activities ranging from about 0.1 nM to 500 nM.

[1513] In some embodiments, the IC values ​​of the compounds of the present invention 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 are as follows: 50 Less than about 100 nM, preferably less than about 50 nM for the compounds listed in the present invention, further preferably less than about 20 nM, more preferably less than about 10 nM, and most preferably less than 1 nM for the compounds listed in the present invention.

[1514] Table 2 IC of compounds against cell proliferation inhibition 50 value

[1515]

[1516]

[1517]

[1518]

[1519] Table 3 IC of compounds against cell proliferation inhibition 50 value

[1520]

[1521]

[1522] “NA” stands for not tested.

[1523] 6. Experimental conclusions:

[1524] The compounds of the embodiments 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.

[1525] Test Example 3: In vivo pharmacodynamic study of NCI-H716 in a BALB / c nude mouse subcutaneous xenograft tumor model

[1526] 1. Experimental purpose:

[1527] The efficacy of the test compound in the human colon adenocarcinoma cell line NCI-H716 subcutaneous xenograft tumor model in BALB / c nude mice was evaluated.

[1528] 2. Experimental instruments and reagents:

[1529] 2.1 Instruments:

[1530] Clean bench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

[1531] CO2 incubator (Thermo-311, Thermo)

[1532] Centrifuge (Centrifuge 5720R, Eppendorf)

[1533] Constant temperature water bath (HSW-12, Shanghai Yiheng Scientific Instrument Co., Ltd. )

[1534] Electronic pipette assistant (Easypet 3, Eppendorf)

[1535] Automated cell counter (Countess II, Life Technologies)

[1536] Electronic balance (BSA2202S-CW, Sartorius)

[1537] Vernier caliper (CD-6″AX, Mitutoyo, Japan)

[1538] Cell culture flasks (T25 / T75 / T225, Corning)

[1539] 2.2 Reagents:

[1540] RPMI-1640 (22400-089, Gibco)

[1541] Fetal bovine serum (FBS) (10099-141C, Gibco)

[1542] 0.25% Trypsin-EDTA (25200-056, Gibco)

[1543] Phosphate buffered saline (PBS) (10010-023, Gibco)

[1544] Matrigel Matrix (356234, Corning)

[1545] 3. Experimental operation and data processing:

[1546] 3.1 Experimental operation:

[1547] NCI-H716 cells were taken from the cell bank, revived, added to complete culture medium (RPMI1640 + 10% FBS + 1% P / S), and cultured in a CO2 incubator (incubator temperature was 37°C, CO2 concentration was 5%). When the cell number expanded to the number required for in vivo inoculation, NCI-H716 cells were collected. Counted using an automatic cell counter, the cells were resuspended in a mixture of PBS and Matrigel (1:1) according to the counting results to prepare a cell suspension (density 5×10 7 / mL) and placed in an ice box for use.

[1548] Female BALB / c nude mice aged 6-8 weeks (18-20 g, Shanghai Institute of Family Planning Science, Experimental Animal Management Department) were used. The mice were housed in an SPF-grade animal room, in single cages, with 5 mice per cage. All cages, bedding, and water were sterilized with high temperature before use, and all animals were free to eat and drink. Before the experiment began, the nude mice were marked with disposable ear tags for large and small mice. Before inoculation, the skin at the inoculation site was disinfected with 75% medical alcohol. Each mouse was inoculated subcutaneously on the right back with 0.1 mL (containing 5*10 6 When the tumor volume reaches 60-200mm 3 Dosing began at 4:00 AM, with 5 mice per group. Each test compound was administered via the tail vein twice weekly for a total of 5 doses (D0, D4, D7, D11, and D14). Tumor volume and mouse body weight were measured twice weekly, and tumor TGI (%) was calculated.

[1549] 3.2 Data Processing:

[1550] Tumor volume (mm 3 ), and the calculation formula is: V = 0.5*D*d*d, where D and d are the long and short diameters of the tumor, respectively.

[1551] Calculation of TGI (%):

[1552] When the tumor did not regress, TGI (%) = [(1-(average tumor volume of a treatment group at the end of drug administration - average tumor volume of the treatment group at the beginning of drug administration)) / (average tumor volume of the solvent control group at the end of treatment - average tumor volume of the solvent control group at the beginning of treatment)] × 100%;

[1553] When the tumor regressed, TGI (%) = [1-(average tumor volume of a treatment group at the end of drug administration-average tumor volume of the treatment group at the beginning of drug administration) / average tumor volume of the treatment group at the beginning of drug administration] × 100%.

[1554] 4. Experimental results:

[1555] Table 4 Pharmacodynamic parameters

[1556]

[1557] 5 Experimental Conclusions:

[1558] The above data show that the compound of Example 83 of the present invention (1.5 mpk, BIW, IV) exhibited significant tumor inhibition 18 days after administration.

[1559] Test Example 4: Pharmacokinetic Evaluation Test in Mice

[1560] 1. Experimental purpose:

[1561] The PKPD behavior of the compounds after a single tail vein administration in mice (tumor) was studied.

[1562] 2. Experimental Plan

[1563] 2.1 Experimental Animals

[1564] Species: Mouse

[1565] Strain: BALB / c nude mice

[1566] Age and weight: 8-10 weeks old, weight 17-20 grams

[1567] Gender: Female

[1568] Supplier: Shanghai Xipu-Bikai Laboratory Animal Co., Ltd.

[1569] 2.2 Drug preparation:

[1570] Weigh 1 mg of the test compound and add 0.098 mL of DMA to fully dissolve the drug. Take 0.045 mL of the solution and add 2.55 mL of the solvent. Vortex to obtain a 1.5 mg / mL solution.

[1571] 2.3 Dosage regimen:

[1572] 2.3.1. After tumor inoculation, wait until the tumor volume is 300-500mm 3 PDPK experiments were started.

[1573] 2.3.2. Tumor-bearing mice were fasted overnight but not water-deprived, and euthanized at a specific time point 24 hours after drug administration.

[1574] 2.4 Sample collection:

[1575] After euthanasia, blood was collected from the heart and placed into a centrifuge tube containing EDTA-2K. The tube was manually inverted several times and then placed on ice for 5 minutes at 8000 rpm at 4°C. 100 μL of the centrifuged plasma was transferred to a new, labeled centrifuge tube, quickly frozen on dry ice, and stored at -80°C for PK analysis.

[1576] After blood collection, remove the tumor tissue and divide it into two portions (~0.1 g each). Place the portion into labeled 2 mL centrifuge tubes and store in a -80°C freezer. One portion will be used for PK testing (must be weighed); the other portion will be used for PD testing.

[1577] 2.5 Liquid phase analysis

[1578] Liquid phase conditions: Shimadzu LC-20AD pump

[1579] Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[1580] Chromatographic column: C18 (50*4.6mm, 5μm particle size)

[1581] Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is methanol

[1582] Flow rate: 1.0 mL / min

[1583] Elution time: 0-4.0 minutes, eluent is as follows:

[1584]

[1585] 2.6 Test results and analysis

[1586] The main pharmacokinetic parameters were calculated using WinNonlin 8.2.

[1587] Table 5 Pharmacokinetic parameters of the compounds of the present invention administered via tail vein in mice

[1588]

[1589] 3. Experimental conclusions:

[1590] The data in the table show that in the mouse pharmacokinetic evaluation experiment, the example compounds of the present invention showed higher exposure after tail vein administration and had more advantageous distribution in the tumor.

Claims

1. A compound represented by general formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof: in: R2' is independently selected from hydrogen; R3 is selected from -(CH2) n1 NR a R b ; R7 is selected from C 1-6 Alkoxy or C 1-6 Haloalkoxy; R8 is selected from C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-6 The cycloalkyl and 3-8 membered heterocyclic groups are optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 is substituted by one or more substituents in a haloalkoxy group; R a and R b Each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The halogenated alkoxy group, the C 1-6 The alkyl group is optionally further substituted with C 1-6 is substituted by an alkoxy group; n1 is 1.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R a Independently selected from C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy, the C 1-3 The alkyl group is optionally further substituted with C 1-3 Alkoxy substituted, R b Independently selected from C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R8 is selected from cyclopropyl, oxetanyl, azetidine or pyrrolidinyl, and the cyclopropyl, oxetanyl and azetidine are optionally further substituted with one or more substituents selected from cyano, hydroxyl, amino, fluorine, chlorine, bromine, oxo, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, hydroxymethyl or hydroxyisopropyl.

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R a Independently selected from methyl, ethyl, methoxy, wherein the methyl, ethyl is optionally further substituted by one or more substituents selected from hydroxy, methyl, ethyl, methoxy, difluoromethyl or trifluoromethyl; R b Independently selected from methyl, ethyl or methoxy.

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R7 is selected from methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

6. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R8 is selected from 7. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R a or R b Each independently selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl; R7 is selected from methoxy; R8 is selected from C 3-6 Cycloalkyl.

8. The compound according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R a or R b are each independently selected from methyl.

9. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (VI): R6 is independently selected from methoxy; R7 is independently selected from C 1-3 Alkoxy or C 1-3 Haloalkoxy, R8 is selected from C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-6 The cycloalkyl and 3-8 membered heterocyclic groups are optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, oxo, C 1-6 Alkyl, 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 or C 1-6 is substituted by one or more substituents in a haloalkoxy group, R a and R b Each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The halogenated alkoxy group, the C 1-6 The alkyl group is optionally further substituted with C 1-6 Alkoxy substituted; Or, R a and R b Together with the adjacent nitrogen atom, it forms a 4-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen or oxygen atoms, which is optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 is substituted by one or more substituents in a haloalkoxy group; R4 is a hydroxyl group.

10. The compound according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R7 is independently selected from methoxy, ethoxy, monofluoromethoxy, difluoromethoxy or trifluoromethoxy; R8 is selected from C 3-6 Cycloalkyl or 4-6 membered heterocyclic group containing 1 nitrogen or oxygen atom; optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, azido, nitro, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 C substituted with haloalkyl or cyano 1-3 The alkyl group is substituted with one or more substituents.

11. The compound according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R a or R b Each independently selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R6 and R7 are each independently selected from methoxy; R8 is selected from C 3-6 Cycloalkyl.

12. The compound according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R8 is selected from 13. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The specific structure of the compound is as follows:

14. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The specific structure of the compound is as follows:

15. A compound represented by the general formula (M), its stereoisomer or a pharmaceutically acceptable salt thereof: R3 is selected from -C(O)R g ; R g Selected from hydroxyl, C 1-3 Alkoxy or -NR a R b ; R4 is selected from hydroxyl; R6 is selected from methoxy; R7 is selected from C 1-3 Alkoxy or C 1-3 Haloalkoxy; R8 is selected from C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-6 The cycloalkyl and 3-8 membered heterocyclic groups are optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, oxo, C 1-6 Alkyl, 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 or C 1-6 is substituted by one or more substituents in a haloalkoxy group; R a and R b Each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The halogenated alkoxy group, the C 1-6 The alkyl group is optionally further substituted with C 1-6 Alkoxy substituted; Or, R a and R b Together with the adjacent nitrogen atom, it forms a 4-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen or oxygen atoms, which is optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is substituted with one or more substituents.

16. A method for preparing the compound represented by the general formula (VI) according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The following steps are involved: The general formula (M-1) is reacted to obtain the general formula (M-2), the general formula (M-2) is reacted to obtain the general formula (M-3), and the general formula (M-3) is reduced to obtain the general formula (VI); Pg is selected from C 1-3 Alkoxy; R4 is selected from hydroxyl; R6 is selected from methoxy; R7 is selected from C 1-3 Alkoxy or C 1-3 Haloalkoxy; R8 is selected from C 3-6 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-6 The cycloalkyl and 3-8 membered heterocyclic groups are optionally further substituted with deuterium, halogen, amino, hydroxy, cyano, azido, nitro, oxo, C 1-6 Alkyl, 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 or C 1-6 is substituted by one or more substituents in a haloalkoxy group; R a and R b Each independently selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 The halogenated alkoxy group, the C 1-6 The alkyl group is optionally further substituted with C 1-6 Alkoxy substituted; Or, R a and R b Together with the adjacent nitrogen atom, it forms a 4-10 membered heterocyclic group containing 1-3 atoms selected from nitrogen or oxygen atoms, which is optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, azido, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 The haloalkoxy group is substituted with one or more substituents.

17. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 13, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

18. Use of the compound according to any one of claims 1 to 13, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 17 in the preparation of a drug for treating and / or preventing cancer; wherein: The cancer is selected from colorectal cancer, lung cancer, pancreatic cancer, breast cancer or lymphoma.

19. A pharmaceutical composition comprising a therapeutically effective dose of the compound of claim 14, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

20. Use of the compound according to claim 14, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19 in the preparation of a drug for treating and / or preventing cancer; wherein: The cancer is selected from colorectal cancer or pancreatic cancer.

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