Nitrogen-containing heterocyclic compound, pharmaceutical composition thereof, and use thereof

Abstract

Disclosed in the present invention are a nitrogen-containing heterocyclic compound, a pharmaceutical composition thereof, and use thereof. Specifically, disclosed in the present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of the pharmaceutically acceptable salt thereof, or a stereoisomer thereof. The nitrogen-containing heterocyclic compound of the present invention has a relatively strong inhibitory effect on OGA and has very good application prospects in preventing and / or treating various diseases associated with OGA.

Description

Nitrogen-containing heterocyclic compounds, their pharmaceutical compositions and applications

[0001] This application claims priority to Chinese patent application 2024107014579, filed on May 31, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to nitrogen-containing heterocyclic compounds, their pharmaceutical compositions, and their applications. Background Technology

[0003] Many proteins in cells, including those in the nucleus and cytoplasm, can undergo post-translational modification by adding the monosaccharide 2-acetamino-2-deoxy-β-D-glucosinolate (N-acetylglucosamine). This modification is called O-linked N-acetylglucosamine (O-GlcNAc). The enzyme responsible for this modification is O-GlcNAc transferase (OGTase), while another enzyme, O-GlcNAcase (OGA), can remove this modification, allowing the protein to perform its function.

[0004] O-GlcNAc-modified proteins regulate a variety of cellular functions, including transcription, protein degradation, and cell signaling. O-GlcNAc is also present on the cytoskeletal protein "tau," which is important for stabilizing the intracellular microtubule network.

[0005] In the brains of Alzheimer's disease (AD) patients, tau protein is hyperphosphorylated, leading to impaired normal function and the formation of abnormal neurofibrillary tangles (NFTs). Research has found that hyperphosphorylation within neurons is associated with O-GlcNAc modification; increased phosphorylation levels lead to decreased O-GlcNAc levels, and vice versa. This may be due to impaired glucose transport and metabolism, causing tau protein hyperphosphorylation. Inhibiting O-GlcNAc enzymes could prevent tau hyperphosphorylation, thereby compensating for the decline in brain glucose metabolism, potentially becoming a therapeutic target for AD and other neurodegenerative diseases. Summary of the Invention

[0006] The technical problem to be solved by this invention is to overcome the deficiency of the limited variety of O-GlcNAcase (OGA) inhibitors in the prior art, and to provide a class of nitrogen-containing heterocyclic compounds, their pharmaceutical compositions, and applications. These compounds have a strong inhibitory effect on OGA and show great promise for the prevention and / or treatment of various OGA-related diseases.

[0007] This invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0008] L 1 For connecting bonds, C1-C6 alkylene groups, -O-, #1 -CR x R y -O- or #1 -O-CR x R y -, #1 The end is connected to ring A;

[0009] Each R x and R y Independently hydrogen or C1-C6 alkyl;

[0010] Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R atoms. a The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-12 membered bicyclic heterocyclic alkyl group with one, two, or three heteroatoms; and the ring B is connected to L via a carbon atom. 1 Connected;

[0011] Each R a Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" or a C1-C6 alkyl substituted with one or more halogens;

[0012] L 2 For methylene or linking bonds; each R 1 Independently hydrogen, halogen, -CN, -OH, phenyl, C1-C6 alkyl, C1-C6 alkoxy, -NR 1-3 R 1-4 -C(=O)NR 1-3 R 1-4 , by one or more R 1-1 Substituted C1-C6 alkyl groups or those with one or more R 1-2 Substituted C1-C6 alkoxy groups; n is 0, 1, 2, or 3;

[0013] Or, two adjacent R 1 The atoms connected to them together form a group consisting of one or more R atoms. m The substituted C3-C7 cycloalkenyl group or the group with one or more R m The substituted heteroatom is "a 3-7 membered heterocyclic alkenyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms";

[0014] Each R mIndependently hydrogen, halogen, -CN, -OH, phenyl, C1-C6 alkyl, C1-C6 alkoxy, -NR 1-3 R 1-4 -C(=O)NR 1- 3 R 1-4 , by one or more R 1-1 Substituted C1-C6 alkyl groups or those with one or more R 1-2 Substituted C1-C6 alkoxy groups;

[0015] R 1-1 and R 1-2 Each is an independent halogen;

[0016] R 1-3 and R 1-4 Each independently of hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogens;

[0017] R 1-1-1 It is a C1-C6 alkyl group;

[0018] Ring A is a 5-10 membered heteroaromatic ring with one, two, or three heteroatoms selected from N, O, and S, and having one, two, or three heteroatoms.

[0019] The ring C is "a 5-membered heteroaromatic ring with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three";

[0020] m can be 0, 1, 2, or 3;

[0021] R 2 Independent of halogen, -NR 2-1 R 2-2 C1-C6 alkyl groups or those with one or more R 2-3 Substituted C1-C6 alkyl groups;

[0022] R 2-1 and R 2-2 Each independently is hydrogen, C1-C 10 alkyl, Or C3-C7 cycloalkyl;

[0023] R 2-4 For C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 alkenyl or -NR 2-4-1 R 2-4-2 ;

[0024] R 2-4-1 and R 2-4-2Each is independently hydrogen or C1-C 10 alkyl;

[0025] R 2-5 For C1-C 10 alkyl;

[0026] R 2-3 for

[0027] In one aspect of the present invention, The definition is Case 1:

[0028] L 1 For -O-, #1 -CR x R y -O- or #1 -O-CR x R y -, #1 The end is connected to ring A;

[0029] Each R x and R y Independently hydrogen or C1-C6 alkyl;

[0030] Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R atoms. a The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-12 membered bicyclic heterocyclic alkyl group with one, two, or three heteroatoms; and the ring B is connected to L via a carbon atom. 1 Connected;

[0031] Each R a Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" or a C1-C6 alkyl substituted with one or more halogens;

[0032] L 2 It is a methylene group or a linker bond.

[0033] In one aspect of the present invention, The definition is case 2:

[0034] L 1 It is a linking bond or a C1-C6 alkylene group;

[0035] Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R atoms.a The substituted heteroatom is "a 5-12 membered bicyclic heterocyclic alkyl group selected from N, O, and S, with one, two, or three heteroatoms"; and the ring B is connected to L via a carbon atom. 1 Connected;

[0036] R a For R r ;

[0037] Each R r Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl or a C1-C6 alkyl substituted with one or more halogens, with one, two or three heteroatoms selected from N, O and S";

[0038] L 2 For -CH2- or a connecting key.

[0039] In one aspect of the present invention, in case 2, L 1 It is a C1-C6 alkylene group.

[0040] In one aspect of the present invention, in cases 1 and 2, ring B is connected to L via nitrogen atoms. 2 Connected.

[0041] This invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0042] Each R 1 Independently hydrogen, halogen, -CN, -OH, phenyl, C1-C6 alkyl, C1-C6 alkoxy, -NR 1-3 R 1-4 -C(=O)NR 1- 3 R 1-4 , by one or more R 1-1 Substituted C1-C6 alkyl groups or those with one or more R 1-2 Substituted C1-C6 alkoxy groups; n is 0, 1, 2, or 3;

[0043] Or, two adjacent R 1 The atoms connected to them together form a group consisting of one or more R atoms. m The substituted C3-C7 cycloalkenyl group or the group with one or more R m The substituted heteroatom is "a 3-7 membered heterocyclic alkenyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms";

[0044] Each Rm Independently hydrogen, halogen, -CN, -OH, phenyl, C1-C6 alkyl, C1-C6 alkoxy, -NR 1-3 R 1-4 -C(=O)NR 1- 3 R 1-4 , by one or more R 1-1 Substituted C1-C6 alkyl groups or those with one or more R 1-2 Substituted C1-C6 alkoxy groups;

[0045] R 1-1 and R 1-2 Each is an independent halogen;

[0046] R 1-3 and R 1-4 Each independently of hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogens;

[0047] R 1-1-1 It is a C1-C6 alkyl group;

[0048] Ring A is "a 5-10 membered heteroaromatic ring with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three" or C6-C. 10 Aromatic rings;

[0049] The ring C is "a 5-membered heteroaromatic ring with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three";

[0050] m can be 0, 1, 2, or 3;

[0051] R 2 Independent of halogen, -NR 2-1 R 2-2 C1-C6 alkyl groups or those with one or more R 2-3 Substituted C1-C6 alkyl groups;

[0052] R 2-1 and R 2-2 Each independently is hydrogen, C1-C 10 alkyl, Or C3-C7 cycloalkyl;

[0053] R 2-4 For C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 alkenyl or -NR 2-4-1 R 2-4-2 ;

[0054] R2-4-1 and R 2-4-2 Each is independently hydrogen or C1-C 10 alkyl;

[0055] R 2-5 For C1-C 10 alkyl;

[0056] R 2-3 for

[0057] The definition is any of the following cases:

[0058] Scenario 1:

[0059] L 1 For -O-, #1 -CR x R y -O- or #1 -O-CR x R y -, #1 The end is connected to ring A;

[0060] Each R x and R y Independently hydrogen or C1-C6 alkyl;

[0061] Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R atoms. a The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-12 membered bicyclic heterocyclic alkyl group with one, two, or three heteroatoms.

[0062] Each R a Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" or a C1-C6 alkyl substituted with one or more halogens;

[0063] L 2 Methylene or linking bond;

[0064] Scenario 2:

[0065] L 1 For connection key;

[0066] Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R atoms. rThe substituted heteroatom is a 5-12 membered bicyclic heterocyclic alkyl group selected from N, O, and S, with one, two, or three heteroatoms; simultaneously, ring B is not... z and q are independently 0 or 1, and not both 0 at the same time;

[0067] Each R r Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl or a C1-C6 alkyl substituted with one or more halogens, with one, two or three heteroatoms selected from N, O and S";

[0068] L 2 For -CH2- or a connecting key.

[0069] In certain preferred embodiments of the present invention, certain groups in the compound represented by Formula I, its pharmaceutically acceptable salt, or a solvate of any of the foregoing are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0070] In one embodiment of the invention, each “C1-C6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; for example, methyl.

[0071] In one embodiment of the invention, each “C1-C6 alkoxy” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; for example, methoxy.

[0072] In one embodiment of the present invention, the "5-10 membered heteroaromatic ring" is a "5-6 membered heteroaromatic ring" with heteroatoms selected from one or two types of N and O, and the number of heteroatoms is two or three; for example... For example,

[0073] In one embodiment of the present invention, the "5-membered heteroaromatic ring" is a "5-6-membered heteroaromatic ring" with two heteroatoms selected from one or two types of N and S; for example...

[0074] In one aspect of the invention, each "halogen" is independently fluorine, chlorine, bromine, or iodine; for example, fluorine.

[0075] In one embodiment of the present invention, each "C1-C" 10 "Alkyl" is independently a C1-C6 alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; and for another example, methyl.

[0076] In one embodiment of the present invention, in case 1, each "5-12 membered bicyclic heterocyclic alkyl group" is independently a 6-10 membered bicyclic heterocyclic alkyl group with N heteroatom and one heteroatom; for example... For example,

[0077] In one aspect of the present invention, in case 2, each "5-12 membered bicyclic heterocyclic alkyl group" is independently an 8-10 membered bicyclic heterocyclic alkyl group with N and O heteroatoms and two heteroatoms; for example... For example,

[0078] In one aspect of the present invention, the R 1 It is independently C1-C6 alkyl or C1-C6 alkoxy.

[0079] In one embodiment of this invention, n is 1.

[0080] In one embodiment of the present invention, ring A is "a 5-10 membered heteroaromatic ring with one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms being one, two or three".

[0081] In one embodiment of the present invention, m is 2.

[0082] In one aspect of the present invention, the R 2 Independently halogen or -NR 2-1 R 2-2 .

[0083] In one aspect of the present invention, the R 2-1 and R 2-2 Each independently is hydrogen or

[0084] In one aspect of the present invention, the R 2-4 For C1-C 10 alkyl.

[0085] In one aspect of the present invention, in case 1, the L 1 for #1 -O-CR x R y -, #1 The end is connected to ring A.

[0086] In one aspect of the present invention, in case 1, each of the R... x and R yIt is hydrogen independently.

[0087] In one aspect of the present invention, in case 1, ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms".

[0088] In one aspect of the present invention, in case 1, each of the R... a It is independently a C1-C6 alkyl group.

[0089] In one aspect of the present invention, in case 1, the L 2 It is a methylene group.

[0090] In one aspect of the present invention, in case 2, the ring B is surrounded by one or more R... r The substituted heteroatom is a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms; simultaneously, ring B is not... z and q are independently 0 or 1, and not both 0 at the same time.

[0091] In one aspect of the present invention, in case 2, ring B is a 5-12 membered bicyclic heterocyclic alkyl group with heteroatoms of "N and O" or "N, O and S" and the number of heteroatoms is 2, 3 or 4, or is surrounded by one or more R atoms. r The substituted heteroatoms are "N and O" or "N, O and S", and the number of heteroatoms is 2, 3 or 4, belonging to a 5-12 membered bicyclic heterocyclic alkyl group; preferably, it is replaced by one or more R r The substituted heteroatoms are "N and O" or "N, O and S", and the number of heteroatoms is 2, 3 or 4 in a 5-12 membered bicyclic heterocyclic alkyl group.

[0092] In one aspect of the present invention, in case 2, each of the R... r It is independently a C1-C6 alkyl group.

[0093] In one aspect of the present invention, in case 2, each of the L... 2 It is -CH2-.

[0094] In one embodiment of the present invention, ring A is For example,

[0095] In one aspect of the present invention, the R 1 It is methyl or methoxy.

[0096] In one aspect of the present invention, the... In the definition, in case 1,

[0097] The L1 For -O-, #1 -CH2-O- or #1 -O-CH2-, #1 The end is connected to ring A;

[0098] The ring B is #2 End and L 1 Connected, #3 End and L 2 Connected, w can be 0, 1, 2, 3, or 4; for example

[0099] Preferably; the ring B is #2 End and L 1 Connected, #3 End and L 2 Connected, w can be 0, 1, 2, 3, or 4; for example,

[0100] The L 2 It is a methylene group or a linker bond.

[0101] In one aspect of the present invention, the... In the definition, in case 2,

[0102] The L 1 It is a linking bond or a C1-C6 alkyl group;

[0103] Preferably, the L 1 For connection key;

[0104] The ring B is #4 End and L 1 Connected, #5 End and L 2 Connected, v can be 0, 1, 2, 3, or 4; for example,

[0105] Preferably, the ring B is #4 End and L 1 Connected, #5 End and L 2 Connected, v can be 0, 1, 2, 3, or 4; for example,

[0106] The L 2 It is -CH2-.

[0107] In one embodiment of the present invention, the ring C is

[0108] In one aspect of the present invention, the R 2 Fluorine or

[0109] In one aspect of the present invention, the compound represented by Formula I is a compound represented by Formula I-1, Formula I-2, or Formula I-3:

[0110] in,

[0111] The carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof;

[0112] R 1 R 2 Ring A, Ring C, m, n and R a The definition is as described in any embodiment of this invention;

[0113] n1 is 0, 1, 2, 3 or 4;

[0114] L 1 For -O-, #1 -CR x R y -O- or #1 -O-CR x R y -, #1 The end is connected to ring A; each R x and R y Independently hydrogen or C1-C6 alkyl;

[0115] In the compounds shown in Formula I-1

[0116] R 3 R 4 R 5 R 6 R 7 R 8 and R 9 The definition is any of the following schemes:

[0117] Option 1, R 3 R 4 R 5 R 6 and R 9 It is hydrogen; R 7 and R8 The atoms bonded to them together form a 3-6 member nitrogen-containing saturated heterocycle. In the nitrogen-containing saturated heterocycle, in addition to nitrogen, the heteroatom can also be selected from one or two of O and S. The number of heteroatoms is 1, 2 or 3.

[0118] Option 2, R 5 R 7 R 8 and R 4 It is hydrogen; R 6 It is a C1-C6 alkyl group; R 3 and R 9 The atoms bonded to them together form 3-6 member oxygen-containing saturated heterocycles. In the oxygen-containing saturated heterocycles, in addition to oxygen, the heteroatoms can also be selected from one or two of N and S. The number of heteroatoms is 1, 2 or 3.

[0119] Option 3, R 4 R 7 R 8 and R 9 It is hydrogen; R 6 It is a C1-C6 alkyl group; R 3 and R 5 The atoms bonded to them together form 3-6 member oxygen-containing saturated heterocycles. In the oxygen-containing saturated heterocycles, in addition to oxygen, the heteroatoms can also be selected from one or two of N and S. The number of heteroatoms is 1, 2 or 3.

[0120] Option 4, R 3 R 4 R 6 R 8 and R 9 It is hydrogen; R 5 and R 7 The atoms connected to them together form C3-C6 saturated carbon rings;

[0121] Option 5, R 3 R 4 R 5 R 8 and R 9 It is hydrogen; R 6 and R 7 The atoms connected to them together form C3-C6 saturated carbon rings;

[0122] Option 6, R 3 R 5 R 6 R 8 and R 9 It is hydrogen; R 4 and R 7 Together they form C1-C4 alkylene groups; in compounds as shown in Formula I-2, R10 R 11 and R 12 The definition is any of the following schemes:

[0123] Option 1, R 12 For hydrogen, R 10 and R 11 The atoms connected to them together form C3-C6 saturated carbon rings;

[0124] Option 2: R 10 For hydrogen, R 11 and R 12 The atoms connected to them together form C3-C6 saturated carbon rings;

[0125] In the compound shown in Formula I-3, ring D is a C3-C6 saturated carbon ring, and ring D is related to L. 1 The connected carbon atoms are in the R configuration, S configuration, or a mixture thereof.

[0126] In one aspect of the present invention, the compound represented by Formula I is a compound represented by Formulas I-4:

[0127] in,

[0128] The carbon atoms marked with "*" have the configuration of R, S, or a mixture thereof;

[0129] R 1 R 2 The definitions of ring A, ring C, m, and n are as described in any embodiment of the present invention;

[0130] In the compounds shown in Formula I-4

[0131] R 13 It is a C1-C6 alkyl group;

[0132] R 14 and R 15 The atoms bonded to them together form a 3-6 member oxygen-containing saturated heterocycle. In the oxygen-containing saturated heterocycle, in addition to oxygen, the heteroatom can also be selected from one or both of N and S. The number of heteroatoms is 1, 2 or 3.

[0133] This invention provides a compound as shown below:

[0134] or,

[0135] (where carbon atoms marked with "*" indicate chiral carbon atoms) Among a pair of enantiomers, the compound that elutes first under the following conditions: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); gradient: 15%-15%; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the first eluting compound is 2.7-3.8min; preferably, the "pair of enantiomers" refers to the pair of enantiomers that elute first under the following achiral conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v). Among a pair of enantiomers, the compound that elutes later under the following conditions: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min; Preferably, under the conditions described, the retention time of the later-eluting compound is 4.4-6.2min; Preferably, the "pair of enantiomers" refers to a pair of enantiomers that elute first under the following achiral conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v);

[0136] The compound that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 2.7-3.8min.

[0137] Compounds that elute later under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); gradient: 15%-15%; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the later-eluting compounds is 4.4-6.2min.

[0138] The compound that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 25%-25%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 5.1-6.0min.

[0139] Compounds that elute later under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 25%-25%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 6.5-8.3min.

[0140] The first eluting compound under the following conditions: column: Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol / L ammonium bicarbonate aqueous solution, flow rate: 20mL / min, gradient: 28-40%; preferably, under the conditions described, the retention time of the first eluting compound is 8.1-8.7min;

[0141] Compounds eluting later under the following conditions: chromatographic column: Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol / L ammonium bicarbonate aqueous solution, flow rate: 20mL / min, gradient: 28-40%; preferably, under the conditions described, the retention time of compounds eluting later is 9.4-10.01min;

[0142] The compound that elutes first under the following conditions: chromatographic column: Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-0.05% ammonia aqueous solution, flow rate: 20mL / min, gradient: 33-43%; preferably, under the conditions described, the retention time of the compound that elutes first is 7.2-7.7min;

[0143] Compounds that elute later under the following conditions: Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-0.05% ammonia aqueous solution, flow rate: 20mL / min, gradient: 33-43%; preferably, under the conditions described, the retention time of compounds that elute later is 9.6-10.3min.

[0144] The compound that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 120mL / min; Preferably, under the conditions described, the retention time of the first eluting compound is 3.8-5.7min;

[0145] Compounds that elute later under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 120mL / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 6.8-9.7min.

[0146] The compound that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 3.2-5.1min;

[0147] Compounds that elute later under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 6.3-9.4min.

[0148] The compound that elutes first under the following conditions: Column: Waters SFC 80, 250*25mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 80ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 8.5-11.5min.

[0149] Compounds that elute later under the following conditions: Column: Waters SFC 80, 250*25mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 80ml / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 12.0-17.3min.

[0150] The compound that elutes first under the following conditions: Column: Waters SFC 80, 250*25mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 3.2-5.1min.

[0151] Compounds that elute later under the following conditions: Waters SFC 80, 250*25mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 6.3-9.4min. The substance that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-85%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 13.0-14.2min. Substances that elute later under the following conditions: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-85%; Flow rate: 140ml / min. Preferably, under the conditions described, the retention time of the later-eluting compounds is 15.9-20.0min.

[0152] The above retention time test conditions are not a limitation on the compound. As long as the above test conditions are used to determine the retention time, and the obtained retention time is the same as or within the error range described above, and the compound is a stereoisomer of the compound limited by the retention time described above, then it falls within the protection scope of this invention.

[0153] The present invention also provides a pharmaceutical composition comprising:

[0154] (1) The compounds shown in Formula I above, their pharmaceutically acceptable salts, their solvates, solvates of their pharmaceutically acceptable salts, or their stereoisomers; and

[0155] (2) Pharmaceutically acceptable excipients.

[0156] The present invention also provides the use of the compounds shown in Formula I, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or stereoisomers thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of Alzheimer's disease.

[0157] The present invention also provides uses of the compounds represented by Formula I, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, or stereoisomers thereof, or the pharmaceutical compositions thereof, wherein the uses are selected from:

[0158] (1) Preparation of O-acetylglucosidase (O-GlcNAcase, or OGA) inhibitors;

[0159] (2) Prepare drugs for the treatment and / or prevention of diseases associated with O-acetylglucosidase; the diseases associated with O-acetylglucosidase may be Alzheimer's disease.

[0160] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0161] The term "multiple" can refer to 2, 3, or 4.

[0162] The term "alkyl" refers to an alkyl group having a specified number of carbon atoms (e.g., C1-C1). 10Alkyl groups (or C1-C6) that are straight-chain or branched. Alkyl groups include, but are not limited to, methyl, ethyl, etc.

[0163] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group that contains one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds).

[0164] The term "alkoxy" refers to the group R. H -O-, where R H It is an alkyl group as defined above.

[0165] The term "cycloalkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C7) and having one or more (e.g., 1, 2, or 3) carbon-carbon sp groups. 2 It has a double bond, is a single ring, and is not aromatic.

[0166] The term "heterocyclic alkenyl" refers to a cyclic, unsaturated monovalent hydrocarbon group having a specified number of ring atoms (e.g., 3-7), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom type (one or more of N, O, and S), having one or more (e.g., 1 or 2) carbon-carbon sp2 double bonds, and not being aromatic.

[0167] The term "heteroaromatic ring" refers to an aromatic group containing a heteroatom (e.g., a 5-10 membered heteroaromatic ring or a 5-membered heteroaromatic ring), preferably containing one, two, or three independent 5-10 membered aromatic monocyclic or polycyclic rings selected independently from nitrogen, oxygen, and sulfur, and each ring being aromatic. Heteroaromatic rings include, but are not limited to, furan rings, pyridine rings, pyrimidine rings, pyrazine rings, thiophene rings, isoxazole rings, oxazole rings, diazole rings, imidazole rings, pyrrole rings, pyrazole rings, triazole rings, tetraazole rings, thiazole rings, oxadiazole rings, isothiazole rings, thiadiazole rings, etc.

[0168] The term "aromatic ring" refers to a ring with a specified number of carbon atoms (e.g., C6-C). 10 Aromatic rings, whose ring atoms consist only of carbon atoms, are either fused or monocyclic. Examples include benzene rings or naphthalene rings.

[0169] The term "cycloalkyl" refers to a saturated cyclic group having a specified number of carbon atoms in the ring (e.g., C3-C6 or C3-C7) and whose ring atoms consist only of carbon atoms.

[0170] The term "heterocyclic alkyl" refers to a saturated cyclic group having a specified number of ring atoms (e.g., 3-6), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatom (1, 2 or 3 of N, O and S).

[0171] The term "bicyclic heterocyclic alkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-12), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S), which is a fused ring, a bridged ring, or a spiro ring, and each ring is saturated. A fused ring is a polycyclic ring that shares two atoms between its monocyclic rings. A bridged ring is a polycyclic ring that shares two or more atoms between its monocyclic rings. A spiro ring is a polycyclic ring that shares one atom between its monocyclic rings.

[0172] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0173] The "-" at the end of a group indicates that the group is connected to other segments in the molecule through that site. For example, "-CH2-" refers to a methylene group.

[0174] In structural fragments This refers to the connection between this structural segment and other segments in the molecule through this site. For example, It refers to acetaminophen.

[0175] When a carbon atom satisfies the conditions for a chiral carbon atom, but its configuration (r or s) is not explicitly stated, it indicates that the atom is an equimolar mixture or a non-equimolar mixture of both. For example... In this case, the spirocarbon atom at the center of the spiroring is a chiral carbon atom, but its specific configuration is not specified. This indicates that the spirocarbon atom is an equimolar mixture or a non-equimolar mixture of R and S configurations.

[0176] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.

[0177] The term "pharmaceutical composition" refers to a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient and a pharmaceutically acceptable excipient, intended for administration to mammals, such as humans, in need of such treatment.

[0178] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement.

[0179] As described above, "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances prepared from compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids or bases, and formed in combination with stoichiometric or non-stoichiometric solvents.

[0180] The term "pharmaceuticalally acceptable excipient" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative excipients include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. Their formulations are well known to those skilled in the art of cosmetics or topical pharmaceuticals.

[0181] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0182] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0183] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0184] The reagents and raw materials used in this invention are all commercially available.

[0185] The positive and progressive effects of this invention are as follows: This invention provides a class of nitrogen-containing heterocyclic compounds, their pharmaceutical compositions, and applications. These compounds have a strong inhibitory effect on OGA and show great promise for the prevention and / or treatment of various diseases related to OGA. Attached Figure Description

[0186] Figure 1: Two-dimensional NMR spectrum of compound B-4.

[0187] Figure 2: Two-dimensional NMR spectrum of compound B-5. Detailed Implementation

[0188] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0189] Intermediate A

[0190] Synthesis route:

[0191] first step

[0192] Compound A-1 (6.80 g, 41.8 mmol) and pyridine (13.2 g, 167 mmol) were dissolved in dichloromethane (80 mL). Acetic anhydride (12.8 g, 125 mmol) was slowly added dropwise with stirring at 0 °C. The reaction mixture was stirred at 25 °C for 20 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to give compound A-2. 1 ¹H NMR (400MHz, DMSO-d6): δ 13.00 (s, 1H), 9.90 (s, 1H), 2.22 (s, 3H). ESI-MS theoretical calculation: [M+H] + =204.98, measured value 204.9.

[0193] Step 2

[0194] Compound A-2 (3.00 g, 14.7 mmol) and cesium fluoride (22.3 g, 147 mmol) were dissolved in dimethyl sulfoxide (50 mL) and stirred at 140 °C for 20 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and extracted with water (200 mL) and ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain the crude product. The crude product was purified by high-performance liquid chromatography (Waters-spherical-C18-35 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution (v / v), flow rate: 100 mL / min, gradient: 5-25%, retention time: 32-40 min) to obtain intermediate A. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 13.00 (s, ¹H), 9.87 (s, ¹H), 2.21 (s, ³H). ESI-MS theoretical calculation: [M+H] + =189.01, measured value 189.0.

[0195] Intermediate B

[0196] Synthesis route:

[0197] first step

[0198] Ethyl propargyl ester (16.1 g, 164 mmol) was dissolved in tetrahydrofuran (125 mL). Under a nitrogen atmosphere, a tetrahydrofuran solution of n-butyllithium (56.3 mL, 141 mmol, 2.5 mol / L) was added dropwise at -70 °C, and the mixture was stirred at -70 °C for 0.5 hours. A tetrahydrofuran solution of compound B-1 (10 g, 46.9 mmol) (125 mL) was slowly added, and the mixture was stirred at -70 °C for 1 hour. After the reaction was complete, a tetrahydrofuran solution of acetic acid (10.5 mL) (125 mL) was slowly added dropwise, and the mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was extracted with saturated sodium bicarbonate aqueous solution (300 mL) and ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 6 / 1, v / v) to obtain compound B-2. 1 ¹H NMR (400MHz, CDCl₃): δ 4.40–4.33 (m, 1H), 4.28–4.20 (m, 2H), 3.93–3.89 (m, 1H), 3.26–3.16 (m, 1H), 2.28 (s, 1H), 2.07–2.01 (m, 1H), 1.92–1.87 (m, 3H), 1.46 (s, 9H), 1.33–1.27 (m, 6H). ESI-MS theoretical calculation: [M+Na] + =334.17, measured value 333.9.

[0199] Step 2

[0200] Compound B-2 (14.0 g, 45.0 mmol) was dissolved in anhydrous ethanol (200 mL), followed by the addition of 5% wetted palladium / carbon (2.78 g). The mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with anhydrous ethanol (100 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was compound B-3. ESI-MS theoretical calculation: [M + Na] + =338.20, measured value 338.0.

[0201] Step 3

[0202] Compound B-3 (13.0 g, 41.2 mmol) was dissolved in toluene (200 mL) and stirred at 100 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water (300 mL) was added. Extraction was performed with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound B-4 (Rf = 0.5). Its two-dimensional NMR is shown in Figure 1; the absence of NOE signals at H11 and H6 confirms the correct chirality of B-4. 1 ¹H NMR (400MHz, CDCl₃): δ 4.48–4.40 (m, 1H), 4.06–3.95 (m, 1H), 3.22–2.97 (m, 1H), 2.67–2.53 (m, 2H), 2.29–2.09 (m, 1H), 2.05–1.98 (m, 1H), 1.85–1.72 (m, 3H), 1.64–1.58 (m, 1H), 1.46 (s, 9H), 1.31–1.19 (m, 3H). ESI-MS theoretical calculation: [M+Na] + =292.16, measured value 292.0. and compound B-5 (Rf = 0.4). Its two-dimensional NMR is shown in Figure 2; it shows NOE signals in H11 and H6, confirming the correct chirality of B-5. 1 ¹H NMR (400MHz, CDCl₃): δ 4.46–4.40 (m, 1H), 4.06–3.97 (m, 1H), 3.10–2.96 (m, 1H), 2.71–2.56 (m, 2H), 2.29–2.22 (m, 1H), 2.19–2.10 (m, 2H), 1.88–1.82 (m, 1H), 1.78–1.69 (m, 2H), 1.47 (s, 9H), 1.25–1.18 (m, 3H). ESI-MS theoretical calculation: [M+Na] + =292.16, measured value 292.0.

[0203] Step 4

[0204] Compound B-4 (10.2 g, 38.0 mmol) was dissolved in dichloromethane (120 mL). Under a nitrogen atmosphere, a solution of diisobutylaluminum hydride in n-hexane (37.6 mL, 37.6 mmol, 1.0 mol / L) was added dropwise at -30 °C. The mixture was stirred at -30 °C for 2 hours, then at 0 °C for 2 hours. Water (1.5 mL), 15% sodium hydroxide aqueous solution (1.5 mL), and water (3.0 mL) were added to the reaction mixture, and the mixture was stirred at 25 °C for 0.5 hours. Anhydrous magnesium sulfate (30.0 g) was added, and the mixture was filtered. The filter cake was washed with dichloromethane (100 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain compound B1. 1 ¹H NMR (400MHz, CDCl₃): δ 5.57–5.22 (m, 1H), 4.44–4.26 (m, 1H), 3.99–3.82 (m, 1H), 3.27–3.06 (m, 1H), 2.11–1.79 (m, 5H), 1.75–1.50 (m, 4H), 1.46 (s, 9H), 1.32–1.24 (m, 3H). ESI-MS theoretical calculation: [M+Na] + =294.18, measured value 294.0.

[0205] Step 5

[0206] Compound B-5 (5.00 g, 18.6 mmol) was dissolved in dichloromethane (50 mL). Under a nitrogen atmosphere, a solution of diisobutylaluminum hydride in n-hexane (20.4 mL, 20.4 mmol, 1.0 mol / L) was added dropwise at -30 °C. The mixture was stirred at -30 °C for 2 hours, then at 0 °C for 2 hours. Water (2.0 mL), 15% sodium hydroxide aqueous solution (2.0 mL), and water (4.0 mL) were added to the reaction mixture, and the mixture was stirred at 25 °C for 0.5 hours. Anhydrous magnesium sulfate (20.0 g) was added, and the mixture was filtered. The filter cake was washed with dichloromethane (50 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to give compound B2. 1 ¹H NMR (400MHz, CDCl₃): δ 5.55–5.35 (m, 1H), 4.52–4.30 (m, 1H), 4.06–3.87 (m, 1H), 2.98–2.82 (m, 1H), 2.18–1.89 (m, 5H), 1.90–1.60 (m, 4H), 1.54–1.48 (m, 1H), 1.46 (s, 9H), 1.22–1.10 (m, 3H). ESI-MS theoretical calculation: [M+Na] + =294.18, measured value 294.0.

[0207] Example 1

[0208] Synthesis route:

[0209] first step

[0210] Under nitrogen protection, compound 1-1 (4.50 g, 26.5 mmol) was dissolved in dichloromethane (50 mL) and anhydrous ethanol (10 mL). Trimethylbromosilane (12.2 g, 79.4 mmol) was slowly added with stirring at 0 °C. The reaction mixture was stirred at 25 °C for 20 hours. Saturated sodium bicarbonate aqueous solution (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 9 / 1, v / v) to give compound 1-2. 1 H NMR (400MHz, CDCl3): δ4.31-4.13(m,4H), 3.46-4.34(m,2H), 2.47-2.39(m,1H), 1.58-1.54(m,2H), 1.35-1.24(m,6H).

[0211] Step 2

[0212] Compounds 1-2 (5.80 g, 20.8 mmol) were dissolved in N,N-dimethylformamide (100 mL), and 15-crown ether-5 (36.6 g, 166 mmol) and sodium azide (10.8 g, 166 mmol) were added slowly in sequence. The reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was cooled to room temperature, and extracted with water (200 mL) and ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to give compounds 1-3. 1 ¹H NMR (400MHz, CDCl₃): δ 4.37–4.12 (m, 4H), 3.39–3.27 (m, 2H), 2.22–2.14 (m, 1H), 1.52–1.46 (m, 2H), 1.33–1.23 (m, 6H). ESI-MS theoretical calculation: [M+H] + =242.11, measured value 241.9.

[0213] Step 3

[0214] Compounds 1-3 (3.30 g, 13.7 mmol) were dissolved in tetrahydrofuran (40 mL) and water (5 mL), and triphenylphosphine (7.18 g, 27.4 mmol) was added. The reaction mixture was stirred at 25 °C for 3 hours, and then heated to 60 °C and stirred for 36 hours. The reaction mixture was cooled to room temperature, and extracted with water (60 mL) and ethyl acetate (60 mL x 3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compounds 1-4. 1 ¹H NMR (400MHz, CDCl₃): δ 6.16 (s, 1H), 4.31–4.20 (m, 2H), 3.58–3.54 (m, 1H), 3.32–3.28 (m, 1H), 2.47–2.43 (m, 1H), 1.96–1.92 (m, 1H), 1.29 (t, J = 7.2Hz, 3H), 1.20–1.18 (m, 1H). ESI-MS theoretical calculation: [M+H] + =170.07, measured value 170.0.

[0215] Step 4

[0216] Compounds 1-4 (1.68 g, 9.93 mmol) were dissolved in dichloromethane (50 mL). Triethylamine (3.01 g, 29.8 mmol), di-tert-butyl dicarbonate (4.33 g, 19.9 mmol), and 4-dimethylaminopyridine (120 mg, 0.993 mmol) were added. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, water (60 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compounds 1-5. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 4.12 (q, J = 7.2Hz, 2H), 3.78–3.74 (m, 1H), 3.59–3.56 (m, 1H), 2.46–2.43 (m, 1H), 1.81–1.76 (m, 1H), 1.43 (s, 9H), 1.42–1.39 (m, 1H), 1.19 (t, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M + H - 56] + =214.13, measured value 214.0.

[0217] Step 5

[0218] Compounds 1-5 (1.80 g, 6.68 mmol) were dissolved in tetrahydrofuran (40 mL), and a borane dimethyl sulfide solution (5.01 mL, 50.1 mmol, 10.0 mol / L) was added at 25 °C. The reaction mixture was stirred at 55 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to 0 °C, and methanol (40 mL) was slowly added dropwise. The reaction mixture was concentrated under reduced pressure, and water (60 mL) was added to the residue. The residue was extracted with ethyl acetate (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compounds 1-6. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 4.64 (t, J = 5.6Hz, 1H), 3.47–3.40 (m, 3H), 3.38–3.32 (m, 1H), 3.31–3.23 (m, 2H), 1.37 (s, 9H), 1.36–1.33 (m, 1H), 0.75–0.69 (m, 1H), 0.26–0.21 (m, 1H). ESI-MS theoretical calculation: [M + H - 56] + =158.14, measured value 158.0.

[0219] Step 6

[0220] Compounds 1-6 (400 mg, 1.88 mmol) and 4-chloro-6-methoxypyrimidine (299 mg, 2.07 mmol) were dissolved in tetrahydrofuran (20 mL). Under a nitrogen atmosphere, a tetrahydrofuran solution of potassium bis(trimethylsilyl)amino (1.40 mL, 2.24 mmol, 1.60 mol / L) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 3 hours. After the reaction was complete, saturated ammonium chloride aqueous solution (10 mL) was added, followed by extraction with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compounds 1-7. 1 ¹H NMR (400MHz, CDCl₃): δ 8.40 (s, 1H), 6.06 (s, 1H), 4.40–4.35 (m, 2H), 3.95 (s, 3H), 3.72–3.50 (m, 2H), 3.42–3.37 (m, 2H), 1.53–1.48 (m, 1H), 1.43 (s, 9H), 0.91–0.87 (m, 1H), 0.61–0.56 (m, 1H). ESI-MS theoretical calculation: [M+H] + =322.17, measured value 322.3.

[0221] Step 7

[0222] Compounds 1-7 (380 mg, 1.18 mmol) were dissolved in dichloromethane (8 mL), and trifluoroacetic acid (6 mL, 80.5 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was added to water (10 mL). The pH was adjusted to 10 by adding 15% sodium hydroxide aqueous solution at 0 °C, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was compounds 1-8. ESI-MS theoretical calculation: [M+H] + =222.12, measured value 222.1.

[0223] Step 8

[0224] Compounds 1-8 (140 mg, 0.64 mmol) and glacial acetic acid (127 mg, 2.12 mmol) were dissolved in ethyl acetate (10 mL). Sodium triacetoxyborohydride (337 mg, 1.59 mmol) and intermediate A (100 mg, 0.53 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 40 °C for 2 hours, and then at 25 °C for 16 hours. After the reaction was complete, sodium bicarbonate aqueous solution (20 mL) and ethyl acetate (20 mL x 3) were added for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBndge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, flow rate: 20 mL / min, gradient: 38-48%, retention time: 9.5-10.2 min, run time: 17 min) to obtain compound 1. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 8.43 (d, J = 0.8Hz, 1H), 6.24 (d, J = 0.8Hz, 1H), 4.45 (d, J = 11.2Hz, 1H), 4.30 (d, J = 11.2Hz, 1H), 3.87 (s, 3H), 3.65–3.57 (m, 2H), 2.97–2.93 (m, 1H), 2.91–2.87 (m, 1H), 2.43–2.39 (m, 2H), 2.11 (s, 3H), 1.45–1.41 (m, 1H), 0.95–0.90 (m, 1H), 0.61–0.57 (m, 1H). ESI-MS theoretical calculation: [M+H] + =394.13, measured value 394.0.

[0225] Example 2

[0226] Synthesis route:

[0227] first step

[0228] Intermediate B1 (5.60 g, 20.6 mmol) was dissolved in dichloromethane (100 mL). Trimethylcyanosilane (3.07 g, 31.0 mmol) was slowly added dropwise at -70 °C under a nitrogen atmosphere, and the mixture was stirred at -70 °C for 0.2 h. Boron trifluoride diethyl ether (3.22 g, 22.7 mmol) was then slowly added dropwise, and the mixture was stirred at -70 °C for 0.5 h, followed by stirring at 0 °C for 1 h. Saturated sodium bicarbonate aqueous solution (100 mL) was slowly added dropwise to the reaction mixture, followed by di-tert-butyl dicarbonate (2.25 g, 10.3 mmol), and the mixture was stirred at 25 °C for 1 h. Extraction was performed with dichloromethane (100 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 6 / 1, v / v) to give compound 2-1. 1 ¹H NMR (400MHz, CDCl₃): δ 4.78–4.69 (m, 1H), 4.47–4.28 (m, 1H), 4.02–3.81 (m, 1H), 3.22–3.06 (m, 1H), 2.43–2.22 (m, 2H), 2.02–1.93 (m, 1H), 1.92–1.70 (m, 3H), 1.59–1.50 (m, 2H), 1.46 (s, 9H), 1.33–1.20 (m, 3H). ESI-MS theoretical calculation: [M+H-56] + =225.18, measured value 225.0.

[0229] Step 2

[0230] Compound 2-1 (2.80 g, 9.99 mmol) was dissolved in anhydrous ethanol (40 mL), and 50% hydroxylamine aqueous solution (1.98 g, 30.0 mmol) was added. The mixture was stirred at 75 °C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in anhydrous ethanol (60 mL x 2), and the concentration was further reduced under reduced pressure. Ethyl acetate (60 mL) was added to dissolve the residue, and the concentration was further reduced under reduced pressure to obtain compound 2-2. ESI-MS theoretical calculation: [M+H] + =314.20, measured value 314.0.

[0231] Step 3

[0232] Compound 2-2 (1.50 g, 4.79 mmol) was dissolved in N,N-dimethylformamide (30 mL). Under a nitrogen atmosphere, carbonyl diimidazole (1.01 g, 6.23 mmol) and acetic acid (370 mg, 6.23 mmol) were added, and the mixture was stirred at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to give compound 2-3. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 5.14–5.05 (m, 1H), 4.25–4.18 (m, 1H), 3.78–3.69 (m, 1H), 3.05–2.92 (m, 1H), 2.58 (s, 3H), 2.35–2.26 (m, 1H), 2.15–2.07 (m, 1H), 1.90–1.78 (m, 2H), 1.76–1.65 (m, 3H), 1.54–1.48 (m, 1H), 1.42 (s, 9H), 1.21–1.07 (m, 3H). ESI-MS theoretical calculation: [M+Na] + =360.20, measured value 360.0.

[0233] Step 4

[0234] Compound 2-3 (250 mg, 0.741 mmol) was dissolved in dichloromethane (10 mL), and ethyl acetate hydrochloride solution (5 mL, 4.0 mol / L) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 2-4. ESI-MS theoretical calculation: [M+H] + =238.15, measured value 238.0.

[0235] Step 5

[0236] The hydrochloride salt of compound 2-4 (195 mg, 0.721 mmol) was dissolved in ethyl acetate (10 mL). Under nitrogen protection, intermediate A of compound A (129 mg, 0.685 mmol), diisopropylethylamine (279 mg, 2.16 mmol) and sodium triacetoxyborohydride (458 mg, 2.16 mmol) were added sequentially, and the mixture was stirred at 35 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution. Ethyl acetate (30 mL x 3) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. This crude product was purified by high-performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.04% ammonia + 7.5 mmol / L ammonium bicarbonate aqueous solution, flow rate: 20 mL / min, gradient: 27-37%, retention time: 9.1-9.9 min, run time: 17 min) to obtain compounds 2-5. Compounds 2-5 were purified by chiral high-performance liquid chromatography (Waters SFC 150, ...). 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% (v / v) 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min) to separate and purify compound 2 (retention time: 2.7-3.8min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.22 (s, 1H), 5.00 (t, J = 6.8Hz, 1H), 3.83 (d, J = 14.8Hz, 1H), 3.59 (d, J = 14.8Hz, 1H), 2.81–2.73 (m, 1H), 2.56 (s, 3H), 2.25–2.23 (m, 2H), 2.18–2.05 (m, 5H), 1.88–1.76 (m, 2H), 1.69–1.60 (m, 3H), 1.38–1.31 (m, 1H), 1.11 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: [M+H] + =410.16, measured value 410.2. and compound 3 (retention time: 4.4-6.2 min). 1¹H NMR (400MHz, DMSO-d⁶): δ 12.22 (s, 1H), 5.00 (t, J = 6.8Hz, 1H), 3.83 (d, J = 14.8Hz, 1H), 3.59 (d, J = 14.8Hz, 1H), 2.80–2.74 (m, 1H), 2.56 (s, 3H), 2.25–2.23 (m, 2H), 2.17–2.04 (m, 5H), 1.89–1.76 (m, 2H), 1.68–1.60 (m, 3H), 1.38–1.30 (m, 1H), 1.11 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: [M+H] + =410.16, measured value 410.2.

[0237] Example 3

[0238] Synthesis route:

[0239] first step

[0240] Intermediate B2 (1.80 g, 6.63 mmol) was dissolved in dichloromethane (40 mL). Under a nitrogen atmosphere, trimethylcyanosilane (990 mg, 9.95 mmol) was slowly added dropwise at -70 °C, and the mixture was stirred at -70 °C for 0.2 h. Boron trifluoride diethyl ether (1.04 g, 7.29 mmol) was then slowly added dropwise, and the mixture was stirred at -70 °C for 0.5 h, followed by stirring at 0 °C for 1 h. Saturated sodium bicarbonate aqueous solution (50 mL) was slowly added dropwise to the reaction mixture, followed by di-tert-butyl dicarbonate (1.45 g, 6.63 mmol), and the mixture was stirred at 25 °C for 1 h. The mixture was extracted with dichloromethane (50 mL x 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to give compound 4-1. 1 ¹H NMR (400MHz, CDCl₃): δ 4.78–4.73 (m, 1H), 4.40–4.32 (m, 1H), 3.98–3.90 (m, 1H), 3.21–3.04 (m, 1H), 2.35–2.27 (m, 2H), 2.02–1.93 (m, 1H), 1.92–1.72 (m, 3H), 1.60–1.51 (m, 2H), 1.46 (s, 9H), 1.34–1.22 (m, 3H). ESI-MS theoretical calculation: [M+H-56] + =225.18, measured value 225.0.

[0241] Step 2

[0242] Compound 4-1 (600 mg, 2.14 mmol) was dissolved in anhydrous ethanol (20 mL), and 50% hydroxylamine aqueous solution (420 mg, 6.42 mmol) was added. The mixture was stirred at 75 °C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in anhydrous ethanol (30 mL x 2), and the concentration was further reduced under reduced pressure. Ethyl acetate (30 mL) was added to dissolve the residue, and the concentration was further reduced under reduced pressure to obtain compound 4-2. ESI-MS theoretical calculation: [M+H] + =314.20, measured value 314.1.

[0243] Step 3

[0244] Compound 4-2 (650 mg, 2.07 mmol) was dissolved in N,N-dimethylformamide (20 mL). Under a nitrogen atmosphere, carbonyl diimidazole (500 mg, 3.10 mmol) and acetic acid (190 mg, 3.10 mmol) were added, and the mixture was stirred at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and water (50 mL) and ethyl acetate (50 mL × 3) were added to the reaction solution for extraction. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v) to obtain compound 4-3. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 5.03–4.95 (m, 1H), 4.28–4.24 (m, 1H), 3.83–3.76 (m, 1H), 2.94–2.86 (m, 1H), 2.57 (s, 3H), 2.44–2.32 (m, 1H), 2.22–2.11 (m, 2H), 1.90–1.78 (m, 2H), 1.72–1.66 (m, 1H), 1.65–1.60 (m, 1H), 1.46–1.35 (m, 10H), 1.12–1.08 (m, 3H). ESI-MS theoretical calculation: [M+Na] + =360.20, measured value 359.9.

[0245] Step 4

[0246] Compound 4-3 (300 mg, 0.890 mmol) was dissolved in dichloromethane (10 mL), and ethyl acetate hydrochloride solution (5 mL, 4.0 mol / L) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 4-4. ESI-MS theoretical calculation: [M+H] + =238.15, measured value 238.0.

[0247] Step 5

[0248] The hydrochloride salt of compound 4-4 (290 mg, 1.06 mmol) was dissolved in ethyl acetate (10 mL). Under nitrogen protection, intermediate A (227 mg, 1.21 mmol), diisopropylethylamine (470 mg, 3.66 mmol), and sodium triacetoxyborohydride (776 mg, 3.66 mmol) were added sequentially, and the mixture was stirred at 35 °C for 12 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. This crude product was purified by high-performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.04% ammonia + 7.5 mmol / L ammonium bicarbonate aqueous solution, flow rate: 20 mL / min, gradient: 30-40%, retention time: 8.2-9.2 min, run time: 17 min) to obtain compounds 4-5. Compounds 4-5 were purified by chiral high-performance liquid chromatography (Waters SFC 150, ...). 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 25%-25%; Flow rate: 140ml / min) to separate and purify compound 4 (retention time: 5.1-6.0min). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.18 (s, 1H), 5.02 (t, J = 6.8Hz, 1H), 3.80 (d, J = 15.2Hz, 1H), 3.58 (d, J = 15.2Hz, 1H), 2.61–2.58 (m, 1H), 2.56 (s, 3H), 2.46–2.38 (m, 1H), 2.33–2.22 (m, 2H), 2.09 (s, 3H), 2.07–2.02 (m, 1H), 1.89–1.74 (m, 2H), 1.69–1.55 (m, 3H), 1.33–1.24 (m, 1H), 1.08 (d, J = 6.4Hz, 3H). ESI-MS theoretical calculation: [M+H] + =410.16, measured value 410.2. and compound 5 (retention time: 6.5-8.3 min). 1H NMR (400MHz, DMSO-d6): δ12.19(s,1H),5.00(t,J=6.8Hz,1H),3.82(d,J=15.2 Hz,1H),3.60(d,J=15.2Hz,1H),2.63-2.58(m,1H),2.56(s,3H),2.41-2.32(m ,2H),2.30-2.21(m,1H),2.11(s,3H),2.08-2.01(m,1H),1.85-1.75(m,2H),1 .68-1.65(m,2H),1.55-1.47(m,1H),1.41-1.34(m,1H),1.05(d,J=6.4Hz,3H). ESI-MS theoretical calculation value: [M+H] + =410.16, measured value 410.0.

[0249] Example 4

[0250] Synthesis route:

[0251] first step

[0252] Sodium tert-butoxide (362 mg, 3.76 mmol) was dissolved in acetonitrile (20 mL). Under a nitrogen atmosphere, compound 6-2 (500 mg, 2.51 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Then, compound 6-1 (366 mg, 2.76 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature, and water (50 mL) was added. Ethyl acetate (50 mL × 3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 6-3. 1 H NMR (400MHz, CDCl3): δ4.62(s,2H),3.61-3.48(m,2H),3.41-3.33(m,2H),3.20-3.17(m,1H),2.61(s,3H),1.82-1.78(m,2H),1.42(s,9H).

[0253] Step 2

[0254] Compound 6-3 (320 mg, 1.08 mmol) was dissolved in ethyl acetate hydrochloride solution (10 mL, 4.0 mol / L) and stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 6-4. ESI-MS theoretical calculation: [M+H] + =196.10, measured value 196.1.

[0255] Step 3

[0256] The hydrochloride salt of compound 6-4 (170 mg, 0.734 mmol) and intermediate A (110 mg, 0.58 mmol) were dissolved in ethyl acetate (15 mL). Under nitrogen protection, diisopropylethylamine (150 mg, 1.16 mmol) and sodium triacetoxyborohydride (369 mg, 1.74 mmol) were added, and the mixture was stirred at 30 °C for 16 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (20 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was then purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.05% ammonia aqueous solution, flow rate: 20 mL / min, gradient: 31-41%, retention time: 8.1-8.8 min, run time: 17 min) to obtain compound 6. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.22 (s, 1H), 4.54 (s, 2H), 3.56 (s, 2H), 3.50–3.49 (m, 1H), 2.90 (d, J = 8.8Hz, 2H), 2.59 (s, 3H), 2.37 (d, J = 8.8Hz, 2H), 2.12 (s, 3H), 1.59–1.58 (m, 2H). ESI-MS theoretical calculation: [M+H] + =368.11, measured value 368.1.

[0257] Example 5

[0258] Synthesis route:

[0259] first step

[0260] Under nitrogen protection, compound 7-1 (1.00 g, 4.44 mmol) was dissolved in anhydrous methanol (20 mL), and sodium borohydride (504 mg, 13.3 mmol) was slowly added at 0 °C. The mixture was stirred at 0 °C for 16 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 7-2. 1H NMR (400MHz, CDCl3): δ4.33-4.26(m,1H),3.52-3.46(m,2H),3.36-3.31(m, 2H),2.62-2.56(m,2H),2.20-2.12(m,2H),1.53-1.46(m,2H),1.45(s,9H).

[0261] Step 2

[0262] Sodium tert-butoxide (1.65 g, 17.2 mmol) was dissolved in acetonitrile (30 mL). Under a nitrogen atmosphere, compound 7-2 (1.30 g, 5.72 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Then, compound 6-1 (1.52 g, 11.4 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature, and water (50 mL) was added. Ethyl acetate (50 mL × 3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 7-3. 1 H NMR (400MHz, CDCl3): δ4.55(s,2H),4.11-4.06(m,1H),3.55-3.47(m,2H),3.32-3 .23(m,2H),2.62-2.54(m,5H),2.23-2.16(m,2H),1.62-1.56(m,2H),1.45(s,9H).

[0263] Step 3

[0264] Compound 7-3 (1.50 g, 4.64 mmol) was dissolved in dioxane (10 mL), and dioxane hydrochloride (10 mL, 40 mmol, 4 mol / L) was added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 7-4. ESI-MS theoretical calculation: [M+H] + =224.13, measured value 224.1.

[0265] Step 4

[0266] The hydrochloride salt of compound 7-4 (473 mg, 1.82 mmol) and intermediate A (200 mg, 1.06 mmol) were dissolved in ethyl acetate (20 mL). Under nitrogen protection, diisopropylethylamine (274 mg, 2.12 mmol) and sodium triacetoxyborohydride (674 mg, 3.18 mmol) were added, and the mixture was stirred at 30 °C for 16 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compounds 7-5. Compound 7 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, flow rate: 20 mL / min, gradient: 28-40%, run time: 17 min) to obtain compound 7 (retention time: 8.1-8.7 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 4.46 (s, 2H), 4.14–4.11 (m, 1H), 3.55 (s, 2H), 2.58 (s, 3H), 2.56–2.52 (m, 2H), 2.43–2.35 (m, 2H), 2.34–2.28 (m, 2H), 2.10 (s, 3H), 2.09–2.03 (m, 2H), 1.34–1.26 (m, 2H). ESI-MS theoretical calculation: [M+H] + =396.14, measured value 396.0. and compound 8 (retention time: 9.4-10.01 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 4.50 (s, 2H), 3.86–3.82 (m, 1H), 3.58 (s, 2H), 2.58 (s, 3H), 2.49–2.43 (m, 2H), 2.42–2.37 (m, 2H), 2.36–2.32 (m, 2H), 2.12 (s, 3H), 2.11–2.03 (m, 2H), 1.34–1.26 (m, 2H). ESI-MS theoretical calculation: [M+H] + =396.14, measured value 396.0.

[0267] Example 6

[0268] Synthesis route:

[0269] first step

[0270] Under nitrogen protection, compound 9-1 (900 mg, 4.00 mmol) was dissolved in anhydrous ethanol (40 mL), and sodium borohydride (303 mg, 8.00 mmol) was slowly added at 0 °C. The mixture was stirred at 0 °C for 1 hour. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 9-2. 1 H NMR (400MHz, CDCl3): δ4.00-3.89(m,2H),2.99-2.92(m,1H),1.94-1.88(m,1H),1.79-1.70(m,1H),1.62-1.58(m,1H),1.57 -1.52(m,1H),1.46(s,9H),1.45-1.40(m,1H),1.18-1.14(m,1H),0.85-0.80(m,1H),0.60-0.54(m,1H),0.48-0.42(m,1H).

[0271] Step 2

[0272] Sodium tert-butoxide (507 mg, 5.28 mmol) was dissolved in acetonitrile (15 mL). Under a nitrogen atmosphere, compound 9-2 (400 mg, 1.76 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Then, compound 6-1 (350 mg, 2.64 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature, and water (50 mL) was added. Ethyl acetate (50 mL × 3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 9-3. 1 H NMR (400MHz, CDCl3): δ4.61(s,2H),3.99-3.94(m,1H),3.80-3.73(m,1H),2.96-2.89(m,1H),2.60(s,3H),2.01-1.97(m,1H),1.89-1.83 (m,1H),1.56-1.49(m,1H),1.45(s,9H),1.42-1.39(m,1H),1.19-1.15(m,1H),0.86-0.81(m,1H),0.58-0.54(m,1H),0.46-0.41(m,1H).

[0273] Step 3

[0274] Compound 9-3 (280 mg, 0.870 mmol) was dissolved in dichloromethane (5 mL), and dioxane hydrochloride (5 mL, 20 mmol, 4 mol / L) was added at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 9-4. ESI-MS theoretical calculation: [M+H] + =224.13, measured value 224.1.

[0275] Step 4

[0276] The hydrochloride salt of compound 9-4 (154 mg, 0.593 mmol) and intermediate A (100 mg, 0.530 mmol) were dissolved in ethyl acetate (20 mL). Under nitrogen protection, diisopropylethylamine (206 mg, 1.59 mmol) and sodium triacetoxyborohydride (337 mg, 1.59 mmol) were added, and the mixture was stirred at 30 °C for 16 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was then purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid solution, flow rate: 20 mL / min, gradient: 13-23%, retention time: 6.8-7.8 min, run time: 17 min) to obtain the monoformate salt of compound 9. 1 ¹H NMR (400MHz, DMSO-d6): δ 12.16 (s, 1H), 8.13 (s, 1H), 4.58 (s, 2H), 3.94–3.90 (m, 1H), 3.66–3.62 (m, 2H), 2.78–2.75 (m, 1H), 2.65–2.59 (m, 1H), 2.58 (s, 3H), 2.11 (s, 3H), 1.85–1.72 (m, 2H), 1.55–1.48 (m, 1H), 1.28–1.22 (m, 1H), 0.52–0.49 (m, 1H), 0.44–0.35 (m, 3H). ESI-MS theoretical calculation: [M+H] + =396.14, measured value 396.0.

[0277] Example 7

[0278] Synthesis route:

[0279] first step

[0280] Under nitrogen protection, compound 10⁻¹ (2.00 g, 9.47 mmol) was dissolved in anhydrous methanol (16 mL), and sodium borohydride (360 mg, 9.47 mmol) was slowly added at 0 °C. The mixture was stirred at 0 °C for 1 hour. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 10⁻². 1 H NMR (400MHz, DMSO-d6): δ4.86 (d, J = 3.2Hz, 1H), 4.18-4.14 (m, 1H), 3.94-3.88 (m, 1H), 3.54-3.48 (m, 1H), 2.97-2.92 (m,1H),2.45-2.36(m,1H),1.88-1.82(m,1H),1.56-1.49(m,1H),1.45-1.39(m,1H),1.38(s,9H),1.12-1.08(m,1H).

[0281] Step 2

[0282] Sodium tert-butoxide (675 mg, 7.03 mmol) was dissolved in acetonitrile (25 mL). Under a nitrogen atmosphere, compound 10⁻² (600 mg, 2.81 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Then, compound 6⁻¹ (484 mg, 3.65 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature, and water (50 mL) was added. Ethyl acetate (50 mL × 3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 10⁻³. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 4.56–4.48 (m, 2H), 4.12–4.08 (m, 1H), 4.01–3.95 (m, 1H), 3.40–3.34 (m, 1H), 3.04–2.98 (m, 1H), 2.76–2.72 (m, 1H), 2.59 (s, 3H), 1.95–1.91 (m, 1H), 1.64–1.58 (m, 1H), 1.48–1.43 (m, 1H), 1.38 (s, 9H), 1.26–1.20 (m, 1H). ESI-MS theoretical calculation: [M+Na] + =332.17, measured value 332.0.

[0283] Step 3

[0284] Compound 10⁻³ (300 mg, 0.97 mmol) was dissolved in dichloromethane (10 mL), and ethyl acetate hydrochloride (3 mL, 12 mmol, 4 mol / L) was added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 10⁻⁴. ESI-MS theoretical calculation: [M + H] + =210.12, measured value 210.0.

[0285] Step 4

[0286] The monohydrochloride salt of compound 10-4 (238 mg, 0.969 mmol) and intermediate A (204 mg, 1.08 mmol) were dissolved in ethyl acetate (20 mL). Under nitrogen protection, diisopropylethylamine (442 mg, 3.42 mmol) and sodium triacetoxyborohydride (725 mg, 3.42 mmol) were added, and the mixture was stirred at 35 °C for 16 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was then purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid solution, flow rate: 20 mL / min, gradient: 31-41%, retention time: 7.7-9.4 min, run time: 17 min) to obtain the monoformate salt of compound 10. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.17 (s, 1H), 8.15 (s, 1H), 4.51–4.44 (m, 2H), 4.02–3.98 (m, 1H), 3.70 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 13.2 Hz, 1H), 3.15–3.13 (m, 1H), 2.79–2.76 (m, 1H), 2.62–2.54 (m, 4H), 2.49–2.45 (m, 1H), 2.12 (s, 3H), 1.78–1.71 (m, 1H), 1.69–1.63 (m, 1H), 1.32–124 (m, 2H). ESI-MS theoretical calculation: [M+H] + =382.13, measured value 382.0.

[0287] Example 8

[0288] Synthesis route:

[0289] first step

[0290] Under nitrogen protection, compound 10-2 (500 mg, 2.34 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL). Triphenylphosphine (800 mg, 3.04 mmol) and p-nitrobenzoic acid (590 mg, 3.51 mmol) were slowly added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Diisopropyl azodicarbonate (640 mg, 3.16 mmol) was slowly added dropwise, and the reaction mixture was stirred at 25 °C for 12 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 11-1. ESI-MS theoretical value: [M+H-56] + =307.15, measured value 307.2.

[0291] Step 2

[0292] Compound 11-1 (850 mg, 2.35 mmol) was dissolved in methanol (10 mL), and potassium carbonate (650 mg, 4.70 mmol) was slowly added at 0 °C. The mixture was stirred at 25 °C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain compound 11-2. 1 H NMR (400MHz, DMSO-d6): δ4.82(d,J=3.6Hz,1H),4.02-3.97(m,1H),3.80-3.75(m,1H),3.10-2.94(m,1H),2 .73-2.67(m,1H),2.32-2.29(m,1H),1.84-1.78(m,1H),1.70-1.65(m,1H),1.36(s,9H),1.32-1.20(m,2H).

[0293] Step 3

[0294] Sodium tert-butoxide (162 mg, 1.22 mmol) was dissolved in acetonitrile (25 mL). Under a nitrogen atmosphere, compound 11-2 (200 mg, 0.94 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Then, compound 6-1 (226 mg, 2.35 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature, and water (50 mL) was added. Ethyl acetate (50 mL × 3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 11-3. 1 H NMR (400MHz, DMSO-d6): δ4.59-4.51(m,2H),4.06-4.00(m,1H),3.81-3.75(m,1H),3.16-3.04(m,1H),2.75-2.6 9(m,1H),2.67-2.62(m,1H),2.58(s,3H),1.90-1.85(m,1H),1.61-1.55(m,1H),1.50-1.43(m,2H),1.37(s,9H).

[0295] Step 4

[0296] Compound 11-3 (201 mg, 0.65 mmol) was dissolved in dichloromethane (10 mL), and ethyl acetate hydrochloride (3 mL, 12 mmol, 4 mol / L) was added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 11-4. ESI-MS theoretical calculation: [M+H] + =210.12, measured value 210.0.

[0297] Step 5

[0298] The hydrochloride salt of compound 11-4 (136 mg, 0.553 mmol) and intermediate A (116 mg, 0.620 mmol) were dissolved in ethyl acetate (20 mL). Under nitrogen protection, diisopropylethylamine (252 mg, 1.95 mmol) and sodium triacetoxyborohydride (413 mg, 1.95 mmol) were added, and the mixture was stirred at 35 °C for 16 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was then purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid solution, flow rate: 20 mL / min, gradient: 31-41%, retention time: 7.0-8.5 min, run time: 17 min) to obtain the monoformate salt of compound 11. 1 ¹H NMR (400MHz, DMSO-d6): δ 12.17 (s, 1H), 8.14 (s, 1H), 4.56–4.48 (m, 2H), 3.67–3.63 (m, 1H), 3.55–3.49 (m, 2H), 3.37–3.31 (m, 1H), 3.20–3.16 (m, 1H), 2.69–2.61 (m, 1H), 2.58 (s, 3H), 2.12 (s, 3H), 2.06–2.01 (m, 1H), 1.96–1.92 (m, 1H), 1.48–1.42 (m, 2H), 1.29–1.22 (m, 1H). ESI-MS theoretical calculation: [M+H] + =382.13, measured value 382.0.

[0299] Example 9

[0300] Synthesis route:

[0301] first step

[0302] Sodium tert-butoxide (565 mg, 5.88 mmol) was dissolved in acetonitrile (15 mL). Under a nitrogen atmosphere, compound 12-1 (450 mg, 1.96 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Then, compound 6-1 (520 mg, 3.92 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature, and water (50 mL) was added. Ethyl acetate (50 mL × 3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 12-2.1 H NMR (400MHz, DMSO-d6): δ6.32(s,1H),4.57-4.50(m,2H),3.54-3.36(m,1H),2.58(s,3H),2.10-2.0 4(m,2H),1.83-1.58(m,3H),1.53-1.46(m,1H),1.38(s,9H),1.36-1.29(m,2H),1.18-1.12(m,3H).

[0303] Step 2

[0304] Compound 12-2 (250 mg, 1.08 mmol) was dissolved in dichloromethane (5 mL), and ethyl acetate hydrochloride (3 mL, 12 mmol, 4 mol / L) was added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 12-3. ESI-MS theoretical calculation: [M+H] + =226.15, measured value 226.0.

[0305] Step 3

[0306] The monohydrochloride salt of compound 12-3 (165 mg, 0.630 mmol) and intermediate A (115 mg, 0.618 mmol) were dissolved in ethyl acetate (15 mL). Under nitrogen protection, diisopropylethylamine (237 mg, 1.83 mmol) and sodium triacetoxyborohydride (388 mg, 1.83 mmol) were added, and the mixture was stirred at 35 °C for 16 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12-4. Compound 12 was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.05% ammonia aqueous solution, flow rate: 20 mL / min, gradient: 33-43%, run time: 17 min) to obtain compound 12 (retention time: 7.2-7.7 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 11.57 (s, 1H), 4.53 (s, 2H), 3.64 (s, 2H), 3.52–3.49 (m, 1H), 2.58 (s, 3H), 2.11 (s, 3H), 2.01–1.92 (m, 1H), 1.82–1.76 (m, 2H), 1.50–1.42 (m, 4H), 1.38–1.34 (m, 2H), 1.03 (s, 3H). ESI-MS theoretical calculation: [M+H] +=398.16, measured value 398.0. and compound 13 (retention time: 9.6-10.3 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 11.06 (s, 1H), 4.54 (s, 2H), 3.61 (s, 2H), 3.38–3.34 (m, 1H), 2.58 (s, 3H), 2.11 (s, 3H), 1.94–1.86 (m, 1H), 1.68–1.55 (m, 6H), 1.21–1.14 (m, 2H), 1.01 (s, 3H). ESI-MS theoretical calculation: [M+H] + =398.16, measured value 398.0.

[0307] Example 10

[0308] Synthesis route:

[0309] first step

[0310] Under nitrogen protection, compound 14-1 (5.00 g, 21.6 mmol) was dissolved in anhydrous methanol (50 mL). Cerium trichloride (12.1 g, 32.4 mmol) and sodium borohydride (1.19 g, 31.35 mmol) were slowly added at 0 °C, and the mixture was stirred at 25 °C for 1 hour. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 14-2. 1 H NMR (400MHz, DMSO-d6): δ7.41-7.30(m,5H),6.82-6.73(m,1H),5.15(s,2H),5.01-4.89(m,1H), 4.85-4.77(m,1H),4.04-4.01(m,1H),3.69-3.64(m,1H),3.40-3.33(m,1H),1.74-1.69(m,2H).

[0311] Step 2

[0312] Under nitrogen protection, compound 14-2 (2.50 g, 10.7 mmol) was dissolved in dichloromethane (300 mL). Diethylzinc (32.2 mL, 32.2 mmol, 1 mol / L n-hexane solution) and diiodomethane (14.4 g, 53.6 mmol) dissolved in dichloromethane (15 mL) solution were slowly added at 0 °C. The mixture was stirred at 25 °C for 16 hours. 1 mol / L dilute hydrochloric acid (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 14-3. ESI-MS theoretical value: [M+H] + =248.12, measured value 248.0.

[0313] Step 3

[0314] Compound 14-3 (910 mg, 3.68 mmol) was dissolved in methanol (20 mL), and 5% wet palladium on carbon (90 mg) and di-tert-butyl dicarbonate (1.61 g, 7.36 mmol) were added. The mixture was stirred at 25 °C for 16 hours under a hydrogen balloon atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 14-4. 1 H NMR (400MHz, DMSO-d6): δ4.71 (d, J = 5.2Hz, 1H), 4.08-4.03 (m, 1H), 3.64-3.48 (m, 1H), 2.89-2.81 (m, 1H), 2.70-2.51 (m,1H),1.69-1.62(m,1H),1.39(m,9H),1.35-1.30(m,1H),1.05-0.98(m,1H),0.71-0.67(m,1H),0.45-0.41(m,1H).

[0315] Step 4

[0316] Sodium tert-butoxide (744 mg, 7.74 mmol) was dissolved in acetonitrile (15 mL). Under a nitrogen atmosphere, compound 14-4 (550 mg, 2.58 mmol) was added, and the mixture was stirred at 0 °C for 0.5 h. Then, compound 6-1 (683 mg, 5.16 mmol) was added, and the mixture was stirred at 40 °C for 16 h. The reaction mixture was cooled to room temperature, and water (50 mL) was added. Ethyl acetate (50 mL × 3) was used for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 14-5. 1H NMR (400MHz, CDCl3): δ4.78-4.66(m,2H),4.18-4.12(m,1H),3.92-3.69(m,1H),3.12-3.00(m,1H),2.83-2.64(m,1H),2 .60(s,3H),1.96-1.89(m,1H),1.56-1.49(m,1H),1.47(s,9H),1.31-1.24(m,1H),0.90-0.86(m,1H),0.67-0.63(m,1H).

[0317] Step 5

[0318] Compound 14-5 (530 mg, 1.71 mmol) was dissolved in dichloromethane (5 mL), and ethyl acetate hydrochloride (3 mL, 12 mmol, 4 mol / L) was added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 14-6. ESI-MS theoretical calculation: [M+H] + =210.12, measured value 210.0.

[0319] Step 6

[0320] The monohydrochloride salt of compound 14-6 (343 mg, 1.40 mmol) and intermediate A (220 mg, 1.17 mmol) were dissolved in ethyl acetate (10 mL). Under nitrogen protection, diisopropylethylamine (455 mg, 3.51 mmol) and sodium triacetoxyborohydride (744 mg, 3.51 mmol) were added, and the mixture was stirred at 30 °C for 16 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was then purified by high-performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-10 mmol / L ammonium bicarbonate aqueous solution, flow rate: 20 mL / min, gradient: 26-36%, retention time: 8.4-9.0 min, run time: 17 min) to obtain the racemic mixture. The racemic mixture was then purified by chiral high-performance liquid chromatography (Waters SFC 150, ...). 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 120mL / min, Run time: 12min) Compound 14 was separated and purified (retention time: 3.8-5.7min). 1¹H NMR (400MHz, DMSO-d6): δ 12.20 (s, 1H), 4.68–4.50 (m, 2H), 4.10–4.02 (m, 1H), 3.73–3.58 (m, 2H), 2.58 (s, 3H), 2.48–2.32 (m, 2H), 2.23–2.16 (m, 1H), 2.15 (s, 3H), 1.62–1.54 (m, 1H), 1.42–1.28 (m, 2H), 0.66–0.58 (m, 1H), 0.40–0.30 (m, 1H). ESI-MS theoretical calculation: [M+H] + =382.13, measured value 382.0. And compound 15 (retention time: 6.8-9.7 min). 1 ¹H NMR (400MHz, DMSO-d6): δ 12.20 (s, 1H), 4.66–4.53 (m, 2H), 4.10–4.02 (m, 1H), 3.70–3.63 (m, 2H), 2.58 (s, 3H), 2.50–2.33 (m, 2H), 2.20–2.16 (m, 1H), 2.15 (s, 3H), 1.61–1.55 (m, 1H), 1.42–1.31 (m, 2H), 0.64–0.58 (m, 1H), 0.38–0.32 (m, 1H). ESI-MS theoretical calculation: [M+H] + =382.13, measured value 382.0.

[0321] Example 11

[0322] Synthesis route:

[0323] first step

[0324] Intermediate B1 (1.10 g, 38.0 mmol) and diethyl cyanomethyl phosphate (0.73 mL, 4.41 mmol) were dissolved in tetrahydrofuran (15 mL). Under a nitrogen atmosphere, bis(trimethylsilylaminolithium) (4.41 mL, 4.41 mmol, 1.0 mol / L tetrahydrofuran solution) was slowly added dropwise at -70 °C. The mixture was stirred at -70 °C for 1 hour and then at 25 °C for 12 hours. Saturated ammonium chloride aqueous solution (50 mL) was slowly added dropwise to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 16-1. 1¹H NMR (400MHz, CDCl₃): 4.35–4.31 (m, 1H), 4.22–4.19 (m, 1H), 3.90–3.86 (m, 1H), 3.17–3.11 (m, 1H), 2.62–2.53 (m, 2H), 2.16–2.09 (m, 1H), 1.86–1.70 (m, 4H), 1.67–1.57 (m, 3H), 1.47–1.42 (m, 9H), 1.29–1.24 (m, 3H). ESI-MS theoretical calculation: [M+H] + =295.19, measured value 295.1.

[0325] Step 2

[0326] Compound 16-1 (1.10 g, 3.74 mmol) was dissolved in anhydrous ethanol (15 mL), and 50% hydroxylamine aqueous solution (740 mg, 11.2 mmol) was added. The mixture was stirred at 75 °C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in anhydrous ethanol (30 mL x 2), and the concentration was further reduced under reduced pressure. Ethyl acetate (30 mL) was added to dissolve the residue, and the concentration was further reduced under reduced pressure to obtain compound 16-2. ESI-MS theoretical calculation: [M+H] + =328.22, measured value 328.5.

[0327] Step 3

[0328] Compound 16-2 (1.20 g, 3.67 mmol) was dissolved in N,N-dimethylformamide (20 mL). Under a nitrogen atmosphere, carbonyl diimidazole (930 mg, 5.50 mmol) and acetic acid (340 mg, 5.50 mmol) were added, and the mixture was stirred at 120 °C for 12 hours. The reaction solution was cooled to room temperature, and water (50 mL) and ethyl acetate (50 mL × 3) were added to the reaction solution for extraction. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 16-3. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 4.32–4.26 (m, 1H), 4.19–4.14 (m, 1H), 3.72–3.68 (m, 1H), 2.94–2.80 (m, 3H), 2.58–2.50 (m, 3H), 2.02–1.96 (m, 1H), 1.70–1.63 (m, 3H), 1.54–1.49 (m, 3H), 1.41–1.33 (m, 10H), 1.07 (d, J = 7.2 Hz, 3H). ESI-MS theoretical calculation: [M + Na] + =352.22, measured value 352.1.

[0329] Step 4

[0330] Compound 16-3 (590 mg, 1.68 mmol) was dissolved in dichloromethane (10 mL), and ethyl acetate hydrochloride solution (5 mL, 4.0 mol / L) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give the monohydrochloride salt of compound 16-4. ESI-MS theoretical calculation: [M+H] + =252.16, measured value 252.4.

[0331] Step 5

[0332] The hydrochloride salt of compound 16-4 (420 mg, 1.46 mmol) was dissolved in ethyl acetate (8 mL). Under nitrogen protection, intermediate A (299 mg, 1.59 mmol), diisopropylethylamine (647 mg, 5.01 mmol), and sodium triacetoxyborohydride (1.06 g, 5.01 mmol) were added sequentially, and the mixture was stirred at 35 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. This crude product was purified by high-performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.04% ammonia + 7.5 mmol / L ammonium bicarbonate aqueous solution, flow rate: 20 mL / min, gradient: 27-36%, retention time: 9.6-10.4 min, run time: 17 min) to obtain compound 16-5. Compound 16-5 was further purified by chiral high-performance liquid chromatography (Waters SFC 150, ...). 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 140ml / min, Run time: 11min) Compound 16 was separated and purified (retention time: 3.2-5.1min). 1¹H NMR (400MHz, DMSO-d⁶): δ 12.21 (s, 1H), 4.23–4.20 (m, 1H), 3.80 (d, J = 14.8 Hz, 1H), 3.58 (d, J = 14.8 Hz, 1H), 2.86–2.80 (m, 1H), 2.76–2.71 (m, 2H), 2.54 (s, 3H), 2.25–2.19 (m, 1H), 2.12 (s, 3H), 2.10–1.99 (m, 2H), 1.70–1.63 (m, 3H), 1.55–1.46 (m, 3H), 1.36–1.29 (m, 1H), 1.07 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =424.17, measured value 423.9. and compound 17 (retention time: 6.3-9.4 min). 1 HNMR (400MHz, DMSO-d6): δ 12.21 (s, 1H), 4.24–4.19 (m, 1H), 3.80 (d, J = 14.8 Hz, 1H), 3.58 (d, J = 14.8 Hz, 1H), 2.85–2.80 (m, 1H), 2.76–2.71 (m, 2H), 2.54 (s, 3H), 2.23–2.18 (m, 1H), 2.12 (s, 3H), 2.11–2.03 (m, 2H), 1.70–1.64 (m, 3H), 1.59–1.47 (m, 3H), 1.28–1.22 (m, 1H), 1.07 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =424.17, measured value 423.9.

[0333] Example 12

[0334] Synthesis route:

[0335] first step

[0336] Compound 2-1 (3.20 g, 11.4 mmol) was dissolved in methanol (30 mL), and sodium methoxide (925 mg, 17.1 mmol) was added. The mixture was stirred at 25 °C for 16 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 18-1. 1H NMR (400MHz, CDCl3): δ4.53-4.49(m,1H),4.35-4.30(m,1H),3.90-3.83(m,1H),3.71(s,3H),3.25-3.13(m,1H ),2.30-2.18(m,1H),2.12-2.03(m,1H),1.82-1.67(m,5H),1.56-1.52(m,1H),1.44(s,9H),1.34-1.26(m,3H).

[0337] Step 2

[0338] Compound 18-1 (3.00 g, 9.57 mmol) was dissolved in tetrahydrofuran (15 mL) and water (15 mL), and then lithium hydroxide monohydrate (803 mg, 19.1 mmol) was added. The mixture was stirred at 25 °C for 16 hours. After the reaction was completed, 1 mol / L hydrochloric acid aqueous solution (40 mL) was slowly added dropwise to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 18-2. 1 ¹H NMR (400MHz, DMSO-d6): δ 12.45 (s, 1H), 4.42–4.36 (m, 1H), 4.23–4.15 (m, 1H), 3.74–3.68 (m, 1H), 3.15–3.03 (m, 1H), 2.28–2.16 (m, 1H), 1.96–1.89 (m, 1H), 1.71–1.58 (m, 5H), 1.41–1.32 (m, 10H), 1.24–1.16 (m, 3H). ESI-MS theoretical calculation: [M+H] + =300.17, measured value 300.1.

[0339] Step 3

[0340] In a vacuum glove box, compound 18-2 (100 mg, 0.33 mmol), 4-bromo-6-methoxypyrimidine (62.4 mg, 0.33 mmol), cesium carbonate (215 mg, 0.66 mmol), nickel chloride dimethoxyethane (14.5 mg, 0.066 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridine (13.3 mg, 0.050 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and then [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium(III) hexafluorophosphate (3.7 mg, 0.0033 mmol) were added, and the mixture was stirred at 25 °C for 16 hours under 420 nm blue light irradiation. After the reaction was completed, water (5 mL) was added to the reaction solution, and ethyl acetate (15 mL × 3) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 18-3. 1 ¹H NMR (400MHz, DMSO-d⁶): δ 8.71 (s, 1H), 6.87 (s, 1H), 4.93 (t, J = 7.2Hz, 1H), 4.27–4.24 (m, 1H), 3.92 (s, 3H), 3.86–3.79 (m, 1H), 3.13–3.07 (m, 1H), 2.41–2.36 (m, 1H), 1.79–1.71 (m, 6H), 1.55–1.46 (m, 1H), 1.40 (s, 9H), 1.22 (d, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =364.22, measured value 364.1.

[0341] Step 4

[0342] Compound 18-3 (180 mg, 0.50 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid solution (1.5 mL, 20.1 mmol) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with isopropanol / dichloromethane (v / v = 1 / 10, 20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 18-4. ESI-MS theoretical value: [M+H] + =264.16, measured value 264.0.

[0343] Step 5

[0344] Compound 18-4 (80.0 mg, 0.30 mmol) was dissolved in ethyl acetate (3 mL). Under nitrogen protection, intermediate A (84.7 mg, 0.45 mmol), diisopropylethylamine (58.2 mg, 0.45 mmol), and sodium triacetoxyborohydride (191 mg, 0.90 mmol) were added sequentially, and the mixture was stirred at 35 °C for 2 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. This crude product was purified by high-performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, flow rate: 20 mL / min, gradient: 8-18%, retention time: 7.00-7.09 min, run time: 17 min) to obtain compound 18-5. Compound 18-5 was further purified by chiral high-performance liquid chromatography (Waters SFC 80, ...). 250*25mm10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 80ml / min, Run time: 19min) Compound 18 was separated and purified (retention time: 8.5-11.5min). 1 H NMR (400MHz, DMSO-d6): δ12.22(s,1H),8.69(s,1H),6.85(s,1H),4.84(t,J=7.2H z,1H),3.91(s,3H),3.84(d,J=14.8Hz,1H),3.60(d,J=14.8Hz,1H),2.81-2.77(m ,1H),2.41-2.37(m,1H),2.30-2.25(m,1H),2.17-2.12(m,4H),1.87-1.85(m,1H) ,1.80-1.69(m,4H),1.61-1.59(m,1H),1.57-1.50(m,1H),1.12(d,J=6.0Hz,3H). ESI-MS theoretical calculation value: [M+H] + =436.17, measured value 436.1. and compound 19 (retention time: 12.0-17.3 min). 1H NMR (400MHz, DMSO-d6): δ12.21(s,1H),8.69(s,1H),6.84(s,1H),4.85(t,J=7.2H z,1H),3.90(s,3H),3.84(d,J=14.8Hz,1H),3.60(d,J=14.8Hz,1H),2.81-2.77(m ,1H),2.43-2.38(m,1H),2.30-2.26(m,1H),2.14-2.09(m,4H),1.89-1.82(m,1H) ,1.79-1.68(m,4H),1.61-1.55(m,1H),1.46-1.42(m,1H),1.12(d,J=6.0Hz,3H). ESI-MS theoretical calculation value: [M+H] + =436.17, measured value 436.1.

[0345] Example 13

[0346] Synthesis route:

[0347] first step

[0348] In a vacuum glove box, compound 18-2 (100 mg, 0.33 mmol), 2-bromopyrazine (52.5 mg, 0.33 mmol), cesium carbonate (215 mg, 0.66 mmol), nickel chloride dimethoxyethane (14.5 mg, 0.066 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridine (13.3 mg, 0.050 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and then [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium(III) hexafluorophosphate (3.7 mg, 0.0033 mmol) were added, and the mixture was stirred at 25 °C for 16 hours under 420 nm blue light irradiation. After the reaction was completed, water (5 mL) was added to the reaction solution, and ethyl acetate (15 mL × 3) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain compound 20-1. 1¹H NMR (400MHz, DMSO-d⁶): δ 8.73 (s, 1H), 8.59–8.56 (m, 2H), 5.12–5.06 (m, 1H), 4.29–4.24 (m, 1H), 3.82–3.78 (m, 1H), 3.17–3.12 (m, 1H), 2.39–2.34 (m, 1H), 2.00–1.95 (m, 1H), 1.83–1.71 (m, 5H), 1.55–1.43 (m, 1H), 1.40 (s, 9H), 1.23 (d, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H] + =334.21, measured value 334.1.

[0349] Step 2

[0350] Compound 20-1 (160 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid solution (1.5 mL, 20.1 mmol) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 20-2. ESI-MS theoretical value: [M+H] + =234.15, measured value 234.0.

[0351] Step 3

[0352] Compound 20-2 (140 mg, 0.60 mmol) was dissolved in ethyl acetate (3 mL). Under nitrogen protection, intermediate A (169 mg, 0.90 mmol), diisopropylethylamine (116 mg, 0.90 mmol), and sodium triacetoxyborohydride (382 mg, 1.80 mmol) were added sequentially, and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (20 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. This crude product was purified by high-performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, flow rate: 20 mL / min, gradient: 8-18%, retention time: 7.70-9.50 min, run time: 17 min) to obtain compound 20-3. Compound 20-3 was further purified by chiral high-performance liquid chromatography (Waters SFC 80, ...). 250*25mm10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min, Run time: 11min) Compound 20 was separated and purified (retention time: 3.2-5.1min). 1 H NMR (400MHz, DMSO-d6): δ8.70(d,J=2.0Hz,1H),8.58-8.56(m,1H),8.55(d,J=2.0Hz ,1H),5.00(t,J=7.2Hz,1H),3.84(d,J=14.8Hz,1H),3.60(d,J=14.8Hz,1H),2.83-2 0.78 (m, 1H), 2.40-2.36 (m, 1H), 2.34-2.29 (m, 1H), 2.16-2.11 (m, 4H), 2.01-1.97 (m, 1H), 1.82-1.78 (m, 2H), 1.70-1.64 (m, 3H), 1.55-1.49 (m, 1H), 1.12 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =406.16, measured value 406.0. and compound 21 (retention time: 6.3-9.4 min). 1 H NMR (400MHz, DMSO-d6): δ12.21(s,1H),8.68(s,1H),8.57-8.54(m,2H),5.02(t ,J=7.2Hz,1H),3.84(d,J=14.8Hz,1H),3.60(d,J=14.8Hz,1H),2.82-2.79(m,1H ),2.42-2.37(m,1H),2.32-2.26(m,1H),2.19-2.10(m,4H),2.04-1.95(m,1H), 1.81-1.69(m,4H),1.66-1.62(m,1H),1.47-1.40(m,1H),1.13(d,J=6.0Hz,3H). ESI-MS theoretical calculation value: [M+H] + =406.16, measured value 406.1.

[0353] Example 14

[0354] Synthesis route:

[0355] 22 and 23 are one, two, or three of compounds A, B, C, and D, respectively; and 22 and 23 have different types of components.

[0356] first step

[0357] Intermediate 22-1 (10.0 g, 46.9 mmol) was dissolved in tetrahydrofuran (200 mL). Under a nitrogen atmosphere, acetylenyl magnesium bromide (93.8 mL, 46.9 mmol, 0.5 mol / L tetrahydrofuran solution) was slowly added dropwise at -70 °C. The mixture was stirred at -70 °C for 0.5 h and then at 25 °C for 3 h. Saturated ammonium chloride aqueous solution (200 mL) was slowly added dropwise to the reaction mixture. Ethyl acetate (300 mL x 3) was added for extraction. The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 22-2. 1 ¹H NMR (400MHz, CDCl₃): 4.35–4.31 (m, 1H), 3.90–3.85 (m, 1H), 3.24–3.16 (m, 1H), 2.46 (s, 1H), 2.03–1.98 (m, 1H), 1.91–1.84 (m, 3H), 1.63 (s, 1H), 1.49–1.45 (m, 9H), 1.29 (d, J = 7.2 Hz, 3H). ESI-MS theoretical calculation: [M + H - 56] + =184.15, measured value 184.1.

[0358] Step 2

[0359] Compound 22-2 (6.90 g, 28.8 mmol) was dissolved in acetonitrile (70 mL), and cuprous iodide (270 mg, 1.44 mmol) was added. Ethyl diazonate (3.62 g, 31.7 mmol) was slowly added dropwise to the reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 1 hour, then at 25 °C for 12 hours. A saturated ammonium chloride aqueous solution (200 mL) was slowly added dropwise to the reaction mixture, followed by extraction with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 22-3. ESI-MS theoretical value: [M+H] + =326.19, measured value 326.1.

[0360] Step 3

[0361] Compound 22-3 (6.70 g, 20.6 mmol) was dissolved in ethanol (70 mL). Under a nitrogen atmosphere, 10% wet palladium on carbon (220 mg) was added. The reaction mixture was stirred at 25 °C for 16 hours under a hydrogen balloon atmosphere. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 22-4. 1 ¹H NMR (400MHz, CDCl₃): 4.32–4.28 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.86–3.82 (m, 1H), 3.22–3.18 (m, 1H), 2.28 (t, J = 7.2 Hz, 2H), 1.69–1.52 (m, 6H), 1.50–1.45 (m, 1H), 1.43 (s, 9H), 1.40–1.36 (m, 1H), 1.28 (d, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =330.22, measured value 330.1.

[0362] Step 4

[0363] Compound 22-4 (4.20 g, 12.8 mmol) was dissolved in toluene (45 mL), and p-toluenesulfonic acid monohydrate (220 mg, 1.28 mmol) was added. The mixture was stirred at 25 °C for 16 hours. Saturated sodium bicarbonate aqueous solution (100 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 22-5. 1 ¹H NMR (400MHz, CDCl₃): 4.41–4.36 (m, 1H), 3.95–3.89 (m, 1H), 3.31–3.27 (m, 1H), 2.51 (t, J = 7.2Hz, 2H), 1.94–1.65 (m, 8H), 1.45 (s, 9H), 1.33 (d, J = 7.2Hz, 3H). ESI-MS theoretical calculation: [M+H-56] + =228.18, measured value 228.0.

[0364] Step 5

[0365] Compound 22-5 (2.00 g, 7.06 mmol) was dissolved in dichloromethane (20 mL). Under a nitrogen atmosphere, diisobutylaluminum hydride (6.99 mL, 6.99 mmol, 1.0 mol / L n-hexane solution) was slowly added dropwise at -30 °C, and the mixture was stirred at -30 °C for 2 hours. Water (0.5 mL), 15% sodium hydroxide aqueous solution (1.5 mL), and water (0.5 mL) were added to the reaction mixture, and the mixture was stirred at 25 °C for 0.5 hours. Anhydrous magnesium sulfate (10.0 g) was added, and the mixture was filtered. The filter cake was washed with dichloromethane (50 mL x 3). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain compound 22-6. ESI-MS theoretical value: [M+H-56] + =286.19, measured value 286.1.

[0366] Step 6

[0367] Compound 22-6 (1.46 g, 5.12 mmol) was dissolved in dichloromethane (15 mL). Under a nitrogen atmosphere, trimethylcyanosilane (762 mg, 7.68 mmol) and boron trifluoride diethyl ether (799 mg, 5.63 mmol) were slowly added dropwise at -70 °C. The mixture was stirred at -70 °C for 0.5 h and then at 0 °C for 1 h. Saturated sodium bicarbonate aqueous solution (100 mL) was slowly added dropwise to the reaction mixture. Ethyl acetate (100 mL x 3) was added for extraction. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 22-7. 1 ¹H NMR (400MHz, DMSO-d6): 4.81–4.71 (m, 1H), 4.21–4.12 (m, 1H), 3.72–3.66 (m, 1H), 3.04–2.87 (m, 1H), 2.26–2.19 (m, 1H), 1.94–1.88 (m, 1H), 1.65–1.57 (m, 4H), 1.41–1.35 (m, 11H), 1.32–1.27 (m, 1H), 1.20–1.15 (m, 3H), 1.15–1.08 (m, 1H). ESI-MS theoretical calculation: [M+H-56] + =239.19, measured value 239.0.

[0368] Step 7

[0369] Compound 22-7 (300 mg, 1.02 mmol) was dissolved in anhydrous ethanol (5 mL), and 50% hydroxylamine aqueous solution (202.14 mg, 3.06 mmol) was added. The mixture was stirred at 75 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in anhydrous ethanol (60 mL) and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL) and concentrated under reduced pressure to give compound 22-8. ESI-MS theoretical calculation: [M+H] + =328.22, measured value 328.3.

[0370] Step 8

[0371] Compound 22-8 (330 mg, 1.01 mmol) was dissolved in tetrahydrofuran (10 mL). Under a nitrogen atmosphere, triethylamine (150 mg, 1.52 mmol), 1,8-diazobispyrocyclo[5.4.0]undec-7-ene (615 mg, 4.04 mmol), and acetyl chloride (95.0 mg, 1.21 mmol) were added, and the mixture was stirred at 120 °C for 4 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and water (50 mL) was added. Ethyl acetate (50 mL x 3) was added for extraction. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 22-9. ESI-MS theoretical calculation: [M+H] + =352.22, measured value 352.1.

[0372] Step 9

[0373] Compound 22-9 (260 mg, 0.74 mmol) was dissolved in dichloromethane (5 mL), and ethyl acetate hydrochloride (1 mL, 4 mmol, 4 mol / L) was added at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (20 mL) was added. Extraction was performed with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 22-10. ESI-MS theoretical value: [M+H] + =252.16, measured value 252.1.

[0374] Step 10

[0375] Compound 22-10 (185 mg, 0.74 mmol) was dissolved in ethyl acetate (5 mL). Under nitrogen protection, intermediate A (132 mg, 0.70 mmol), diisopropylethylamine (287 mg, 2.22 mmol), and sodium triacetoxyborohydride (471 mg, 2.22 mmol) were added sequentially, and the mixture was stirred at 25 °C for 12 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution (30 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product containing the target compound. This crude product was purified by high-performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, flow rate: 20 mL / min, gradient: 10-23%, retention time: 8.2-10.0 min, run time: 17 min) to obtain compound 22-11. Compound 22-11 was further purified by chiral high-performance liquid chromatography (Waters SFC 150, ...). 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-85%; Flow rate: 140ml / min, Run time: 22min) Separation and purification yielded substance 22 (retention time: 13.0-14.2min, one of compounds A, B, C and D, or a mixture of two or three). 1 ¹H NMR (400MHz, DMSO-d⁶): δ 12.21 (s, 1H), 4.79–4.76 (m, 1H), 3.80 (d, J = 14.8 Hz, 1H), 3.63 (d, J = 14.8 Hz, 1H), 2.72–2.69 (m, 1H), 2.56 (s, 3H), 2.44–2.39 (m, 1H), 2.25–2.16 (m, 5H), 1.83–1.79 (m, 1H), 1.74–1.59 (m, 4H), 1.55–1.49 (m, 1H), 1.45–1.36 (m, 2H), 1.20–1.15 (m, 1H), 1.06 (d, J = 6.0 Hz, 3H). ESI-MS theoretical calculation: [M+H] + =424.17, measured value 424.1. and substance 23 (retention time: 15.9-20.0 min, one of compounds A, B, C and D, or a mixture of two or three); and the components of substance 22 and substance 23 are different. 1H NMR (400MHz, DMSO-d6): δ12.21(s,1H),4.83-4.80(m,1H),3.76(d,J=14.8Hz ,1H),3.63(d,J=14.8Hz,1H),2.69-2.63(m,1H),2.56(s,3H),2.44-2.39(m,1 H),2.25-2.16(m,2H),2.12(s,3H),1.78-1.74(m,3H),1.66-1.63(m,2H),1. 55-1.49(m,2H),1.40-1.34(m,1H),1.21-1.18(m,1H),1.13(d,J=6.0Hz,3H). ESI-MS theoretical calculation value: [M+H] + =424.17, measured value 424.1.

[0376] Example 15

[0377] Synthesis route:

[0378] first step

[0379] In a vacuum glove box, compound 18-2 (100 mg, 0.33 mmol), 4-bromo-2-methoxypyridine (93.1 mg, 0.49 mmol), cesium carbonate (215 mg, 0.66 mmol), nickel chloride dimethoxyethane (14.5 mg, 0.066 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridine (13.3 mg, 0.050 mmol) were dissolved in N,N-dimethylformamide (2.0 mL), and then [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium(III) hexafluorophosphate (3.7 mg, 0.0033 mmol) were added. The mixture was stirred at 25 °C for 16 hours under 420 nm blue light irradiation. After the reaction was complete, water (5 mL) was added to the reaction solution, followed by extraction with ethyl acetate (15 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 24-1. ESI-MS theoretical value: [M+H] + =363.22, measured value 363.1.

[0380] Step 2

[0381] Compound 24-1 (70.0 mg, 0.19 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid solution (0.5 mL, 6.73 mmol) was added. The mixture was stirred at 25 °C for 1 hour. After the reaction was complete, sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 24-2. ESI-MS theoretical value: [M+H] + =263.17, measured value 263.1.

[0382] Step 3

[0383] Compound 24-2 (50.0 mg, 0.19 mmol) was dissolved in ethyl acetate (3 mL). Under nitrogen protection, intermediate A (53.6 mg, 0.29 mmol), diisopropylethylamine (36.8 mg, 0.29 mmol), and sodium triacetoxyborohydride (121 mg, 0.57 mmol) were added sequentially, and the mixture was stirred at 40 °C for 2 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (20 mL) was slowly added dropwise to the reaction solution, followed by extraction with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product containing the target compound. The crude product was purified by high performance liquid chromatography (Waters-XBridge-C18-10 μm-19*250 mm, mobile phase: acetonitrile-0.1% formic acid aqueous solution, flow rate: 20 mL / min, gradient: 16-26%, retention time: 7.1-7.8 min, run time: 17 min) to obtain compound 24. 1 ¹H NMR (400MHz, DMSO-d6): δ 12.21 (s, 1H), 8.09–8.06 (m, 1H), 6.91–6.88 (m, 1H), 6.70 (s, 1H), 4.89–4.87 (m, 1H), 3.84–3.80 (m, 4H), 3.63–3.59 (m, 1H), 2.82–2.78 (m, 1H), 2.38–2.29 (m, 2H), 2.16–2.12 (m, 4H), 1.75–1.59 (m, 6H), 1.52–1.44 (m, 1H), 1.13–1.10 (m, 3H). ESI-MS theoretical calculation: [M+H] + =435.18, measured value 435.0.

[0384] Example 1

[0385] Inhibitory effect of the compound on O-linked N-acetylglucosamine hydrolase (O-GlcNAcase, OGA)

[0386] 1. Experimental materials are shown in Table 1 below.

[0387] Table 1

[0388] 2. Experimental instruments and equipment are shown in Table 2 below.

[0389] Table 2

[0390] 3. OGA enzyme reaction method

[0391] 3.1 Preparation of enzymes and reaction substrates

[0392] The OGA enzyme buffer system contains 50 mM NaH2PO4, 100 mM NaCl, and 0.1% BSA;

[0393] Substrate 4-MUF-NAG was added to buffer solution to prepare a 280 μM 2x substrate solution;

[0394] Add OGA enzyme to buffer solution to prepare a 5 nM 2x enzyme solution;

[0395] 3.2. Compound Preparation

[0396] The test compound and positive control drug are prepared into a storage solution of the required concentration using DMSO.

[0397] 3.3 Experimental Procedure

[0398] 1) In a 384-well Echo plate, 45 μL of the compound to be tested is used as the highest test concentration (10 μM). Take 15 μL of the compound from the first concentration well and add it to the second concentration well. Perform 3-fold dilutions in sequence, diluting a total of 10 concentrations. Transfer 40 μL of 100% DMSO to two empty wells as controls without the compound and without the enzyme.

[0399] 2) Use an Echo 650 to transfer 100 nL of different concentrations of the test compound into a 384-well test plate;

[0400] 3) Transfer 10 μL of 2x OGA enzyme solution into the reaction wells of the 384 detection plate containing the compound;

[0401] 4) Transfer 10 μL of 2x substrate solution into the reaction well of the 384 detection plate containing the compound to start the reaction. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 15 minutes.

[0402] 5) Add buffer to the negative control wells, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 15 minutes;

[0403] 6) Remove the test plate and place it into the Synergy multi-functional microplate analyzer to read the values.

[0404] 4. Data Reading

[0405] Dynamically read RFU values ​​on Synergy (Ex355 / Em460)

[0406] 5. Data Analysis

[0407] 1) Copy the RFU read value

[0408] 2) Convert the above data into a suppression percentage using a formula.

[0409] Percent inhibition=(max-sample RFU) / (max-min)*100

[0410] "min" represents the reading of the control wells without enzyme; "max" represents the reading of the control wells with DMSO added.

[0411] 3) Import the data into GraphPad Prism for curve fitting.

[0412] Fitting formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0413] The experimental results are shown in Table 3 below:

[0414] Table 3

[0415] Experimental conclusion:

[0416] The experimental samples (compounds) were prepared according to the corresponding examples, and the results are shown in the table above. The compounds of this application have an inhibitory effect on O-linked N-acetylglucosamine hydrolase (O-GlcNAcase, OGA) in this experimental system.

[0417] Example 2

[0418] Inhibitory effect of the compound on the activity of O-linked N-acetylglucosamine hydrolase (O-GlcNAcase, OGA) in cells.

[0419] 1. Experimental Procedure

[0420] a) Resuspend the SH-SY5Y cells to 2*10⁻⁶. 4 Inoculate at a density of 100 mL into 96-well plates and incubate overnight at 37°C with 5% CO2.

[0421] b) On the second day, add the test drug (10 μM, 0.1% DMSO solution) and treat in a 37°C, 5% CO2 incubator for 24 hours.

[0422] c) After drug treatment, discard the culture medium, wash twice with PBS, add 50 mL of cell lysis buffer (manufacturer: CST, catalog number: 9803S), and lyse SH-SY5Y cells for 45 minutes at 4℃ and 350 rpm for later use.

[0423] d) Biotin-labeled wheat germ lectin (WGA, Vector Biology) was pre-coated onto MSD plates and incubated at room temperature for 1 hour.

[0424] e) After incubating at room temperature for 1 hour, wash the plate three times with 200 mL of 1×PBST.

[0425] f) Then add 35 mL of cell lysate and incubate the plate at room temperature for 3 hours, then wash the plate three times with 200 mL of 1×PBST.

[0426] g) After washing, add 50 mL of goat anti-mouse antibody (manufacturer: Abcam, catalog number: AB2739, volume ratio: 1:1000) to each well of the plate, incubate for 1.5 hours, and then wash the plate three times with 200 mL of 1×PBST.

[0427] h) Add 50 mL / well of anti-goat mouse antibody (manufacturer: MSD, catalog number: R32AC; volume ratio: 1:2500), and incubate the plate at room temperature for 1 hour. Then wash the plate three times with 200 mL of 1×PBST.

[0428] i) Add 150 mL of reading buffer T (manufacturer: MSD, part number: R92TC) and use the MSD instrument to take the reading.

[0429] Data processing:

[0430] The IC50 of the compound was calculated using GraphPad Prism 8 software by fitting the following equation:

[0431] Y = Bottom + (Top - Bottom) / (1 + 10) ^ ((LogIC 50 -X)*HillSlope))

[0432] Where X is the Log value of the detected concentration of the analyte, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages of the drug on O-linked N-acetylglucosamine hydrolases in cells, respectively. HillSlope: Hill slope (reflects the steepness of the curve; positive values ​​indicate positive regulation, and negative values ​​indicate negative regulation).

[0433] The experimental results are shown in Table 4 below:

[0434] Table 4

[0435] Comparative Example 1:

[0436] Experimental conclusion:

[0437] The experimental results are shown in the table above. In this experimental system, the compound of this application has a good inhibitory effect on O-linked N-acetylglucosamine hydrolase (O-GlcNAcase, OGA) expressed in cells.

[0438] Example 3: Evaluation of the pharmacokinetic properties of the compound in mice

[0439] Experimental objective:

[0440] The pharmacokinetic properties of the compounds obtained in the embodiments of the present invention in CD-1 mice were evaluated.

[0441] Experimental procedure:

[0442] Candidate compounds were prepared into clear solutions or suspensions using designated solvents and administered to three mice via single intravenous injection and oral administration, respectively. The solvent for both intravenous and oral administration was an aqueous solution containing 10% sulfobutyl-β-cyclodextrin. The drug concentration was 0.4 mg / ml for intravenous administration and 0.5 mg / ml for oral administration. Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes (ethylenediaminetetraacetic acid dipotassium anticoagulant tubes). The supernatant was obtained by centrifugation, and proteins were precipitated by adding acetonitrile solution containing an internal standard. After centrifugation, the supernatant was collected, and an equal volume of water was added. The supernatant was then injected into the plasma. Blood drug concentrations were quantitatively analyzed and pharmacokinetic parameters were calculated using LCMS / MS.

[0443] The experimental methods are shown in Table 5 below:

[0444] Table 5

[0445] The experimental results are shown in Table 6 below:

[0446] Table 6

[0447] Experimental conclusion:

[0448] The results showed that the compound of this application has good pharmacokinetic properties.

[0449] Evaluation of the brain penetration properties of the compound in Example 4

[0450] Experimental objective:

[0451] The brain tissue / plasma partition coefficient of the compounds obtained in the embodiments of the present invention was evaluated in CD-1 mice.

[0452] The experimental materials are shown in Table 7 below:

[0453] Table 7

[0454] Experimental procedure:

[0455] Candidate compounds were prepared into clear solutions or suspensions using designated solvents and administered orally once to three CD-1 mice. The oral administration solvent was an aqueous solution containing 10% sulfobutyl-β-cyclodextrin, with a drug concentration of 0.5 mg / ml. Whole blood and brain tissue samples were collected one hour after administration into commercially available EDTA2K anticoagulant tubes. The samples were centrifuged to obtain the supernatant plasma and brain tissue homogenates. Acetonitrile solution containing an internal standard was added to precipitate proteins. The supernatant was centrifuged again, and an equal volume of water was added. After further centrifugation, the supernatant was injected into the plasma and brain tissue samples for quantitative analysis using LCMS / MS.

[0456] The experimental methods are shown in Table 8 below:

[0457] Table 8

[0458] The experimental results are shown in Table 9 below:

[0459] Table 9

[0460] Experimental conclusion:

[0461] The results showed that the compound of this application had a larger brain-blood partition coefficient, indicating that it has good brain penetration properties and better therapeutic effects.

[0462] Example 5: Study on the metabolic stability of the compound in liver microsomes of mice, rats, dogs, monkeys and humans.

[0463] 1. Incubation steps

[0464] Test compounds or positive controls (including testosterone, diclofenac, and propafenone) were incubated once at 1.0 μM (solvent: acetonitrile) with liver microsomes (from Corning, Xenotech, or other trusted suppliers, with microsomes from multiple donors for each species) at a final concentration of 0.5 mg / mL (100 mM potassium phosphate buffer (PB Buffer)).

[0465] The mixture will be preheated at 37°C for 10 minutes, and the reaction will be initiated by adding a cofactor system (1.0 mM NADPH). Test compounds incubated with liver microsomes at 37°C without the cofactor system will serve as negative controls.

[0466] 2. Sampling

[0467] Reaction samples will be taken at multiple time points (e.g., 0, 5, 15, 30, 45, and 60 minutes), while samples without the cofactor system (NCF) will be taken at 60 minutes. All samples will be immediately mixed with pre-cooled acetonitrile containing the internal standard (IS) to terminate the reaction.

[0468] 3. Single-point testing

[0469] Each test condition is measured once (n=1).

[0470] 4. Sample Analysis

[0471] The samples will be analyzed using LC-MS / MS; the disappearance of the test compound will be assessed based on the peak area ratio of the analyte to the internal standard (IS) (no standard curve required).

[0472] 5. Data Summary

[0473] Provides an Excel summary of data, including calculated intrinsic clearance rate and half-life (T). 1 / 2 )value.

[0474] 6. Calculation of microparticle clearance rate

[0475] Calculate the microsomal clearance rate using the following formula:

[0476] when

[0477] C t: This indicates the drug concentration at time t;

[0478] C0: represents the drug concentration at the initial time (t=0);

[0479] e: is the base of the natural logarithm, approximately equal to 2.71828;

[0480] k e : Represents the elimination rate constant, describing the rate at which a drug is eliminated from the body;

[0481] t: Indicates time.

[0482] Liver weight: 40 g / kg (rat), 30 g / kg (monkey), 32 g / kg (dog), 20 g / kg (human) and 88 g / kg (mouse).

[0483] ■Using CL int(mic) Calculate liver clearance rate:

[0484] ■ Microsomal protein / liver weight: 45 mg / g (applicable to 5 species).

[0485] 7. The experimental results are shown in Table 10 below:

[0486] Table 10

[0487] Experimental conclusion:

[0488] The results showed that the compound of this application has relatively stable properties for liver microsomal clearance.

[0489] Example 6: Bidirectional permeability test in MDR1-MDCK II cells

[0490] Cell culture:

[0491] MDR1-MDCK II cells obtained from the Netherlands Cancer Institute will be seeded onto PET membranes in 96-well insert plates and cultured for 4-7 days before use in experiments.

[0492] Validation of monolayer cell integrity:

[0493] The integrity of the monolayer cells was verified by conducting a Luciferox rejection experiment.

[0494] Monolayer cell quality verification:

[0495] The validation was performed in repeat wells by measuring the one-way (A→B) permeability of naldolol (a marker of low permeability), metoprolol (a marker of high permeability), and the two-way permeability of digoxin (a marker of P-glycoprotein substrate).

[0496] Standard test conditions:

[0497] Buffer solution: HBSS (Hank's balanced salt solution) containing 10 mM HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid), pH 7.40 ± 0.05;

[0498] The compound was first dissolved in DMSO solution to a concentration of 1 mM, then diluted with buffer to the test concentration, and then added to the A side of the cells. Test compound concentration: 2.0 μM;

[0499] Number of repetitions: n = 2;

[0500] Direction: Includes bidirectional transportation from A to B and from B to A;

[0501] Incubation conditions: 37±1℃, 5% CO2, relative saturated humidity.

[0502] Preparation of T0 solution:

[0503] 50 μL of the dosing solution (a 2.0 μM solution of the test compound) is mixed with 100 μL of buffer and 250 μL of stop solution containing an appropriate internal standard (IS) (commonly a methanol or acetonitrile solution of 250 nM tolbutamide and 100 nM labetalol) to form the T0 sample.

[0504] Sample processing:

[0505] Add 75 μL (A→B direction) or 250 μL (B→A direction) of the dosing solution (2.0 μM solution of the test compound) to the donor well, and add 250 μL (A→B direction) or 75 μL (B→A direction) of the blank incubation solution (buffer) to the recipient well; after incubation for 2.5 hours, take appropriate volumes of solution from the donor and recipient wells as the dosing end sample and the receiving end sample, respectively, and immediately mix them with the buffer and stop solution. The sample collection method is shown in Table 11 below:

[0506] Table 11

[0507] Sample analysis:

[0508] All samples (including T0 samples, dosing end samples, receiving end samples, and blank samples) will be analyzed using LC-MS / MS. The concentration of the test compound will be expressed as the ratio of the peak area of ​​the analyte to the peak area of ​​the index (IS), without the need for a standard curve.

[0509] The experimental results are shown in Table 12 below:

[0510] Table 12

[0511] Experimental conclusion:

[0512] The results show that the compound of this application has the characteristics of high isopermeability and low efflux.

[0513] Example 7: In vitro protein binding assay of the compound in mouse, rat, dog, monkey and human plasma

[0514] 1. Test matrix

[0515] Frozen plasma from different species (using EDTA-K2 as an anticoagulant, a mixture of plasma from multiple individuals) was used as the test matrix. The plasma could be purchased from a commercial supplier or prepared from animals.

[0516] 2. Positive control

[0517] Warfarin was used as a positive control.

[0518] 3. Test compounds

[0519] The test compound was added to a blank matrix (plasma from humans, mice, rats, dogs, and monkeys; mice: supplier: BioIVT: batch number: MSE504436; dogs: BioIVT BGL142338; monkeys: Guangdong Blooming-spring Biological Technology Development Co., Ltd., MON-EDTA-PPL-20220414; rats: BioIVT RAT567006; humans: Biopredic International PHPLA03K2NFBBK004) to obtain a matrix sample with a final concentration of 2 μM.

[0520] 4. Balanced dialysis

[0521] Add 150 μL of matrix sample to one side of a 96-well balanced dialysis plate (HTD dialysis), and add an equal volume of dialysis buffer (ready-to-use phosphate-buffered saline (PBS); supplier: Thermo Fisher Scientific, catalog number: 28372) to the other side.

[0522] Before incubation, a matrix sample was collected (and balanced with an equal volume of dialysis buffer) as the T0 sample for recovery calculation.

[0523] 5. Incubation conditions

[0524] Place the dialysis plate in a humid incubator and rotate it slowly for 4 hours at a temperature of 37°C.

[0525] 6. Sample processing

[0526] After incubation, samples were taken from the matrix sample side and the dialysis buffer side; plasma samples and buffer samples were obtained.

[0527] Balance the plasma sample with an equal volume of dialysis buffer; then match the buffer sample with an equal volume of blank matrix.

[0528] The balanced sample was quenched with a stop solution containing an internal standard (an acetonitrile solution containing torasemil (250 nM) and labetalol (250 nM).

[0529] 7. Sample Analysis

[0530] Samples were analyzed using LC / MS / MS. The concentration of the test compound in plasma and buffer samples was expressed as the peak area ratio of analyte to internal standard (IS) (no standard curve required).

[0531] 8. The experimental results are shown in Table 13 below:

[0532] Table 13

[0533] 9. Experimental Conclusion:

[0534] The results showed that the compound of this application has a good drug release rate in plasma proteins.

[0535] Example 8: Inhibitory effect of the compound on cytochrome P450 enzyme

[0536] 1. CYP450 enzyme activity assay

[0537] CYP450 enzyme activity was determined using a 5-in-1 probe substrate. For each reaction, enzyme activity was measured at seven non-zero concentrations of the compound (e.g., 0.050, 0.150, 0.500, 1.50, 5.00, 15.0, or 50.0 μM), with each concentration measured once (n=1). A known inhibitor of each isoenzyme was tested repeatedly at a single concentration (1.00 μM or 3.00 μM) (n=2) as a positive control.

[0538] 2. Incubation mixture

[0539] An incubation mixture containing mixed human liver microsomes (Corning, Xenotech, or other qualified suppliers); at 0.200 mg / mL, the probe substrate and standard inhibitor (listed in Table 14 below) or test compound will be heated at 37.0 °C for 10 minutes. The reaction will be initiated by adding NADPH (1.00 mM).

[0540] Table 14

[0541] 3. Reaction terminated

[0542] Ten minutes later, the reaction was terminated by adding pre-cooled acetonitrile containing the internal standard (IS) (an acetonitrile solution containing torasemil (250 nM) and labetalol (250 nM)).

[0543] 4. Measurement of metabolites

[0544] Metabolites generated from the probe substrate were measured using LC MS / MS and evaluated based on the analyte / internal standard peak area ratio.

[0545] 5. Calculation of Remaining Activity

[0546] Calculate the residual activity (expressed as a percentage of control activity). Determine the IC50 of the test compound using a 3- or 4-parameter logistic sigmoid equation from SigmaPlot or XLfit. 50 value.

[0547] 6. The experimental results are shown in Table 15 below:

[0548] Table 15

[0549] 7. Experimental Conclusion:

[0550] The results showed that the compound in this application does not have CYP inhibitory properties.

[0551] Evaluation of the inhibitory activity of compound 9 on hERG potassium ion channels

[0552] Experimental objective:

[0553] The inhibitory effect of the embodiments of the present invention on the potassium ion channel of hERG (human ether-à-go-go related gene) was tested using the fully automated patch-clamp Qpatch technique.

[0554] Cell preparation:

[0555] Chinese hamster ovary cells stably expressing the hERG receptor were cultured in culture flasks. When the cell density reached 60–80%, the culture medium (composition: 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 μg / mL G418 (Invitrogen), and 100 μg / mL Hygromycin B (Invitrogen)) was removed. The cells were washed once with 7 mL of phosphate-buffered saline, and then digested with 3 mL of cell dissociation reagent. After complete digestion, 3 mL of culture medium was added for neutralization, followed by centrifugation. The supernatant was removed, and the cells were resuspended in 5 mL of culture medium to ensure a cell density of 2–5 × 10⁶ cells / mL. 6 / mL.

[0556] Patch clamp testing:

[0557] In whole-cell recording mode, the cell membrane was clamped at -80 mV. Before a 5-second +40 mV depolarization stimulus, a 50-millisecond -50 mV pre-voltage was applied, followed by repolarization to -50 mV for 5 seconds, then back to -80 mV. This voltage stimulus was applied every 15 seconds, and after 2 minutes of recording, extracellular fluid was administered for 5 minutes of recording before the drug delivery process began. Compound concentrations were started at the lowest test concentration, and each test concentration was administered for 2.5 minutes.

[0558] Data processing:

[0559] Data analysis and processing were performed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of hERG potassium current (the peak hERG tail current induced at -50mV) by different compound concentrations was calculated using the following formula:

[0560] Inhibition%=[1–(I / Io)]×100%

[0561] Wherein, Inhibition% represents the percentage by which the compound inhibits the hERG potassium current, and the IC50 of the compound is calculated using Inhibition%. 50 Values. I and Io represent the amplitudes of the hERG potassium current before and after drug administration, respectively.

[0562] The IC50 of the compound was calculated using GraphPad Prism 8 software by fitting the following equation:

[0563] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0564] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0565] The experimental results are shown in Table 16 below:

[0566] Table 16

[0567] Experimental conclusion:

[0568] The results of the inhibitory effect of the compounds of this invention on the hERG potassium ion channel are shown in the table above. It can be seen that the compounds of this invention have a low risk of inhibiting the hERG potassium ion channel, even reaching levels above 10 μM.

Claims

1. A compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. L 1 For connecting bonds, C1-C6 alkylene groups, -O-, #1 -CR x R y -O- or #1 -O-CR x R y -, #1 The end is connected to ring A; Each R x and R y Independently hydrogen or C1-C6 alkyl; Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R... a The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-12 membered bicyclic heterocyclic alkyl group with one, two, or three heteroatoms; and the ring B is connected to L via a carbon atom. 1 Connected; Each R a Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" or a C1-C6 alkyl substituted with one or more halogens; L 2 For methylene or linking bonds; each R 1 Independently hydrogen, halogen, -CN, -OH, phenyl, C1-C6 alkyl, C1-C6 alkoxy, -NR 1-3 R 1-4 -C(=O)NR 1-3 R 1-4 , by one or more R 1-1 Substituted C1-C6 alkyl groups or those with one or more R 1-2 Substituted C1-C6 alkoxy groups; n is 0, 1, 2, or 3; Or, two adjacent R 1 The atoms connected to them together form a group consisting of one or more R atoms. m The substituted C3-C7 cycloalkenyl group or the group with one or more R m The substituted heteroatom is "a 3-7 membered heterocyclic alkenyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms"; Each R m Independently hydrogen, halogen, -CN, -OH, phenyl, C1-C6 alkyl, C1-C6 alkoxy, -NR 1-3 R 1-4 -C(=O)NR 1- 3 R 1-4 , by one or more R 1-1 Substituted C1-C6 alkyl groups or those with one or more R 1-2 Substituted C1-C6 alkoxy groups; R 1-1 and R 1-2 Each is an independent halogen; R 1-3 and R 1-4 Each independently of hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogens; R 1-1-1 It is a C1-C6 alkyl group; Ring A is "a 5-10 membered heteroaromatic ring with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three"; The ring C is "a 5-membered heteroaromatic ring with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three"; m can be 0, 1, 2, or 3; R 2 Independent of halogen, -NR 2-1 R 2-2 C1-C6 alkyl groups or those with one or more R 2-3 Substituted C1-C6 alkyl groups; R 2-1 and R 2-2 Each independently is hydrogen, C1-C 10 alkyl, Or C3-C7 cycloalkyl; R 2-4 For C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 alkenyl or -NR 2-4-1 R 2-4-2 ; R 2-4-1 and R 2-4-2 Each is independently hydrogen or C1-C 10 alkyl; R 2-5 For C1-C 10 alkyl; R 2-3 for 2. The compound of Formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, It satisfies any one of the following conditions; (1) The definition is Case 1: L 1 For -O-, #1 -CR x R y -O- or #1 -O-CR x R y -, #1 The end is connected to ring A; Each R x and R y Independently hydrogen or C1-C6 alkyl; Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R... a The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-12 membered bicyclic heterocyclic alkyl group with one, two, or three heteroatoms; and the ring B is connected to L via a carbon atom. 1 Connected; Each R a Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" or a C1-C6 alkyl substituted with one or more halogens; L 2 Methylene or linking bond; (2) The definition is case 2: L 1 It is a linking bond or a C1-C6 alkylene group; Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R... a The substituted heteroatom is a 5-12 membered bicyclic heterocyclic alkyl group selected from N, O, and S, with one, two, or three heteroatoms; and the ring B is connected to L via a carbon atom. 1 Connected; R a For R r ; Each R r Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl or a C1-C6 alkyl substituted with one or more halogens, with one, two or three heteroatoms selected from N, O and S"; L 2 -CH2- or a connecting key; Preferably, it satisfies any one of the following conditions; (1) In case 2 described above, L 1 It is a C1-C6 alkylene group; (2) In cases 1 and 2, ring B is connected to L via nitrogen atoms. 2 Connected.

3. A compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. Each R 1 Independently hydrogen, halogen, -CN, -OH, phenyl, C1-C6 alkyl, C1-C6 alkoxy, -NR 1-3 R 1-4 -C(=O)NR 1- 3 R 1-4 , by one or more R 1-1 Substituted C1-C6 alkyl groups or those with one or more R 1-2 Substituted C1-C6 alkoxy groups; n is 0, 1, 2, or 3; Or, two adjacent R 1 The atoms connected to them together form a group consisting of one or more R atoms. m The substituted C3-C7 cycloalkenyl group or the group with one or more R m The substituted heteroatom is "a 3-7 membered heterocyclic alkenyl group selected from one, two or three of N, O and S, and having one, two or three heteroatoms"; Each R m Independently hydrogen, halogen, -CN, -OH, phenyl, C1-C6 alkyl, C1-C6 alkoxy, -NR 1-3 R 1-4 -C(=O)NR 1- 3 R 1-4 , by one or more R 1-1 Substituted C1-C6 alkyl groups or those with one or more R 1-2 Substituted C1-C6 alkoxy groups; R 1-1 and R 1-2 Each is an independent halogen; R 1-3 and R 1-4 Each independently of hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted with one or more halogens; R 1-1-1 It is a C1-C6 alkyl group; Ring A is "a 5-10 membered heteroaromatic ring with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three" or C6-C 10 Aromatic rings; The ring C is "a 5-membered heteroaromatic ring with one, two, or three heteroatoms selected from N, O, and S, and the number of heteroatoms is one, two, or three"; m can be 0, 1, 2, or 3; R 2 Independent of halogen, -NR 2-1 R 2-2 C1-C6 alkyl groups or those with one or more R 2-3 Substituted C1-C6 alkyl groups; R 2-1 and R 2-2 Each independently is hydrogen, C1-C 10 alkyl, Or C3-C7 cycloalkyl; R 2-4 For C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 alkenyl or -NR 2-4-1 R 2-4-2 ; R 2-4-1 and R 2-4-2 Each is independently hydrogen or C1-C 10 alkyl; R 2-5 For C1-C 10 alkyl; R 2-3 for The definition is any of the following cases: Scenario 1: L 1 For -O-, #1 -CR x R y -O- or #1 -O-CR x R y -, #1 The end is connected to ring A; Each R x and R y Independently hydrogen or C1-C6 alkyl; Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R... a The substituted heteroatom is selected from one, two, or three of N, O, and S, and is a 5-12 membered bicyclic heterocyclic alkyl group with one, two, or three heteroatoms. Each R a Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" or a C1-C6 alkyl substituted with one or more halogens; L 2 Methylene or linking bond; Scenario 2: L 1 For connection key; Ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one or more R... r The substituted heteroatom is a 5-12 membered bicyclic heterocyclic alkyl group selected from N, O, and S, with one, two, or three heteroatoms; simultaneously, ring B is not... z and q are independently 0 or 1, and not both 0 at the same time; Each R r Independently, it is a C1-C6 alkyl, halogen, C3-C6 cycloalkyl, C1-C6 alkoxy, "a 3-6 membered heterocycloalkyl with one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" or a C1-C6 alkyl substituted with one or more halogens; L 2 For -CH2- or a connecting key.

4. The compound of formula I as claimed in any one of claims 1-3, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, It satisfies one or more of the following conditions; (1) Each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; for example, methyl; (2) Each "C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; for example, methoxy; (3) The "5-10 membered heteroaromatic ring" is a "5-6 membered heteroaromatic ring" in which the heteroatoms are selected from one or two types of N and O, and the number of heteroatoms is two or three; for example For example, (4) The "5-membered heteroaromatic ring" is a "5-6-membered heteroaromatic ring" in which the heteroatoms are selected from one or two types of N and S, and the number of heteroatoms is two; for example (5) Each "halogen" is independently fluorine, chlorine, bromine or iodine; for example, fluorine; (6) Each "C1-C 10 "alkyl" is independently a C1-C6 alkyl; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl; and for another example, methyl; (7) In case 1, each "5-12 membered bicyclic heterocyclic alkyl group" is independently a 6-10 membered bicyclic heterocyclic alkyl group with N heteroatom and 1 heteroatom; for example... For example, and (8) In case 2, each "5-12 membered bicyclic heterocyclic alkyl group" is independently an 8-10 membered bicyclic heterocyclic alkyl group with N and O heteroatoms and two heteroatoms; for example...

5. The compound of Formula I as claimed in any one of claims 1-3, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, It satisfies one or more of the following conditions; (1) The R 1 Independently, it is a C1-C6 alkyl or C1-C6 alkoxy group; (2) n is 1; (3) The ring A is "a 5-10 membered heteroaromatic ring with one, two or three heteroatoms selected from N, O and S, and the number of heteroatoms is one, two or three"; (4) The value of m is 2; (5) The R 2 Independently halogen or -NR 2-1 R 2-2 ; (6) The R 2-1 and R 2-2 Each independently is hydrogen or (7) The R 2-4 For C1-C 10 alkyl; (8) In case 1, the L 1 for #1 -O-CR x R y -, #1 The end is connected to ring A; (9) In case 1, each of the R x and R y Independently hydrogen; (10) In case 1, ring B is "a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two or three of N, O and S, with one, two or three heteroatoms"; (11) In case 1, each of the R a Independently, it is a C1-C6 alkyl group; (12) In case 1, the L 2 It is methylene; (13) In case 2, the ring B is surrounded by one or more R r The substituted heteroatom is a 5-12 membered bicyclic heterocyclic alkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms; meanwhile, ring B is not... z and q are independently 0 or 1, and not both 0 at the same time; (14) In case 2, each of the R r Independently C1-C6 alkyl; and (15) In case 2, each of the L 2 It is -CH2-.

6. The compound of formula I as claimed in any one of claims 1-3, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, In case 2, ring B is a 5-12 membered bicyclic heterocyclic alkyl group with heteroatoms of "N and O" or "N, O and S" and 2, 3 or 4 heteroatoms, or is surrounded by one or more R atoms. r The substituted heteroatoms are "N and O" or "N, O and S", and the number of heteroatoms is 2, 3 or 4 in a 5-12 membered bicyclic heterocyclic alkyl group.

7. The compound of Formula I as claimed in claim 6, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, In scenario 2, ring B is surrounded by one or more R... r The substituted heteroatoms are "N and O" or "N, O and S", and the number of heteroatoms is 2, 3 or 4 in a 5-12 membered bicyclic heterocyclic alkyl group.

8. The compound of formula I as claimed in any one of claims 1-3, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, It satisfies one or more of the following conditions; (1) The ring A is For example, (2) The R 1 It is methyl or methoxy; (3) The In the definition, in case 1, The L 1 For -O-, #1 -CH2-O- or #1 -O-CH2-, #1 The end is connected to ring A; The ring B is #2 End and L 1 Connected, #3 End and L 2 Connected, w can be 0, 1, 2, 3, or 4; for example Preferably; the ring B is #2 End and L 1 Connected, #3 End and L 2 Connected, w can be 0, 1, 2, or 3; for example, The L 2 Methylene or linking bond; (4) In the definition, in case 2, The L 1 It is a linking bond or a C1-C6 alkyl group; Preferably, the L 1 For connection key; The ring B is #4 End and L 1 Connected, #5 End and L 2 Connected, v can be 0, 1, 2, 3, or 4; for example, Preferably, the ring B is #4 End and L 1 Connected, #5 End and L 2 Connected, v can be 0, 1, 2, or 3; for example, The L 2 It is -CH2-; (5) The ring C is and (6) The R 2 Fluorine or 9. The compound of Formula I as claimed in any one of claims 1-3, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, The compound shown in Formula I is a compound shown in Formula I-1, Formula I-2 or Formula I-3 as follows: in, The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof; R 1 R 2 Ring A, Ring C, m, n and R a The definition is as described in any one of claims 1-8; n1 is 0, 1, 2, 3 or 4; L 1 For -O-, #1 -CR x R y -O- or #1 -O-CR x R y -, #1 The end is connected to ring A; each R x and R y Independently hydrogen or C1-C6 alkyl; In the compounds shown in Formula I-1 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 The definition is any of the following schemes: Option 1, R 3 R 4 R 5 R 6 and R 9 It is hydrogen; R 7 and R 8 The atoms bonded to them together form a 3-6 member nitrogen-containing saturated heterocycle. In the nitrogen-containing saturated heterocycle, in addition to nitrogen, the heteroatom can also be selected from one or two of O and S. The number of heteroatoms is 1, 2 or 3. Option 2, R 5 R 7 R 8 and R 4 It is hydrogen; R 6 It is a C1-C6 alkyl group; R 3 and R 9 The atoms bonded to them together form 3-6 member oxygen-containing saturated heterocycles. In the oxygen-containing saturated heterocycles, in addition to oxygen, the heteroatoms can also be selected from one or two of N and S. The number of heteroatoms is 1, 2 or 3. Option 3, R 4 R 7 R 8 and R 9 It is hydrogen; R 6 It is a C1-C6 alkyl group; R 3 and R 5 The atoms bonded to them together form 3-6 member oxygen-containing saturated heterocycles. In the oxygen-containing saturated heterocycles, in addition to oxygen, the heteroatoms can also be selected from one or two of N and S. The number of heteroatoms is 1, 2 or 3. Option 4, R 3 R 4 R 6 R 8 and R 9 It is hydrogen; R 5 and R 7 The atoms connected to them together form C3-C6 saturated carbon rings; Option 5, R 3 R 4 R 5 R 8 and R 9 It is hydrogen; R 6 and R 7 The atoms connected to them together form C3-C6 saturated carbon rings; Option 6, R 3 R 5 R 6 R 8 and R 9 It is hydrogen; R 4 and R 7 Together they form C1-C4 alkylene groups; In the compound shown in Formula I-2, R 10 R 11 and R 12 The definition is any of the following schemes: Option 1, R 12 For hydrogen, R 10 and R 11 The atoms connected to them together form C3-C6 saturated carbon rings; Option 2: R 10 For hydrogen, R 11 and R 12 The atoms connected to them together form C3-C6 saturated carbon rings; In the compound shown in Formula I-3, ring D is a C3-C6 saturated carbon ring, and ring D is related to L. 1 The connected carbon atoms are in the R configuration, S configuration, or a mixture thereof.

10. The compound of Formula I as claimed in any one of claims 1-3, its pharmaceutically acceptable salt, its solvate, a solvate of its pharmaceutically acceptable salt, or a stereoisomer thereof, characterized in that, The compound shown in Formula I is the same as the compound shown in Formulas I-4 below: in, The carbon atoms marked with "*" have the R configuration, S configuration, or a mixture thereof; R 1 R 2 The definitions of ring A, ring C, m, and n are as described in any one of claims 1-9; In the compounds shown in Formula I-4 R 13 It is a C1-C6 alkyl group; R 14 and R 15 The atoms bonded to them together form a 3-6 member oxygen-containing saturated heterocycle. In the oxygen-containing saturated heterocycle, in addition to oxygen, the heteroatom can also be selected from one or both of N and S. The number of heteroatoms is 1, 2 or 3.

11. A compound as shown below: or, (where carbon atoms marked with "*" indicate chiral carbon atoms) Among a pair of enantiomers, the compound that elutes first under the following conditions: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); gradient: 15%-15%; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the first eluting compound is 2.7-3.8min; preferably, the "one pair of enantiomers" are the one pair of enantiomers that elute first under the following achiral conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v); Among a pair of enantiomers, the compound that elutes later under the following conditions: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min; Preferably, under the conditions described, the retention time of the later-eluting compound is 4.4-6.2min; Preferably, the "one pair of enantiomers" refers to the one pair of enantiomers that elute first under the following achiral conditions: silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1, v / v); The compound that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 2.7-3.8min. Compounds that elute later under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); gradient: 15%-15%; flow rate: 120ml / min; preferably, under the conditions described, the retention time of the later-eluting compounds is 4.4-6.2min. The compound that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 25%-25%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 5.1-6.0min. Compounds that elute later under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 25%-25%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 6.5-8.3min. The first eluting compound under the following conditions: column: Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol / L ammonium bicarbonate aqueous solution, flow rate: 20mL / min, gradient: 28-40%; preferably, under the conditions described, the retention time of the first eluting compound is 8.1-8.7min; Compounds eluting later under the following conditions: chromatographic column: Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-10mmol / L ammonium bicarbonate aqueous solution, flow rate: 20mL / min, gradient: 28-40%; preferably, under the conditions described, the retention time of compounds eluting later is 9.4-10.01min; The compound that elutes first under the following conditions: chromatographic column: Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-0.05% ammonia aqueous solution, flow rate: 20mL / min, gradient: 33-43%; preferably, under the conditions described, the retention time of the compound that elutes first is 7.2-7.7min; Compounds that elute later under the following conditions: Waters-XBridge-C18-10μm-19*250mm, mobile phase: acetonitrile-0.05% ammonia aqueous solution, flow rate: 20mL / min, gradient: 33-43%; preferably, under the conditions described, the retention time of compounds that elute later is 9.6-10.3min. The compound that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 120mL / min; Preferably, under the conditions described, the retention time of the first eluting compound is 3.8-5.7min; Compounds that elute later under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 120mL / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 6.8-9.7min. The compound that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 3.2-5.1min; Compounds that elute later under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 6.3-9.4min. The compound that elutes first under the following conditions: Column: Waters SFC 80, 250*25mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 80ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 8.5-11.5min. Compounds that elute later under the following conditions: Column: Waters SFC 80, 250*25mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 45%-55%; Flow rate: 80ml / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 12.0-17.3min. The compound that elutes first under the following conditions: Column: Waters SFC 80, 250*25mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 3.2-5.1min. Compounds that elute later under the following conditions: Waters SFC 80, 250*25mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-15%; Flow rate: 120ml / min; Preferably, under the conditions described, the retention time of the later-eluting compounds is 6.3-9.4min. The substance that elutes first under the following conditions: Column: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-85%; Flow rate: 140ml / min; Preferably, under the conditions described, the retention time of the first eluting compound is 13.0-14.2min. Substances that elute later under the following conditions: Waters SFC 150, 250*30mm 10μm; Mobile phase A: supercritical CO2, Mobile phase B: methanol (with 0.1% 7.0mol / L ammonia methanol solution); Gradient: 15%-85%; Flow rate: 140ml / min. Preferably, under the conditions described, the retention time of the later-eluting compounds is 15.9-20.0min.

12. A pharmaceutical composition comprising: (1) The compound of Formula I as claimed in any one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and (2) Pharmaceutically acceptable excipients.

13. Use of the compound of Formula I as claimed in any one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition of claim 12, in the preparation of a medicament for the prevention and / or treatment of Alzheimer's disease.

14. Use of the compound of Formula I as claimed in any one of claims 1-11, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or the pharmaceutical composition of claim 12, wherein the use is selected from: (1) Preparation of O-acetylglucosidase (O-GlcNAcase, or OGA) inhibitors; (2) Prepare drugs for the treatment and / or prevention of diseases associated with O-acetylglucosidase; the diseases associated with O-acetylglucosidase may be Alzheimer's disease.

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