IRAK4 degradation agent and application thereof

Abstract

The invention relates to an IRAK4 degradation agent and application thereof, in particular to a bifunctional compound shown in the following formula (I), an isomer, a deuterated substance or pharmaceutically acceptable salt of the bifunctional compound, and application of the compound in treating IRAK4-mediated related diseases. # imgabs0 #

Description

IRAK4 degraders and their applications

[0001] This application claims priority to Chinese Patent Application No. 2023102043068, filed on March 3, 2023, Chinese Patent Application No. 2023105328859, filed on May 11, 2023, Chinese Patent Application No. 2023107154349, filed on June 15, 2023, Chinese Patent Application No. 2023110041666, filed on August 9, 2023, and Chinese Patent Application No. 2024101967699, filed on February 22, 2024. The entire text of the above-mentioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] The present disclosure belongs to the field of medicine, and specifically relates to a compound that binds to interleukin-1 receptor-associated kinase 4 (IRAK4), its isomers, its deuterated products or pharmaceutically acceptable salts thereof, and its pharmaceutical composition, preparation method and medical use. Background Art

[0003] Proteolysis-targeting chimeras (PROTACs) are a newly emerging drug discovery technology. Unlike traditional small molecule inhibitors, PROTACs work by delivering these proteins to the proteasome for complete degradation, defying the traditional definition of a drug. Compared to traditional small molecule inhibitors, PROTACs offer several advantages, such as transforming targets from "undruggable" to "druggable," avoiding reliance on "space-occupying" mechanisms, and addressing drug resistance.

[0004] PROTAC is a bifunctional conjugate molecule consisting of three parts: one end is a ligand structure targeting the target protein (TBM, a small molecule inhibitor or common functional group that can recognize the target protein); the other end is a ligand structure that can recruit a protein degradation system, such as an E3 ligase; and in the middle is a connector (linker) connecting the two ligands. PROTAC molecules bind to the target protein (TBM) and bring the target protein and the E3 ligase together, allowing E3 to ubiquitinate and tag the target protein (the E2 enzyme connected by the E3 ligase brings the TBM to a sufficiently close adjacent position for polyubiquitination). The ubiquitinated target protein can be degraded through the proteasome pathway. There are more than 600 E3 ligases in the human body, but so far only about 10 have been developed as protein degraders (CRBN, VHL, IAP, MDM2, DCAF15, DCAF16 and RNF114, etc.). The most widely used are CRBN and VHL. These two E3 ligases have the highest domain of action and can flexibly and efficiently degrade a wide range of target proteins. Their relatively wide expression can achieve high levels of systemic degradation.

[0005] Interleukin-1 receptor-associated kinase 4 (IRAK-4) is a member of the IRAK family of intracellular serine-threonine kinases. It mediates inflammatory signaling pathways mediated by Toll-like receptor (TLR) and IL-1 receptor (IL-1R) activation, playing a connecting role in innate immune signaling. IRAK4 can be activated by being recruited by MyD88 to form the Myddosome, which in turn activates downstream IRAK1 / 2, leading to their subsequent hyperphosphorylation, dissociation from the complex, and binding to TRAF6. The activated TRAF6 complex triggers downstream signaling pathways to produce proinflammatory cytokines (NF-κB, CREB, AP-1, IRFs, etc.). Inhibition of IRAK4 may play a crucial role in the pathogenesis and progression of inflammatory diseases. Currently, no inhibitors targeting IRAK4 have been approved. Therefore, knocking out IRAK4 using PROTAC technology may be an alternative strategy for treating IRAK4-related diseases.

[0006] KT-474, developed by Kymera, is an effective, highly selective, orally bioavailable IRAK4 degrader. It targets IRAK4 primarily by acting as a heterobifunctional molecule—binding to IRAK4 and recruiting E3 ubiquitin ligase to "tag" IRAK4, thereby utilizing the proteasome degradation system to degrade IRAK4. KT-474 is primarily used to treat IL-1R / TLR-driven diseases, including atopic dermatitis (HS) and hidradenitis suppurativa (AD), as well as rheumatoid arthritis (RA) and other inflammatory diseases. In preclinical studies, KT-474 has potent anti-inflammatory activity. Results from healthy patients in a Phase I clinical trial showed that a single dose of KT-474 dose-dependently reduced the levels of IRAK4 and various proinflammatory cytokines, with good safety and tolerability.

[0007] Although IRAK4 degraders are currently under development for the treatment of inflammatory diseases, there is still great uncertainty before these products can be marketed. Clinically, there is still a lack of drugs with structural diversity, therapeutic differentiation, and good safety. Therefore, the continued development of new IRAK4 degraders to increase the types of clinical samples and increase patient accessibility is still of great clinical significance.

[0008] Summary of the Invention

[0009] The present disclosure provides a bifunctional compound targeting IRAK4 (i.e., a protac molecule targeting IRAK4), which can effectively recruit IRAK4 to E3 ubiquitin ligase for degradation.

[0010] The bifunctional compound targeting IRAK4 disclosed in the present invention, i.e., an IRAK4 degrader, is a triplet compound comprising a target structure, a linker, and a degrader, as shown in formula (X).

[0011] Among them, the target structure can specifically bind to the target protein, such as IRAK protein, and is connected to the linker through a covalent bond in the triplet compound; the linker is the connecting group between the target structure and the degrader, one end is covalently bound to the target structure, and the other end is covalently bound to the degrader; the degrader can bind to the ubiquitin ligase, such as E3 ubiquitin ligase, and is covalently bound to the linker.

[0012] Specifically, in the first aspect, the present disclosure provides a bifunctional compound represented by the following general formula (I), its isomer, its deuterated product or a pharmaceutically acceptable salt thereof,

[0013] Wherein, ring C is phenyl, 5-6 membered heteroaryl, 9-10 membered fused heteroaryl;

[0014] R 1 Selected from -CN, -NR 1a R1b 、-OH、halogen、C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocyclic group, 7-9 membered bridged heterocyclic group, 6-10 membered fused heterocyclic group, 3-6 membered cycloalkyl-NH-, phenyl, 5-6 membered heteroaryl, 9-10 membered fused heteroaryl, wherein the heterocyclic group, bridged heterocyclic group, fused heterocyclic group, cycloalkyl, heteroaryl, fused heteroaryl are optionally substituted by one or more Rx, wherein Rx is selected from -NH2, -NR 1a R 1b 、-CN、-OH、halogen、C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0015] R 1a 、R 1b are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group-C 1-6 alkyl-;

[0016] m is selected from 0, 1, 2, 3, 4;

[0017] Ring B is selected from 5-6 membered heteroaryl, 9-10 membered fused heteroaryl;

[0018] R 2 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy;

[0019] q is selected from 0, 1, 2, 3, 4;

[0020] Lx is -C(O)-NR La -;

[0021] R La Selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl;

[0022] Ring A is selected from a divalent group optionally substituted by one or more Rz: 7-11 membered spirocycloalkyl, 7-11 membered spiroheterocyclyl, 7-9 membered bridged cycloalkyl, 7-9 membered bridged heterocyclyl, wherein Rz is selected from halogen, -OH, -NH2, C1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl;

[0023] L is -(B 1 )n1-(B 2 )n2-(B 3 )n3-;

[0024] B 1 C 1-6 Alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n1 is selected from 0, 1;

[0025] B 2 Selected from the following divalent rings optionally substituted with one or more Ry: C 3-6 Cycloalkylene, C 5-8 alkylene bridged, 4-6 membered heterocyclylene, 6-8 membered heterocyclylene bridged, phenylene, 6-8 membered heterocycloalkenylene, wherein Ry is selected from oxo, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl; n2 is selected from 0, 1;

[0026] B 3 Selected from saturated or unsaturated C 1-6 An alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n3 is selected from 0, 1;

[0027] R a 、R b are independently selected from H, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and R a 、R b Not at the same time H;

[0028] Alternatively, R on the same carbon atom a 、R b Together with the carbon atom to which it is connected, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group;

[0029] R c Selected from H, C 1-6 alkyl;

[0030] Degradons are ligands that bind to E3 enzymes.

[0031] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated product or its pharmaceutically acceptable salt has the structure shown in the following formula (IA):

[0032] Among them, R 1 Selected from -CN, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heterocyclic group, 7-9 membered bridged heterocyclic group, 6-10 membered fused heterocyclic group, 3-6 membered cycloalkyl-NH-, wherein the heterocyclic group, bridged heterocyclic group, fused heterocyclic group, cycloalkyl are optionally substituted by one or more Rx, wherein Rx is selected from -NH2, -OH, halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0033] m is selected from 0, 1, 2, 3, 4;

[0034] R 2 Selected from C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0035] Ring A is selected from the following divalent groups: 7-11 membered spirocycloalkylene, 7-11 membered spiroheterocyclylene, 7-9 membered bridged cycloalkylene, 7-9 membered bridged heterocyclylene;

[0036] L is selected from -(B 1 )n1-(B 2 )n2-(B 3 )n3-;

[0037] B 1 Selected from C 1-3 Alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n1 is selected from 0, 1;

[0038] B 2 Selected from the following divalent rings optionally substituted with one or more Ry: C 3-6 Cycloalkylene, C 5-8 alkylene bridged, 4-6 membered heterocyclylene, 6-8 membered heterocyclylene bridged, phenylene, 6-8 membered heterocycloalkenylene, wherein Ry is selected from oxo, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl; n2 is selected from 0, 1;

[0039] B3 Selected from saturated or unsaturated C 1-6 An alkylene chain wherein any methylene unit thereof is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n3 is selected from 0, 1;

[0040] R a 、R b are independently selected from H, deuterium, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, and R a 、R b Not at the same time H;

[0041] Alternatively, R on the same carbon atom a 、R b Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group;

[0042] R c Selected from H, C 1-4 alkyl.

[0043] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated substance or its pharmaceutically acceptable salt,

[0044] Among them, R 1 Selected from -CN, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heterocyclic group, 7-9 membered bridged heterocyclic group, 6-10 membered fused heterocyclic group, 3-6 membered cycloalkyl-NH-, wherein the heterocyclic group, bridged heterocyclic group, fused heterocyclic group, cycloalkyl are optionally substituted by one or more Rx, wherein Rx is selected from -NH2, -OH, halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0045] m is selected from 0, 1, 2, 3, 4;

[0046] R 2 Selected from C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0047] Ring A is selected from the following divalent groups: 7-11 membered spirocycloalkylene, 7-11 membered spiroheterocyclylene, 7-9 membered bridged cycloalkylene, 7-9 membered bridged heterocyclylene;

[0048] L is selected from -(B 1 )n1-(B 2)n2-(B 3 )n3-;

[0049] B 1 Selected from C 1-3 Alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n1 is selected from 0, 1;

[0050] B 2 Selected from the following divalent rings optionally substituted with one or more Ry: C 3-6 Cycloalkylene, C 6-8 alkylene bridged, 4-6 membered heterocyclylene, 6-8 membered heterocyclylene bridged, phenylene, 6-8 membered heterocycloalkenylene, wherein Ry is selected from oxo, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl; n2 is selected from 0, 1;

[0051] B 3 Selected from saturated or unsaturated C 1-6 An alkylene chain wherein any methylene unit thereof is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n3 is selected from 0, 1;

[0052] R a 、R b are independently selected from H, deuterium, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, and R a 、R b Not at the same time H;

[0053] Alternatively, R on the same carbon atom a 、R b Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group;

[0054] R c Selected from H, C 1-4 alkyl.

[0055] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated substance or its pharmaceutically acceptable salt,

[0056] Among them, R 1 Selected from -CN, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4Alkoxy, 5-6 membered heterocyclic group, 7-9 membered bridged heterocyclic group, 6-10 membered fused heterocyclic group, 3-6 membered cycloalkyl-NH-, wherein the heterocyclic group, bridged heterocyclic group, fused heterocyclic group, cycloalkyl are optionally substituted by one or more Rx, wherein Rx is selected from -NH2, -OH, halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0057] m is selected from 0, 1, 2, 3, 4;

[0058] R 2 Selected from C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0059] Ring A is selected from the following divalent groups: 7-11 membered spirocycloalkylene, 7-11 membered spiroheterocyclylene, 7-9 membered bridged cycloalkylene, 7-9 membered bridged heterocyclylene;

[0060] L is selected from -(B 1 )n1-(B 2 )n2-(B 3 )n3-;

[0061] B 1 Selected from C 1-3 Alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n1 is selected from 0, 1;

[0062] B 2 Selected from the following divalent rings optionally substituted with one or more Ry: C 3-6 Cycloalkylene, C 6-8 Sub-bridged cycloalkyl, 4-6 membered heterocyclyl, 6-8 membered heterocyclyl, wherein Ry is selected from oxo, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl; n2 is selected from 0, 1;

[0063] B 3 Selected from saturated or unsaturated C 1-6 An alkylene chain wherein any methylene unit thereof is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n3 is selected from 0, 1;

[0064] R a 、R b are independently selected from H, halogen, C 1-4 Alkyl, halogenated C1-4 Alkyl, and R a 、R b Not at the same time H;

[0065] Alternatively, R on the same carbon atom a 、R b Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group;

[0066] R c Selected from H, C 1-4 alkyl.

[0067] In another preferred embodiment, the heteroatoms in the heterocyclic group, bridged heterocyclic group, fused heterocyclic group, heteroaryl group, fused heteroaryl group, and spiro heterocyclic group are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is independently 1, 2, 3, or 4.

[0068] In another preferred embodiment, wherein R 1 Selected from -CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic group, 7-9 membered bridged heterocyclic group, 6-10 membered fused heterocyclic group, 3-6 membered cycloalkyl-NH-.

[0069] In another preferred embodiment, wherein R 1 is selected from 7-9 membered bridged heterocyclic groups.

[0070] In another preferred embodiment, wherein R 1 Selected from -F, -CH3, -CN, -CHF2, -CF3, -OCH3,

[0071] m is selected from 1 or 2.

[0072] In another preferred embodiment, wherein R 1 Selected from

[0073] In another preferred embodiment, the Rx is selected from -NH2 or C 1-6 alkyl.

[0074] In another preferred embodiment, m is selected from 1 or 2, preferably 1.

[0075] In another preferred embodiment, ring B is a 5-6 membered heteroaryl group.

[0076] In another preferred embodiment, R 2 C 1-6 Alkyl or halogenated C 1-6 Alkyl, preferably halogenated C 1-6alkyl.

[0077] In another preferred embodiment, wherein R 2 Selected from -CH3, -CH2F, -CHF2, -CF3.

[0078] In another preferred embodiment, wherein R 2 Selected from -CHF2.

[0079] In another preferred embodiment, q is 1.

[0080] In another preferred embodiment, Lx is -C(O)-NR La -*, where the * end is connected to ring B.

[0081] In another preferred embodiment, ring A is selected from the following unsubstituted divalent groups: 7-11 membered spirocycloalkylene, 7-11 membered spiroheterocyclylene, 7-9 membered bridged cycloalkylene, 7-9 membered bridged heterocyclylene.

[0082] In another preferred embodiment, ring A is a 7-9 membered nitrogen-containing spiroheterocyclic group.

[0083] In another preferred embodiment, wherein ring A is selected from The "a" terminal refers to a terminal connected to L in the general formula (IA).

[0084] In another preferred embodiment, wherein ring A is selected from

[0085] In another preferred embodiment, in L, -(B 3 )n3-end is connected to the degrader.

[0086] In another preferred embodiment, wherein L is selected from -B 1 -B 2 -B 3 -, or -B 1 -B 3 -, or -B 2 -B 3 -; preferably, -B 3 -end is connected to the degradation subunit.

[0087] In another preferred embodiment, wherein L is selected from -B 1 -B 2 -B 3 -; preferably, -B 3 -end is connected to the degradation subunit.

[0088] In another preferred embodiment, wherein L is selected from -B 3 -.

[0089] In another preferred embodiment, wherein B 1 Selected from C 1-3 Alkylene chain, 1-2 methylene units of which are optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-; preferably, 1 methylene unit is optionally replaced by -C(O)-.

[0090] In another preferred embodiment, wherein B 3 Selected from unsaturated C 2-6 Hydrocarbylene chains, wherein 1-2 methylene units are optionally replaced by -O-, -C(O)-, -C(R a )(R b )- replaced; the alkylene chain is connected to the degradation unit through the alkynyl end; preferably, one methylene unit is optionally replaced by -O-.

[0091] In another preferred embodiment, wherein R a 、R b are independently selected from H, deuterium, -CH3; and R a 、R b Not at the same time H;

[0092] Alternatively, R on the same carbon atom a 、R b Together with the carbon atom to which it is connected, it forms a cyclopropyl or cyclobutyl group.

[0093] In another preferred embodiment, wherein R c Selected from H, -CH3; preferably H.

[0094] In another preferred embodiment, wherein B 2 Selected from the following groups: Preferred

[0095] In another preferred embodiment, wherein B 2 Selected from the following groups: Where the b end is connected to -(B 3 )n3-connected; preferably

[0096] In another preferred embodiment, wherein B 1 Selected from C 1-3 Alkylene chain, 1-2 methylene units of which are optionally replaced by -O-, -C(O)-, -C(Ra )(R b )-、-N(R c )-replaced;

[0097] B 3 Selected from unsaturated C 2-6 Hydrocarbylene chains, wherein 1-2 methylene units are optionally replaced by -O-, -C(O)-, -C(R a )(R b )-replaced; the alkylene chain is connected to the degradation sub-terminal via the alkynyl end;

[0098] R a 、R b are independently selected from H, deuterium, -CH3; and R a 、R b Not at the same time H;

[0099] Alternatively, R on the same carbon atom a 、R b Together with the carbon atom to which it is attached, it forms a cyclopropyl or cyclobutyl group;

[0100] R c Selected from H, -CH3;

[0101] B 2 Selected from the following groups:

[0102] In another preferred embodiment, wherein B 1 Selected from C 1-3 Alkylene chain, 1-2 methylene units of which are optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-replaced;

[0103] B 3 Selected from unsaturated C 2-6 Hydrocarbylene chains, wherein 1-2 methylene units are optionally replaced by -O-, -C(O)-, -C(R a )(R b )-replaced; the alkylene chain is connected to the degradation sub-terminal through the alkynyl end;

[0104] R a 、R b are independently selected from H, -CH3; and R a 、R b Not at the same time H;

[0105] Alternatively, R on the same carbon atom a 、R bTogether with the carbon atom to which it is attached, it forms a cyclopropyl or cyclobutyl group;

[0106] R c Selected from H, -CH3;

[0107] B 2 Selected from the following groups: Among them B 2 The way a group is described does not restrict the order in which it is connected to the groups on both sides.

[0108] In another preferred embodiment, wherein B 2 Selected from the following groups:

[0109] In another preferred embodiment, wherein B 2 Selected from the following groups:

[0110] In another preferred embodiment, wherein R a 、R b are each independently selected from deuterium.

[0111] In another preferred embodiment, wherein B 3 Selected from C 2-6 An alkynylene chain, wherein 1-2 methylene units are optionally replaced by -O- or -C(O)-; the alkynylene chain is connected to the degron via the alkynyl end.

[0112] In another preferred embodiment, wherein B 3 Select C containing only one triple bond at the terminal 2-6 An alkynylene chain, wherein 1-2 methylene units are optionally replaced by -O- or -C(O)-; the alkynylene chain is connected to the degron via the alkynyl end.

[0113] In another preferred embodiment, wherein B 3 Select C containing only one triple bond at the terminal 2-4 An alkynylene chain, wherein 1-2 methylene units are optionally replaced by -O- or -C(O)-; the alkynylene chain is connected to the degron via the alkynyl end.

[0114] In another preferred embodiment, wherein B 1 Selected from -CH2-, -CD2-, -C(O)-;

[0115] B 2 Selected from the following divalent rings: C 5-6 Cycloalkylene, C 6-8 Bridged cycloalkylene, 6-membered heterocyclylene, 6-8-membered bridged heterocyclylene;

[0116] B3 Selected from

[0117] In another preferred embodiment, wherein L is selected from Preferably, the alkynyl end of L is linked to the degron.

[0118] In another preferred embodiment, wherein L is selected from Preferably, the alkynyl end of L is linked to the degron.

[0119] In another preferred embodiment, wherein L is selected from Preferably, the alkynyl end of L is linked to the degron.

[0120] In another preferred embodiment, wherein L is selected from Preferably, the alkynyl end of L is linked to the degron.

[0121] In another preferred embodiment, wherein L is selected from Preferably, the alkynyl end of L is linked to the degron.

[0122] In another preferred embodiment, wherein L is selected from Preferably, the alkynyl end of L is linked to the degron.

[0123] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated product or its pharmaceutically acceptable salt has a structure shown in the following general formula:

[0124] Rings A and L are as defined in any of the above schemes.

[0125] In another preferred embodiment, each 9-10 membered fused heteroaryl group is a pyrazolopyrimidinyl group, for example

[0126] In another preferred embodiment, each halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0127] In another preferred embodiment, each C 1-6 Alkyl is C 1-4 Alkyl groups, such as methyl.

[0128] In another preferred embodiment, each C 1-6 Alkoxy is C 1-4 Alkoxy groups, such as methoxy groups.

[0129] In another preferred embodiment, the heteroatoms in each 3-6 membered heterocyclic group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1 or 2, for example

[0130] In another preferred embodiment, the heteroatoms in each 7-9 membered bridged heterocyclic group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1 or 2, for example

[0131] In another preferred embodiment, the heteroatoms in each 6-10 membered fused heterocyclic group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1 or 2, for example

[0132] In another preferred embodiment, each 3-6 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclohexyl.

[0133] In another preferred embodiment, each 5-6 membered heteroaryl group is pyrazolyl, for example

[0134] In another preferred embodiment, each 7-11 membered spirocycloalkylene group is

[0135] In another preferred embodiment, each 7-11 membered spiroheterocyclyl group is

[0136] In another preferred embodiment, each 7-9 membered cycloalkylene bridge is

[0137] In another preferred embodiment, each 7-9 membered subbridged heterocyclic group is

[0138] In another preferred embodiment, each C 1-6 The alkylene chain is C 1-4 An alkylene chain, such as methylene or ethylene.

[0139] In another preferred embodiment, each C 3-6 Cycloalkylene is:

[0140] In another preferred embodiment, each C 5-8 The bridged cycloalkyl group is

[0141] In another preferred embodiment, each 4-6 membered heterocyclylene group is

[0142] In another preferred embodiment, each 6-8 membered sub-bridged heterocyclic group is

[0143] In another preferred embodiment, each 6-8 membered heterocycloalkenylene group is

[0144] In another preferred embodiment, each saturated or unsaturated C 1-6 The alkylene chain is an unsaturated C 3-6 Alkyneyl chains, e.g.

[0145] Any substituent and any optional group in the technical solution described in the present disclosure can be combined with each other to form a new complete technical solution. The new technical solution formed has the same or similar technical effects as the solution recorded in this application and is included in the scope of the present disclosure.

[0146] The above technical solutions of the present disclosure can be combined with each other to form new solutions within the scope of the present disclosure.

[0147] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated product or its pharmaceutically acceptable salt is selected from the following compounds:

[0148] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated product or its pharmaceutically acceptable salt is selected from the following compounds:

[0149] In a second aspect of the present disclosure, there is also provided a compound of the following formula (IB), its isomer, its deuterated product or a pharmaceutically acceptable salt thereof:

[0150] wherein Ring B is selected from 8-10 membered fused heteroaryl;

[0151] L1 is selected from -N(R d)-C(O)- or -C(O)-N(R d )-;

[0152] R d Selected from H, C 1-4 alkyl;

[0153] R 3 Selected from C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 alkyl;

[0154] p is selected from 0, 1, 2, 3;

[0155] R 4 Selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, 7-9 membered bridged heterocyclic group;

[0156] q is selected from 0, 1, 2, 3, 4;

[0157] LBM is selected from

[0158] Ring A and L are as defined in any one of the embodiments of the first aspect of the present disclosure.

[0159] In another embodiment of the present disclosure, wherein ring B is selected from

[0160] In another embodiment of the present disclosure, R 3 Selected from -CH3, -CH2CH3, -OCH3, -OCH2CH3; p is selected from 0, 1, 2.

[0161] In another embodiment of the present disclosure, the bifunctional compound, its isomer, its deuterated product or its pharmaceutically acceptable salt has the following structure:

[0162] wherein ring A and L are as defined in any of the above schemes.

[0163] In another embodiment of the present disclosure, the compound of formula (IB), its isomer, its deuterated substance or its pharmaceutically acceptable salt is selected from

[0164] In a third aspect, the present disclosure further provides a pharmaceutical composition comprising a compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, as described in any of the first and second aspects of the present disclosure, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition may be in any pharmaceutically acceptable dosage form. According to the present disclosure, a pharmaceutically acceptable excipient is a substance that is non-toxic, compatible with the active ingredient, and otherwise biologically suitable for use in an organism. The choice of a specific excipient will depend on the mode of administration or the type and condition of disease to be treated in a particular patient. Examples of pharmaceutically acceptable excipients include, but are not limited to, conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, antioxidants, and the like, which are conventionally used in the pharmaceutical field. If necessary, flavoring agents, preservatives, and sweeteners may also be added to the pharmaceutical formulation composition.

[0165] In another preferred embodiment, the content of the compound, its isomer, its deuterated substance or its pharmaceutically acceptable salt in the pharmaceutical composition is 1%-95%.

[0166] In certain embodiments of the present disclosure, in the pharmaceutical composition, the pharmaceutically acceptable excipients include one or more of a filler, a disintegrant, a binder, a glidant, and a lubricant.

[0167] In a fourth aspect, the present disclosure further provides use of the compound described in any one of the first and second aspects of the present disclosure, its isomer, its deuterated product or its pharmaceutically acceptable salt in the preparation of a medicament for preventing and / or treating diseases mediated by IRAK4.

[0168] In another preferred embodiment, the IRAK4-mediated related diseases are selected from immune inflammatory diseases.

[0169] In another preferred embodiment, the IRAK4-mediated related disease is selected from hidradenitis suppurativa, rheumatoid arthritis, atopic dermatitis, lupus erythematosus, gouty arthritis, psoriasis, asthma, chronic obstructive pulmonary disease, polyposis sinusitis, and inflammatory bowel disease.

[0170] In a fifth aspect, the present disclosure further provides a method for treating diseases mediated by IRAK4, comprising administering a therapeutically effective amount of the compound, isomer, deuterated form, or pharmaceutically acceptable salt thereof according to any one of the schemes of the first aspect of the present disclosure to a subject. The subject is primarily a human.

[0171] In another preferred embodiment, the IRAK4-mediated related diseases are selected from immune inflammatory diseases.

[0172] In another preferred embodiment, the IRAK4-mediated related disease is selected from hidradenitis suppurativa, rheumatoid arthritis, atopic dermatitis, lupus erythematosus, gouty arthritis, psoriasis, asthma, chronic obstructive pulmonary disease, polyposis sinusitis, and inflammatory bowel disease.

[0173] In a sixth aspect of the present disclosure, the following compound, its isomer, its deuterated substance or its pharmaceutically acceptable salt is provided:

[0174] wherein Ring A is as defined in any of the above schemes.

[0175] In another preferred embodiment, the compound of formula (Z), its isomer, its deuterated substance or its pharmaceutically acceptable salt is selected from the following structures:

[0176] In another preferred embodiment, the compound of formula (Z), its isomer, its deuterated substance or its pharmaceutically acceptable salt is selected from the following structures:

[0177] In a seventh aspect, the present disclosure provides a compound represented by formula (X), an isomer thereof, a deuterated substance thereof, or a pharmaceutically acceptable salt thereof:

[0178] Where L is B 1-1 -B 2 -B 3-1 -;

[0179] B 1-1 is hydroxy, amino, carboxyl or hydroxy-substituted C 1-3 alkyl;

[0180] B 3-1 C 1-3 Alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-、-S- replaced; R a 、R b are independently selected from H, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and R a 、R b Not at the same time H;

[0181] B 2 As defined in the first aspect of this disclosure.

[0182] In another preferred embodiment, the compound of formula (X), its isomer, its deuterated product or its pharmaceutically acceptable salt is selected from the following structures:

[0183] In an eighth aspect, the present disclosure provides the following compound, its isomer, its deuterated substance or a pharmaceutically acceptable salt thereof:

[0184] The ninth aspect of the present disclosure further includes the use of the compounds, isomers, deuterated substances or pharmaceutically acceptable salts thereof involved in the sixth and seventh aspects in the preparation of an IRAK4 degrader; preferably, the IRAK4 degrader is as described in the first aspect of the present disclosure.

[0185] The tenth aspect of the present disclosure further includes use of the compound, its isomer, its deuterated product or pharmaceutically acceptable salt involved in the eighth aspect in preparing an IRAK4 degrader.

[0186] Description and Definition

[0187] In this disclosure, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this disclosure, definitions of some terms are provided below. When the definitions of terms provided in this disclosure are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and interpretations of the terms provided in this disclosure shall prevail.

[0188] In the present disclosure, the “E3 enzyme” includes enzymes disclosed in the prior art that belong to the E3 family, such as CRBN, VHL, MDM2, IAPs, TRIM24, DCAF15, DCAF16, and RNF114. The ligands of specific E3 enzymes are shown in the literature “Jaeseok Lee, et al., Discovery of E3 Ligase Ligands for Target Protein Degradation Molecules, 2022, 27(19): 6515.”

[0189] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0190] The term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds prepared with relatively nontoxic acids or bases. These salts can be prepared during compound synthesis, isolation, and purification, or by reacting the purified free form of the compound with a suitable acid or base. When the compound contains relatively acidic functional groups, base addition salts are obtained by reaction with alkali metal or alkaline earth metal hydroxides or organic amines. These salts include cations based on alkali and alkaline earth metals, as well as nontoxic ammonium, quaternary ammonium, and amine cations, and also encompass salts of amino acids. When the compound contains relatively basic functional groups, acid addition salts are obtained by reaction with organic or inorganic acids.

[0191] The term "effective prophylactic or therapeutic amount" means that a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is a sufficient amount of the compound to treat a disorder at a reasonable benefit / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the total daily dosage of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, and compositions must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination with or concurrently with the specific compound being used; and similar factors well known in the medical field.

[0192] The “isomers” described in the present disclosure include geometric isomers and stereoisomers, such as atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures and other mixtures thereof, all of which fall within the scope of the present disclosure. The term “enantiomer” refers to stereoisomers that are mirror images of each other. The term “tautomer” refers to a type of functional group isomer that has different hydrogen attachment points due to one or more double bond displacements, for example, a ketone and its enol form are keto-enol tautomers. The term “diastereomer” refers to a stereoisomer in which a molecule has two or more chiral centers and is not a mirror image of the other molecules. The term “cis-trans isomer” refers to different spatial configurations in which double bonds or single bonds of ring carbon atoms in a molecule cannot rotate freely. The term “atropisomer” refers to stereoisomers that can be separated because single bond rotation is hindered or rotates very slowly.

[0193] Stereoisomers of the compounds disclosed herein can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. For example, one enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis or chiral auxiliary derivatization techniques. Alternatively, a single stereoisomer of the compound can be obtained from a mixture using chiral resolution techniques. Alternatively, the enantiomer can be prepared directly using chiral starting materials. Separation of optically pure compounds disclosed herein is typically accomplished using preparative chromatography, employing chiral chromatographic columns to achieve the purpose of separating chiral compounds.

[0194] The “deuterated compound” mentioned in the present disclosure refers to a compound derived from the compounds of the present disclosure in which one or more hydrogen atoms are replaced by deuterium.

[0195] The term "optionally substituted" means that it may be substituted or not substituted. Unless otherwise specified, the type and number of substituents can be any on the basis of chemical feasibility. For example, the term "optionally substituted with one or more R" means that it may be substituted with one or more R or not substituted with R. When any variable appears more than once in the composition or structure of a compound, its definition in each case is independent. For example, if a group is substituted with 0-2 R a substituted, then the group may optionally be replaced by up to two R a is replaced, and in each case R a There are independent options.

[0196] When the substituent appears in the structure Indicates that the atom is a bonding atom, for example Indicates that the C atom on the pyrimidine ring is a bonding atom. A dash "-" in a substituent structure indicates the point of attachment for the substituent, for example, -CH3 is attached through a C atom. Indicates the absolute configuration of a stereocenter, i.e., R or S configuration. It represents cis or trans configuration. Double real bonds or double imaginary bonds both represent cis configuration, and one real and one imaginary bond represent trans configuration.

[0197] In the present disclosure, L is selected from -(B 1 )n1-(B 2 )n2-(B 3 )n3-; When n1 or n2 or n3 is 0, it means that the corresponding group does not exist, and the left and right groups are directly connected by chemical bonds; specifically, when only n1 is 0, L is -(B 2 )n2-(B 3 )n3-; when only n2 is 0, L is -(B 1 )n1-(B 3 )n3-; when only n3 is 0, L is selected from -(B 1)n1-(B 2 )n2-.

[0198] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. The substituent R can be substituted at any position on the benzene ring.

[0199] When a substituent is listed without indicating the atom via which the substituent is attached to a given group or a given formula, then the substituent may be attached via any bondable atom thereof.

[0200] The "alkyl" in this disclosure refers to a group derived from a branched or straight chain saturated aliphatic alkane with a specified number of carbon atoms by removing one hydrogen. For example, "C 1-10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 Alkyl groups, including "C 1-6 Alkyl", "C 1- 4 alkyl", "C 1-3 "alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0201] The "haloalkyl" mentioned in the present disclosure refers to a group obtained by replacing the hydrogen in the alkyl group with one or more halogens, such as "fluoromethyl" including monofluoromethyl, difluoromethyl, and trifluoromethyl; preferably, the "haloalkyl" mentioned in the present disclosure is "halo C 1-6 Alkyl", "halogenated C 1-4 Alkyl". Alkyl is as defined above.

[0202] The "oxo" mentioned in the present disclosure means that the group is substituted by a "=O" structure, such as "-CH2-" is oxoed to form "-C(O)-", and "S" is oxoed to form "S(O)" or "S(O)2".

[0203] The "alkylene group" mentioned in the present disclosure refers to a group derived from a branched or straight chain alkane, alkene, or alkyne with a specified number of carbon atoms by removing two hydrogen atoms, including "alkylene", "alkenylene", and "alkynylene". The alkylene group may be further substituted by other groups; "alkenylene" and "alkynylene" respectively refer to an unsaturated hydrocarbon chain containing at least one double bond or triple bond in the hydrocarbon chain. The "alkylene group" mentioned in the present disclosure includes "C 1-15 "alkylene", preferably "C 2-10 Hydrocarbylene, "C 4-6 Alkylene", "C 2-10 Alkylene", "C 5-7 Alkynylidene", "C7- 10 Alkylene", "C 5-7 Alkenylene", "C 1-6 Hydrocarbylene, "C 1-3 Alkylene", "C 2-6 Preferably, the "alkylene" described in the present disclosure is preferably a "straight-chain alkylene"; specific examples of the alkylene chain include but are not limited to: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH2)CH2-, -CH2CH2CH2CH2-, -CH(CH2)CH2CH2-, -CH(CH2CH2)CH2-, -C(CH2)(CH2)CH2-, -CH2CH2CH2CH2CH2-, etc.; preferably, the "methylene unit" described in the present disclosure refers to -CH2-. Specific examples of the "alkenylene" described in the present disclosure include but are not limited to: -CH=CH-, -CH=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH2CH=CH-, -CH2CH=CHCH2-, -CH2CH=CHCH2CH2-; specific examples of the "alkynylene" described in the present disclosure include but are not limited to -C≡C-, - C≡C-CH2-, -C≡C-CH2CH2CH2-, -CH2-C≡C-CH2CH2CH2-, -C≡C-CH2C≡C-, -C≡C-CH2CH=CH-, etc. Further, as described in the present disclosure, "any methylene unit is optionally replaced", such as any methylene unit in "-CH2CH2CH2-" is replaced by -C(O)-, which may form but is not limited to the following structures -C(O)CH2CH2-, -CH2C(O)CH2-, -CH2CH2C(O)-, -C(O)CH2C(O)-, etc.

[0204] The "ring" described in the present disclosure includes but is not limited to "cycloalkane", "spirocycloalkane", "bridged cycloalkane", "heterocycle", "heterocycloalkene", "spiroheterocycle", "bridged heterocycle", "fused heterocycle", "heteroaromatic ring", "fused heteroaromatic ring" and the like, and the monovalent rings derived therefrom may be "cycloalkyl", "spirocycloalkyl", "bridged cycloalkyl", "heterocyclyl", "heterocyclalkenyl", "spiroheterocyclyl", "bridged heterocyclyl", "heteroaryl", "fused heteroaryl" respectively; the "divalent ring" derived therefrom refers to a group derived from a ring structure by removing two hydrogen atoms, and the bonding sites thereof may be connected to different groups or to different positions of the same group respectively, and the divalent rings derived therefrom may be "cycloalkylene", "bridged cycloalkylene", "spirocycloalkylene", "heterocyclylene", "heterocyclylene", "spiroheterocyclylene", "bridged heterocyclyl", "fused heterocyclylene", "heteroarylene" and the like.

[0205] The "cycloalkane" mentioned in the present disclosure refers to a monocyclic, saturated cyclic alkane structure, in which the carbon atoms in the cycloalkane can be oxidized, that is, the carbon atoms are replaced by -C(O)-. 3-8 Cycloalkanes", "C 3-6 Cycloalkanes", "C 3-5 Specific examples include but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0206] The "spirocycloalkane" mentioned in the present disclosure refers to a cyclic structure formed by two or more adjacent cycloalkanes sharing a ring atom, wherein the carbon atoms in the cycloalkanes may be oxo-substituted, i.e., the carbon atoms are replaced by -C(O)-. 7-11 Spiroalkanes, "C 7-9 Spirocycloalkanes”, etc., specific examples include but are not limited to:

[0207] The "bridged cycloalkane" mentioned in the present disclosure refers to a cyclic structure formed by two or more adjacent cycloalkanes sharing two non-adjacent ring atoms, wherein the carbon atoms in the cycloalkanes may be oxo-substituted, i.e., the carbon atoms are replaced by -C(O)-. 6-10 Bridged cycloalkanes", "C 6-8 Bridged cycloalkanes”, etc., specific examples include but are not limited to: wait.

[0208] The "heterocycle" described in the present disclosure refers to a cyclic structure derived from a "cycloalkane" in which at least one carbon atom is replaced by a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from O, NR, N(O), S, S(O), S(O)2, R is H or any substituent group that may exist, and the "cycloalkane" is as defined above. The heterocycle preferably contains 1-2 heteroatoms selected from NR and / or O, more preferably contains 1 NR and 0-1 NR or O heteroatoms. The heterocycle is preferably a "nitrogen-containing heterocycle", which refers to a heterocycle in which at least one ring atom is NR. The heterocycle includes a 3-8 membered heterocycle, a 3-6 membered heterocycle, a 4-6 membered heterocycle, a 5-6 membered heterocycle, a 4-6 membered nitrogen-containing heterocycle, and a 5-6 membered nitrogen-containing heterocycle. Specific examples include, but are not limited to, tetrahydrofuran, tetrahydropyrrole, piperidine, morpholine, piperazine, wait.

[0209] The term "heterocyclic olefin" as used herein refers to a non-aromatic heterocyclic group containing at least one double bond in a heterocycle. The heterocyclic olefin preferably contains 1-2 heteroatoms selected from NR and / or O, and more preferably contains 1 NR and 0-1 NR or O heteroatoms. The heterocyclic olefin includes 5- to 8-membered heterocyclic olefins and 6- to 8-membered heterocyclic olefins. Specific examples include, but are not limited to: wait.

[0210] The "spiroheterocycle" described in the present disclosure refers to a cyclic structure derived from the replacement of at least one carbon atom in a "spirocycloalkane" by a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from O, NR, N(O), S, S(O), S(O)2, R is H or any substituent group that may exist, and the "spirocycloalkane" is as defined above. It includes but is not limited to a cyclic structure formed by a heterocyclic spiroheterocycle and a heterocyclic spiroheterocycle. The spiroheterocycle preferably contains 1-2 heteroatoms selected from NR and / or O, more preferably contains 1 NR and 0-1 NR or O heteroatoms. The spiroheterocycle is preferably a "nitrogen-containing spiroheterocycle", which refers to a spiroheterocycle in which at least one ring atom is NR. The spiroheterocycle includes a 7-11-membered spiroheterocycle, a 7-9-membered spiroheterocycle, a 7-11-membered nitrogen-containing spiroheterocycle, and a 7-9-membered nitrogen-containing spiroheterocycle. Specific examples include but are not limited to: wait.

[0211] The "bridged heterocycle" described in the present disclosure refers to a cyclic structure derived from a "bridged cycloalkane" in which at least one carbon atom is replaced by a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from O, NR, N(O), S, S(O), S(O)2, R is H or any substituent group that may be present, and the "bridged cycloalkane" is as defined above. The bridged heterocycle is preferably a "nitrogen-containing bridged heterocycle", which refers to a heterocycle in which at least one ring atom is NR. The bridged heterocycle includes "6-10 membered bridged heterocycle", "6-8 membered bridged heterocycle", etc. Specific examples include but are not limited to: wait.

[0212] The "fused heterocycle" described in the present disclosure refers to a saturated cyclic structure formed by sharing two adjacent ring atoms between two or more rings, and at least one ring is a heterocycle, and the "heterocycle" is as defined above. It includes but is not limited to structures formed by heterocycles and heterocycles, and heterocycles and cycloalkanes. The fused heterocycle preferably contains 1-2 heteroatoms selected from NR and / or O, more preferably contains 1 NR and 0-1 NR or O heteroatoms. The fused heterocycle is preferably a "nitrogen-containing fused heterocycle", which refers to a fused heterocycle in which at least one ring atom is NR. The fused heterocycle includes 6-10 membered fused heterocycles and 8-10 membered fused heterocycles. Specific examples include but are not limited to

[0213] The "heteroaromatic ring" described in the present disclosure refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one ring atom is a heteroatom, and the heteroatom is selected from N, O, and S. When the heteroaryl group contains a N atom, its nitrogen oxide is also included. The polycyclic heteroaromatic ring is a fused heteroaromatic ring, which includes but is not limited to a benzo 5-6 membered heteroaromatic ring, a 5-6 membered heteroaromatic ring and a 5-6 membered heteroaromatic ring. The heteroaromatic ring includes a 5-6 membered heteroaromatic ring, a 7-10 membered bicyclic fused heteroaromatic ring, and an 8-14 membered fused heteroaromatic ring. The heteroaromatic ring is preferably a "nitrogen-containing heteroaromatic ring", which refers to a heteroaromatic ring in which at least one ring atom is N. Examples of heteroaromatic rings include but are not limited to pyrrole, furan, thiophene, pyrazole, imidazole, pyrazine, pyridazine, triazine, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, indazole, indole, isoquinoline, quinoxaline, benzoxazole, benzofuran, benzothiophene, benzothiazole, benzimidazole, quinoline, quinazoline, wait.

[0214] Combinations of substituents and / or variables described herein are permissible only if these combinations result in stable compounds or useful synthetic intermediates. A stable compound or structure is one that is sufficiently robust to survive chemical reactions, to be isolated to a useful degree of purity, and to be formulated into an efficacious therapeutic agent.

[0215] As used herein, the term "degrader" refers to a bifunctional compound that can bind between IRAK4 kinase and E3 ligase, causing ubiquitination and subsequent degradation of IRAK4 kinase. In certain embodiments, the DC50 of the degrader is less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0216] Beneficial effects of the compounds disclosed herein:

[0217] (1) The disclosed compounds have good degradation activity on the IRAK4 target and can effectively inhibit the secretion of inflammatory factors.

[0218] (2) The compounds disclosed herein have good pharmacokinetic properties, including high exposure, suitable clearance, and other superior properties.

[0219] (3) The compounds disclosed herein have better safety, such as lower cardiotoxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0220] Figure 1 shows the concentration levels of inflammatory factors in mouse plasma and peritoneal lavage fluid after oral administration of three different dose levels of KT-474, 15 mg / kg, 50 mg / kg, and 150 mg / kg, and the compound of Example 22 of the present disclosure to mice in Test Example 6.

[0221] FIG2 shows the in vivo degradation level of IRAK4 in the spleen of mice after oral administration of KT-474 at three different dose levels of 15 mg / kg, 50 mg / kg, and 150 mg / kg and the compound of Example 22 of the present disclosure in Test Example 6. DETAILED DESCRIPTION

[0222] The preparation methods of some compounds disclosed herein refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0223] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0224] Unless otherwise stated, all reactions disclosed herein are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, and the solvent is a dry solvent, wherein: (i) the temperature is expressed in degrees Celsius (°C), and the operation is carried out at room temperature, which generally refers to 15-35°C, preferably 20-30°C, and more preferably 20-25°C; (ii) the solvent is removed by evaporation under reduced pressure on a rotary evaporator; (iii) the reaction process is tracked by LC-MS or thin layer chromatography (TLC); (iv) the final product has satisfactory hydrogen nuclear magnetic resonance spectrum (1H-NMR) and / or mass spectrum (MS) data. The methods used for purifying the products disclosed herein include, but are not limited to, preparative high performance liquid chromatography, thin layer chromatography, or column chromatography, and the purification reagents used are conventional solvents in the art, such as dichloromethane, methanol, ethyl acetate, petroleum ether, acetonitrile, water, etc. The specific types and proportions used can be determined by conventional methods in the art.

[0225] Test equipment:

[0226] The structures of the compounds disclosed herein are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument in deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and / or deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0227] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Shimadzu 2030Plus-LCMS2020 mass spectrometer, an Agilent 1260-6125B single quadrupole mass spectrometer, or a Shimadzu LCMS-2020 mass spectrometer. HPLC was performed using a Shimadzu LCMS-2020 or Agilent 1260 high-performance liquid chromatograph.

[0228] Preparative high-performance liquid chromatography was performed using a Shimadzu FRC-40 equipped with LC-20AP and PDA-20A (column: Synergi Max-RP, 150×30 mm, 4 m) or a GILSON Trilution LC (column: SunFire Prep C18, 10 μm, 19×250 mm; XBridge Prep C18, 10 μm, 19×250 mm)).

[0229] The starting materials and intermediate compounds used in this disclosure are either commercially available or synthesized in-house. The structures and preparations of the synthesized in-house intermediates are documented in this disclosure. The chirality of the chiral intermediates or chiral products in this disclosure can be determined by the chiral starting materials used. When the reaction site is achiral, the chirality of the starting materials is generally the same as that of the product.

[0230] The chemical abbreviations used in this disclosure and the chemical names they refer to are as follows:

[0231] Synthesis of IRAK4 Warhead A:

[0232] Step 1: Under argon at room temperature, Aa (8.32 g, 36.88 mmol) and (1R,4R)-2-oxa-5-azabicyclo[2,2,1]heptane hydrochloride (5 g, 36.88 mmol) were dissolved in acetonitrile (60 mL). N,N-diisopropylethylamine (14.3 g, 110.63 mmol) was slowly added dropwise with stirring. The reaction mixture was then stirred at 60°C overnight. LC-MS showed complete consumption of the starting material, with the sole product Ab formed. Water (100 mL) was added to the cooled reaction mixture, followed by extraction with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography to yield Ab (10.1 g). 1H NMR (400MHz, CDCl3) δ8.32-8.20(m,2H),6.12(brs,1H),5.45(brs,1H),4.82-4.71(m,1H),4. 42-4.26(m,2H),4.02-3.84(m,2H),3.51-3.37(m,2H),2.12-1.87(m,2H),1.41-1.39(m,3H).

[0233] Step 2: Dissolve Ab (10.1 g, 35.03 mmol) in anhydrous methanol / water (100 mL / 25 mL) at room temperature and add lithium hydroxide monohydrate (8.82 g, 210.19 mmol) with stirring. The reaction solution was then stirred at 60°C overnight. LC-MS showed that a trace amount of starting material remained, and the main product was Ac. The cooled reaction solution was diluted with water (100 mL) and the pH was adjusted to 5 with dilute hydrochloric acid (1 M) in an ice-water bath. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain Ac (8.7 g). 1 H NMR (400MHz, CDCl3) δ8.36-8.28(m,2H),6.40-6.17(m,1H),5.22,4.82(s, 1H),4.68(s,1H),3.99-3.90(m,2H),3.72-3.51(m,2H),2.13-2.03(m,2H).

[0234] Step 3: 1H-pyrazole-5-carboxaldehyde (58.7 g, 610.89 mmol) and TsOH·H2O were dissolved in DCM (580 mL), cooled to 0°C, and DHP (61.6 g, 733.07 mmol) was slowly added. The ice bath was removed, and the mixture was allowed to warm to room temperature overnight. TEA (23.5 mL) was added to the reaction mixture, and the mixture was concentrated by rotary evaporation. The residue was purified on a silica gel column to yield Ad (88 g). 1 H NMR(400MHz, CDCl3) δ10.00(s,1H),7.68(dd,J=2.6,0.6Hz,1H),6.83(d,J=2.8Hz,1H),5.4 9-5.45(m,1H),4.09-4.05m,1H),3.77-3.70(m,1H),2.16-2.03(m,3H),1.77-1.63(m,3H).

[0235] Step 4: Ad (88 g, 488.33 mmol) was dissolved in DCM (500 mL) and DAST (157 g, 976.65 mmol) was added dropwise at 0°C. The ice bath was removed and the reaction was allowed to warm overnight. TLC (PE / EtOAc = 10 / 1) indicated that the reaction was not complete. The reaction solution was slowly quenched with NaHCO₃ (3 L), and the organic phase was separated. The aqueous phase was further extracted with DCM (3 × 1 L). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated by rotary evaporation. The residue was purified on a silica gel column to yield Ae (69.65 g). 1 H NMR (400MHz, CDCl3) δ7.63 (d, J = 2.4Hz, 1H), 6.70 (t, J = 55.0Hz, 1H), 6.51 (d, J = 2.4Hz, 1H), 5. 39-5.35(m,1H),4.07-4.03(m,1H),3.75-3.65(m,1H),2.15-1.97(m,3H),1.74-1.57(m,3H).

[0236] Step 5: Dissolve Ae (25.7 g, 127.10 mmol) in MeOH (254 mL). Add HCl (4 M in 1,4-dioxane) (254 mL, 1.016 mol) at 0°C. Remove the ice bath and allow to react overnight. TLC monitors the reaction for completion. The reaction mixture is concentrated, saturated NaHSO₃ (420 mL) and EtOAc (420 mL) are added, and the mixture is stirred at room temperature for 1 h. The mixture is extracted with EtOAc (3 × 200 mL). The combined organic phases are dried over Na₂SO₄ and concentrated by rotary evaporation to yield Af (16.8 g). 1 H NMR (400MHz, CDCl3) δ7.65-7.63 (m, 1H), 6.80 (t, J = 55.6Hz, 1H), 6.56-6.54 (m, 1H).

[0237] Step 6: Af (14.0 g, 118.56 mmol) was dissolved in concentrated H2SO4 (140 mL), cooled to 0°C in an ice bath, and HNO3 (65%, 40.23 g, 414.95 mmol) was added dropwise. The temperature was slowly warmed to room temperature, then gradually raised to 60°C and allowed to react at 115°C overnight. The reaction mixture was cooled to room temperature, poured into ice water (1 L), and extracted with EtOAc (3 × 1 L). The combined organic phases were dried over Na2SO4, concentrated by rotary evaporation, and purified to yield Ag (7.79 g). 1 H NMR (400MHz, CDCl3) δ8.46 (s, 1H), 7.35 (t, J = 53.6Hz, 1H).

[0238] Step 7: Dissolve tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (9.57 g, 39.99 mmol) in anhydrous methanol (100 mL) at room temperature. Slowly add sodium borohydride (1.82 g, 47.99 mmol) while stirring in an ice-water bath. The reaction solution is slowly returned to room temperature and stirred for 1 hour. Thin layer chromatography shows that the starting material is completely reacted. Saturated aqueous ammonium chloride solution (100 mL) is added to the reaction solution and extracted with ethyl acetate (3×100 mL). The combined organic phases are washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the resulting residue is separated by silica gel column chromatography to obtain Ah (9.14 g). 1 H NMR (400MHz, CDCl3) δ4.37-4.28(m,1H),3.35-3.27(m,4H),2.31-2.25(m, 2H),1.80-1.78(m,1H),1.71-1.65(m,2H),1.54-1.47(m,4H),1.45(s,9H).

[0239] Step 8: Ah (9.14 g, 37.87 mmol) was dissolved in toluene (90 mL) at room temperature. Triphenylphosphine (14.90 g, 56.81 mmol), imidazole (5.16 g, 75.75 mmol), and iodine (14.42 g, 56.81 mmol) were added sequentially with stirring in an ice-water bath. The reaction solution was slowly returned to room temperature and stirred for 1 hour, then heated to 60°C and stirred for 1 hour. LC-MS indicated complete reaction of the starting material. Water (200 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to yield Ai (7.98 g). 1 H NMR (400MHz, CDCl3) δ4.54-4.45(m,1H),3.34-3.30(m,2H),3.29-3.25(m,2H),2.69 -2.63(m,2H),2.45-2.39(m,2H),1.69-1.65(m,2H),1.57-1.53(m,2H),1.44(s,9H).

[0240] Step 9: Dissolve Ai (5 g, 14.24 mmol) and Ag (2.11 g, 12.94 mmol) in N,N-dimethylformamide (50 mL) at room temperature. Add potassium carbonate (3.58 g, 25.88 mmol) with stirring. The reaction mixture was then stirred at 100°C overnight. LC-MS indicated complete reaction of the starting materials. Cool the reaction mixture to room temperature, add water (100 mL), and extract with ethyl acetate (3 x 100 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to yield Aj (3.8 g, yield: 76%). 1 H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 7.32 (t, J = 53.0Hz, 1H), 5.05-5.00 (m, 1H), 3.32-3.29 (m, 2H),3.25-3.21(m,2H),2.44-2.38(m,2H),2.30-2.23(m,2H),1.60-1.53(m,4H),1.39(s,9H).

[0241] Step 10: Aj (3.8 g, 9.83 mmol) was dissolved in tetrahydrofuran (60 mL) at room temperature, and 10% wet palladium on carbon (1.9 g) was added at room temperature. The reaction solution was then stirred at 30°C under the protection of a hydrogen balloon for 3 hours. LC-MS showed that the reaction of the starting material was complete. The reaction solution was filtered and the filter cake was washed with ethyl acetate (100 mL). The combined filtrate was concentrated to give the desired product Ak (3.4 g). MS (ESI) M / Z: 357 [M+H + ].

[0242] Step 11: Ak (2.00 g, 5.61 mmol) and Ac (1.50 g, 5.76 mmol) were dissolved in acetonitrile (40 mL) at room temperature under argon. 1-Methylimidazole (1.60 mL, 20.07 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 2.40 g, 8.55 mmol) were added with stirring in an ice-water bath. The argon atmosphere was replaced three times, and the reaction mixture was stirred at 50°C under argon overnight. LC-MS indicated that the reaction was complete. Saturated aqueous sodium bicarbonate (40 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine (2 × 40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude residue was separated by silica gel column chromatography to obtain the desired product Al (3.40 g). MS (ESI) M / Z: 599.1 [M+H + ].

[0243] Step 12: Al (3.40 g, 5.68 mmol) was dissolved in dichloromethane (40 mL) at room temperature. A hydrochloric acid / 1,4-dioxane solution (4 M, 14 mL, 56 mmol) was added under stirring in an ice-water bath. The reaction mixture was then stirred at room temperature for 2 hours. LC-MS showed that the reaction of the starting material was complete. The reaction mixture was concentrated to obtain the desired crude product A (3.87 g, hydrochloride salt). MS (ESI) M / Z: 499.6 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ9.51(d,J=5.2Hz,1H),8.89(s,2H),8.79(d,J=8.0Hz,1H),8.42(d,J=4 .0Hz,1H),8.26(d,J=5.6Hz,1H),7.14(t,J=53.6Hz,1H),6.89-6.45(m,1H),5.28-5.08(m,1H), 5.00-4.92(m,1H),4.80-4.74(m,1H),3.87-3.73(m,2H),3.65-3.43(m,2H),3.04-2.95(m,4H), 2.47-2.41(m,2H),2.30-2.24(m,2H),2.06-1.92(m,2H),1.88-1.84(m,2H),1.82-1.79(m,2H).

[0244] Synthesis of intermediate B:

[0245] Step 1: Place glutarimide (100 g, 884.0 mmol) in a 500 mL stuffy jar at room temperature, add chloroform (200 mL), and slowly add liquid bromine (141 g, 884.0 mmol) under stirring. After sealing, the reaction solution is stirred at 105 ° C overnight. LC-MS shows that the raw materials are basically reacted and the main product is Bb. The reaction solution is cooled to room temperature and concentrated. The resulting residue is dissolved in ethyl acetate (1 L), washed with saturated sodium bicarbonate aqueous solution (500 mL), washed with saturated brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate is concentrated, and the resulting residue is separated by silica gel column chromatography to obtain the desired product Bb (78 g). MS (ESI) M / Z: 192.0 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.05 (s, 1H), 4.88 (t, J = 4.8Hz, 1H), 2.56-2.52 (m, 2H), 2.49-2.43 (m, 1H), 2.19-2.10 (m, 1H).

[0246] Step 2: Dissolve p-methoxybenzyl alcohol (20.6 g, 148.9 mmol) in dry tetrahydrofuran (500 mL) at room temperature. Add triphenylphosphine (39.1 g, 148.9 mmol) and Bb (26 g, 135.4 mmol) with stirring. The reaction mixture is then cooled to 0°C and slowly added dropwise under argon. Diethyl azodicarboxylate (25.9 g, 148.9 mmol) is added dropwise. After the addition is complete, the reaction mixture is allowed to warm to room temperature and stirred overnight. LC-MS indicates complete reaction of the starting material. The reaction mixture is concentrated, and the residue is purified by silica gel column chromatography to yield the desired product, Bc (29.7 g). 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,2H),6.87-6.78(m,2H),4.90(dd,J=37.9,13.8Hz,2H),4.74-4. 68(m,1H),3.78(s,3H),3.10-2.96(m,1H),2.80-2.69(m,1H),2.42-2.30(m,1H),2.27-2.17(m,1H).

[0247] Step 3: Disperse Bd (19.8 g, 87.4 mmol) in dry tetrahydrofuran (400 mL) at room temperature, stir, and cool to 0°C. Under argon, add potassium tert-butoxide (16.7 g, 148.5 mmol). Stir the reaction mixture at this temperature for 1 hour. Then, raise the temperature to 45°C and slowly add a solution of Bc (30.0 g, 96.1 mmol) in dry tetrahydrofuran (300 mL) dropwise over 6 hours. After the addition is complete, stir the reaction mixture at 45°C for 3 hours. LC-MS indicates that the starting material has reacted substantially. The reaction mixture is cooled to 0°C and quenched by slowly adding saturated brine (300 mL). The organic phase is washed once more with saturated brine (300 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the resulting crude residue is separated by silica gel column chromatography to yield the desired product, Be (18.3 g). 1 H NMR (400MHz, DMSO-d6) δ7.29-7.15(m,3H),7.13-7.04(m,1H),6.94(t,J=8.0Hz,1H),6.89-6.81(m,2H),5.57(dd,J=13.0 ,5.4Hz,1H),4.79(q,J=14.3Hz,2H),3.72(s,3H),3.64(s,3H),3.13-2.94(m,1H),2.88-2.65(m,2H),2.14-1.99(m,1H).

[0248] Step 4: Dissolve Be (18.3 g, 19.9 mmol) in toluene (140 mL) and methanesulfonic acid (70 mL) at room temperature, heat to 120°C, and stir for 5 hours. LC-MS indicates complete reaction. Cool the reaction mixture to room temperature and concentrate. The resulting residue is slowly added dropwise to ice water (1 L), filtered, and dried to obtain the desired product B (10.5 g). 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),7.24(d,J=8.0Hz,1H),7.17(d,J=8.0Hz,1H),6.98(t,J=8.2Hz,1 H),5.41(dd,J=12.4,5.2Hz,1H),3.64(s,3H),2.96-2.82(m,1H),2.77-2.59(m,2H),2.10-1.98(m,1H).

[0249] Example 1

[0250] Step 1: To a dry 100 mL single-necked flask at room temperature was added B (300 mg, 0.89 mmol) and dry N,N-dimethylformamide (5 mL). Hydroxyethyl propargyl ether (179 mg, 1.78 mmol), bis(triphenylphosphine)palladium dichloride (62 mg, 0.089 mmol), cuprous iodide (17 mg, 0.089 mmol), and cesium carbonate (870 mg, 2.67 mmol) were added under argon. The mixture was purged with argon three times and heated to 80°C under argon with stirring for 2 hours. LC-MS indicated the reaction was complete. The reaction mixture was cooled to room temperature and saturated aqueous ammonium chloride (20 mL) was added with stirring. The resulting mixture was extracted with dichloromethane (3 × 50 mL). The combined organic extracts were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to yield the desired compound 1a (103 mg).

[0251] Step 2: 1a (250 mg, 699.56 μmol) and triethylamine (155 mg, 1.54 mmol) were dissolved in dichloromethane (3 mL) at room temperature, and methylsulfonyl chloride (120 mg, 1.05 mmol) was added under ice-water bath and stirring. The reaction solution was then heated to 30 ° C and stirred under argon protection for 1 hour. LC-MS showed that the starting material disappeared. Water (30 mL) was added to the cooled reaction solution and extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with saturated brine (3×0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting residue was purified by thin layer preparative chromatography to give 1b (80 mg). MS (ESI) M / Z: 436.1 [M+H +];434.1[MH - ]. 1 H NMR (400MHz, CDCl3) δ11.23(s,1H),7.20-7.12(m,2H),7.06-7.01(m,1H),5.40(dd,J=12.2,5.4Hz,1H),4.52(s,2H),4.39-4.36( m,2H),3.83-3.80(m,1H),3.71-3.63(m,1H),3.61(s,3H),3.20(s,3H),2.95-2.83(m,1H),2.77-2.60(m,2H),2.07-1.99(m,1H).

[0252] Step 3: 1b (30 mg, 68.89 μmol) and A (crude hydrochloride, 51 mg, 103.34 μmol) were dissolved in acetonitrile (2 mL) at room temperature and under argon protection, and potassium iodide (14 mg, 82.67 μmol) and N,N-diisopropylethylamine (44 mg, 344.47 μmol) were added with stirring. The reaction solution was then reacted at 85 ° C. under argon protection overnight. LC-MS showed that a small amount of raw material remained and the main product was 1. After the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (30 mL) was added thereto, and then extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was purified by thin layer preparative chromatography to obtain 1 (7.93 mg). MS (ESI) M / Z: 838.5 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.2Hz,1H),8.78(d,J=7.6Hz,1H),8.41 -8.39(m,1H),8.25(d,J=5.2Hz,1H),7.27-6.96(m,4H),6.88-6.44(m,1H),5.43-5.36(m ,1H),5.28-5.07(m,1H),5.00-4.90(m,1H),4.79-4.74(m,1H),4.40(s,2H),3.84-3.57( m,8H),3.47-3.43(m,1H),2.93-2.84(m,1H),2.76-2.60(m,2H),2.50-2.10(m,9H),2.06- 1.90(m,4H),1.89-1.55(m,4H).

[0253] Example 2

[0254] Step 1: Dissolve B (6.0 g, 17.7 mmol) and 3-(prop-2-yn-1-yloxy)propan-1-ol (4.0 g, 35.5 mmol) in dry N,N-dimethylformamide (60 mL) at room temperature, stir and add cesium carbonate (14.4 g, 44.4 mmol), bis(triphenylphosphine)palladium dichloride (1.25 g, 1.77 mmol) and cuprous iodide (676 mg, 3.55 mmol) in sequence under argon protection, and then stir the reaction solution at 80 ° C. under argon protection for 5 hours.

[0255] LC-MS showed that the starting material had reacted completely. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated, and ethyl acetate (200 mL) and saturated brine (100 mL) were added to the resulting residue and the mixture was separated. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude residue was separated by silica gel column chromatography to obtain the desired product 2a (2.9 g). 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.17(d,J=7.3Hz,1H),7.12(d,J=7.3Hz,1H),7.03(t,J=7.8Hz,1H),5.40(dd,J=12.6,5.3Hz,1H),4.54-4. 31(m,3H),3.64(s,3H),3.60(t,J=6.5Hz,2H),3.47(t,J=6.3Hz,2H),2.9 7-2.82(m,1H),2.78-2.57(m,2H),2.10-1.98(m,1H),1.77-1.61(m,2H).

[0256] Step 2: 2a (95.0 mg, 255.8 μmol) was dissolved in dichloromethane (4 mL) at room temperature, cooled in an ice-water bath and added with stirring Dess-Martin periodinane (162.7 mg, 383.7 μmol). The reaction solution was stirred at room temperature overnight. LC-MS showed that the starting material disappeared. The reaction solution was filtered, and water (20 mL) and dichloromethane (20 mL) were added to the filtrate to separate the layers. The aqueous phase was extracted with dichloromethane (10 mL×2). The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude product was purified by thin layer preparative chromatography to give 2b (46 mg). MS (ESI) M / Z: 370.1 [M+H + ]. 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.67(t,J=1.9Hz,1H),7.18(d,J=7.6Hz,1H),7.15-7.10(m,1H),7.03(t,J=7.8Hz,1H),5.40 (dd,J=12.6,5.4Hz,1H),4.45(s,2H),3.87(t,J=6.0Hz,2H),3.64(s,3H),2.96-2.82(m,1H),2.81-2.56(m,4H),2.10-1.95(m,1H).

[0257] Step 3: Dissolve 2b (35 mg, 0.09 mmol) and A (crude hydrochloride, 47 mg, 0.09 mmol) in tetrahydrofuran (2 mL) at room temperature, add sodium triacetoxyborohydride (100 mg, 0.47 mmol) under ice-water bath and stirring. The reaction solution was then stirred at room temperature for 2 hours. LC-MS showed that the starting material was completely reacted. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution and extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with saturated brine (2×30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the crude residue was purified by thin-layer preparative chromatography to obtain the desired product 2 (10.79 mg). MS (ESI) M / Z: 852 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.6Hz,1H),8.79(d,J=7.6Hz,1H),8.41 (d,J=4.0Hz,1H),8.26(d,J=5.6Hz,1H),7.27-7.00(m,4H),6.86-6.44(m,1H),5.43-5.3 5(m,1H),5.28-5.07(m,1H),4.96-4.90(m,1H),4.80-4.74(m,1H),4.44(s,2H),3.84-3. 51(m,7H),3.44-3.39(m,2H),2.93-2.60(m,3H),2.51-2.07(m,10H),2.06-1.48(m,9H).

[0258] Example 3

[0259] Step 1: Dissolve 3a (2.0 g, 12.72 mmol) in acetonitrile (63 mL) at room temperature and add potassium carbonate (4.4 g, 31.8 mmol) with stirring. Cool to 0°C in an ice-water bath and add 3-bromopropyne (1.72 g, 13.99 mmol) with stirring. The reaction mixture was then stirred at room temperature for 1 hour. Thin-layer chromatography showed complete consumption of the starting material and the formation of new spots. The reaction mixture was slowly added dropwise to water and extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to afford 3b (2.75 g, yield: 81%) as a colorless liquid. 1 H NMR (400MHz, CDCl3) δ4.14 (q, J = 7.1Hz, 2H), 3.30 (d, J = 2.4Hz, 2H), 2.89-2.85 (m, 2H), 2.35-2.21 (m, 4H), 2.09-1.62 (m, 4H), 1.25 (t, J = 7.1Hz, 3H).

[0260] Step 2: Dissolve 3b (2.03 g, 10.40 mmol) in tetrahydrofuran (15 mL) at room temperature. A solution of lithium aluminum tetrahydride in tetrahydrofuran (2.5 M, 12.48 mL, 31.2 mmol) was slowly added dropwise to the reaction mixture at 0°C with stirring. The reaction mixture was then stirred at 0°C for 1 hour. Thin-layer chromatography showed complete consumption of the starting material and formation of the product. The reaction mixture was slowly added dropwise to ice water to quench the mixture, and the resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to afford 3c (1.18 g). 1 H NMR (400MHz, CDCl3) δ3.50(d,J=6.5Hz,2H),3.30(d,J=2.4Hz,2H),2.92(d,J=11.5H z,2H),2.29-2.12(m,3H),1.82-1.75(m,2H),1.55-1.45(m,1H),1.38-1.20(m,2H).

[0261] Step 3: 3c (159 mg, 1.04 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature. Under argon, B (422 mg, 1.25 mmol), cuprous iodide (39.61 mg, 0.21 mmol), and cesium carbonate (1.36 g, 4.16 mmol) were added. The reaction mixture was purged with argon three times, and then bistriphenylphosphine palladium dichloride (146 mg, 0.21 mmol) was added. The reaction mixture was then stirred at 80°C under argon for 2 hours. LC-MS showed that the starting material was completely consumed and the product was formed. The cooled reaction mixture was diluted with water, and the resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to yield 3d (178 mg). MS (ESI) M / Z: 411.2 [M+H + ].

[0262] Step 4: 3d (100 mg, 0.259 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature, cooled to 0 ° C in an ice-water bath and added with stirring Dess-Martin oxidant (165 mg, 0.389 mmol). The reaction solution was then stirred at room temperature for 4 hours. LC-MS showed that the starting material was completely consumed and the product was generated. The reaction solution was slowly added dropwise to a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting residue was separated by thin layer preparative chromatography to give 3e (48 mg). MS (ESI) M / Z: 409.2 [M+H + ]. 1 H NMR (400MHz, CDCl3) δ9.67(s,1H),8.06(s,1H),7.17(d,J=7.9Hz,1H),6.98(t,J=7.9Hz,1H),6.74(d,J=7.8Hz,1H),5.19(dd ,J=12.6,5.3Hz,1H),3.77(s,3H),3.58(s,2H),2.96-2.90(m,3H),2.84-2.75(m,2H),2.50-2.20(m,5H),2.05-1.95(m,3H).

[0263] Step 5: 3e (24 mg, 0.058 mmol) and A (crude hydrochloride, 32 mg, 0.058 mmol) were dissolved in tetrahydrofuran (1 mL) at room temperature, stirred in an ice-water bath for 20 minutes, and sodium triacetoxyborohydride (50 mg, 0.235 mmol) was added. The reaction solution was then stirred at room temperature overnight. LC-MS showed that the starting material was completely consumed and the product was generated. The reaction solution was slowly added to water to quench, and the resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by thin layer preparative chromatography to obtain 3 (13.8 mg, yield 26%). MS (ESI) M / Z: 891.4 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.1Hz,1H),8.78(d,J=7.7Hz,1H),8.40(s,1 H),8.25(d,J=5.6Hz,1H),7.28-7.00(m,4H),6.89-6.45(m,1H),5.43-5.37(m,1H),5.28-5.08 (m,1H),4.94(s,1H),4.80-4.75(m,1H),3.84-3.71(m,2H),3.65(s,3H),3.58-3.43(m,4H),2 .98-2.65(m,7H),2.33-2.20(m,7H),2.20-1.98(m,5H),1.71-1.64(m,7H),1.24-1.15(m,3H).

[0264] Example 4

[0265] Step 1: Dissolve 1,4-butanediol (11.36 g, 126.09 mmol) in tetrahydrofuran (30 mL) at room temperature, cool to 0°C, and add sodium hydride (60%, 2.02 g, 50.44 mmol) with stirring. The reaction mixture is then stirred at room temperature for 1 hour. A solution of 3-bromopropyne (3.0 g, 25.22 mmol) in tetrahydrofuran (10 mL) is then slowly added dropwise with stirring to 0°C. After the addition is complete, the reaction mixture is stirred at room temperature overnight. Thin-layer chromatography (TLC) shows complete consumption of the starting material and the formation of new spots. The reaction mixture is diluted with water and extracted with ethyl acetate (3 x 40 mL). The combined organic phases are washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the resulting residue is separated by silica gel column chromatography to yield compound 4a (2.75 g). 1H NMR (400MHz, CDCl3) δ4.15 (d, J = 2.4Hz, 2H), 3.67 (t, J = 5.8Hz, 2H), 3.57 (t, J = 5.9Hz, 2H), 2.43 (t, J = 2.4Hz, 1H), 1.78-1.65 (m, 5H).

[0266] The subsequent reaction procedures were carried out in accordance with Example 2. 4 (22.06 mg, yield: 42%) was obtained. MS (ESI) M / Z: 866.5 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=4.8Hz,1H),8.79(d,J=8.0Hz,1H),8.40(d,J=3.6Hz,1H),8.26 (d,J=5.6Hz,1H),7.28-7.00(m,4H),6.89-6.44(m,1H),5.44-5.39(m,1H),5.28-5.08(m,1H),4.95-4.90(m,1H) ,4.80-4.74(m,1H),4.43(s,2H),3.84-3.72(m,2H),3.64-3.62(m,4H),3.59-3.55(m,3H),3.47-3.43(m,1H),2. 91-2.85(m,1H),2.75-2.57(m,3H),2.38-2.28(m,4H),2.20-2.11(m,3H),2.06-1.92(m,4H),1.75-1.50(m,8H).

[0267] Example 5

[0268] Step 1: Dissolve ethyl 2-hydroxymethylisobutyrate (5.0 g, mmol) in N,N-dimethylformamide (50 mL) at room temperature. Add sodium hydride (60%, 2.05 g, 51.3 mmol) under an ice-water bath and stirring. After 20 minutes, add 3-bromopropyne (3.25 mL, 4.48 g, 37.62 mmol) to the reaction solution. Remove the ice-water bath after 20 minutes, and stir the reaction solution at room temperature under argon overnight. Thin-layer chromatography (TLC) shows the disappearance of the starting material and the formation of new spots. Add saturated aqueous ammonium chloride (approximately 50 mL) to the reaction mixture. Extract the resulting product with ethyl acetate (3 × 00 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the resulting residue is separated by silica gel column chromatography to yield 5a (2.12 g). 1H NMR (400MHz, CDCl3) δ4.17-4.11(m,4H),3.53(s,2H),2.41(t,J=2.2Hz,1H),1.25(t,J=7.0Hz,3H),1.20(s,6H).

[0269] Step 2: Dissolve 5a (1.0 g, 5.43 mmol) in methanol / water (10 mL / 5 mL) at room temperature and add sodium hydroxide (2.17 g, 54.3 mmol). Stir the reaction at 100°C for 2 hours. Thin-layer chromatography indicated completion of the reaction. Adjust the pH of the cooled reaction mixture to 5 with concentrated hydrochloric acid, and extract the resulting mixture with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford crude product 5b (772 mg). 1 H NMR (400MHz, CDCl3) δ4.18 (d, J = 2.4Hz, 2H), 3.55 (s, 2H), 2.43 (t, J = 2.2Hz, 1H), 1.24 (s, 6H).

[0270] Step 3: To a solution of A (140 mg, 0.28 mmol) and 5b (50 mg, 0.32 mmol) in N,N-dimethylformamide (2 mL) was added 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 72 mg, 0.56 mmol) under an ice-water bath. After 5 minutes, N,N-diisopropylethylamine (0.1 mL, 0.42 mmol) was added. The reaction was then stirred at room temperature for 5 hours. LC-MS indicated the reaction was complete. Water (approximately 5 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude residue was separated by silica gel column chromatography to obtain the crude product (106 mg). The crude product was further purified by preparative thin-layer chromatography to obtain 5c (58 mg). MS (ESI) M / Z: 637.4 [M+H + ].

[0271] Step 4: Under argon protection, B (15 mg, 0.044 mmol) and 5c (58 mg, 0.091 mmol) were dissolved in N, N-dimethylformamide (2 mL), and cesium carbonate (29 mg, 0.090 mmol), cuprous iodide (2 mg, 0.0089 mmol) and bistriphenylphosphine palladium dichloride (3 mg, 0.0046 mmol) were added in sequence. The reaction solution was then stirred at 80 ° C and under argon protection for 6 hours. LC-MS showed that the reaction was complete. The cooled reaction solution was filtered through celite. The filter cake was washed with ethyl acetate (about 10 mL). The filtrate was added with water and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by thin layer preparative chromatography to give 5 (8.81 mg). MS (ESI) M / Z: 894.3 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.51(d,J=5.6Hz,1H),8.78(d,J=7.6Hz,1H),8.39(d,J=4.0 Hz,1H),8.27(d,J=5.6Hz,1H),7.28-7.01(m,5H),6.88-6.44(m,1H),5.42-5.37(m,1H),5.28-5.0 7(m,1H),4.94-4.85(m,2H),4.77(d,J=16.0Hz,1H),4.47(s,2H),3.81(s,2H),3.65-3.59(m,9H), 2.70-2.57(m,2H),2.33-2.27(m,4H),2.14(t,J=9.6Hz,3H),2.06-1.90(m,5H),1.60-1.44(m,6H).

[0272] Example 6

[0273] Referring to Example 4, the desired product 6 (11.83 mg) was obtained. MS (ESI) M / Z: 877.38 [M+H + ]. 1H NMR(400MHz, DMSO-d6) δ11.11(s,1H),9.50(d,J=5.2Hz,1H),8.79(d,J=7.6Hz,1H),8.40(d,J=2.8 Hz,1H),8.47(d,J=5.6Hz,1H),7.28-7.00(m,4H),6.87-6.44(m,1H),5.44-5.07(m,2 H),4.98-4.74(m,2H),4.45(s,2H),3.84-3.72(m,2H),3.66-3.59(m,4H),3.47-3.35 (m,3H),2.92-2.60(m,4H),2.42-1.93(m,12H),1.79-1.48(m,4H),0.49-0.31(m,4H).

[0274] Example 7

[0275] Referring to Example 5, the desired product 7 (5.06 mg) was obtained. MS (ESI) M / Z: 892.3 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.50(d,J=5.6Hz,1H),8.79(d,J=8.0Hz,1H),8.39(d,d,J=3.6Hz,1H),8.27(d,J=5.6Hz,1H),7.30-6.44(m,5H) ,5.42-5.07(m,2H),4.96-4.75(m,2H),4.45(s,2H),3.84-3.51(m,12H),2 .90-2.55(m,3H),2.28-1.90(m,8H),1.60-1.45(m,4H),0.91-0.73(m,4H).

[0276] Example 8

[0277] Step 1: To a stirred solution of propargyl alcohol (6.4 mL, 110 mmol) in tetrahydrofuran (100 mL) at 0°C under argon was added n-butyl lithium (1.6 M in hexanes, 7 mL, 11.2 mmol) via syringe. The reaction mixture was stirred at 0°C under argon for 10 minutes. Tert-butyl acrylate (14.6 mL, 110 mmol) was slowly added dropwise via syringe at 0°C. The reaction mixture was slowly allowed to return to room temperature and stirred under argon overnight. Thin-layer chromatography indicated that the starting material was essentially consumed. Acetic acid (1 mL) was added to the reaction mixture and stirred for 10 minutes. The resulting mixture was added with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to yield 8a (14 g). 1 H NMR (400MHz, DMSO-d6) δ4.12-4.10(m,2H),3.62(t,J=6.2Hz,2H),3.42-3.40(m,1H),2.44(t,J=6.2Hz,2H),1.40(s,9H).

[0278] Step 2: To a solution of dry B (200 mg, 0.59 mmol) and 8a (220 mg, 1.18 mmol) in dry N,N-dimethylformamide (8 mL) was added N,N-diisopropylethylamine (459 mg, 3.56 mmol) in one portion at room temperature. Bistriphenylphosphine palladium dichloride (28 mg, 0.04 mmol) and cuprous iodide (24 mg, 0.12 mmol) were then added under argon. The reaction mixture was heated to 80°C under argon and stirred for 5 hours. LC-MS showed that the reaction of the starting material was complete and the main product was 8b (40%, 254 nm; [M+H] + =442, RT=1.57 min). The cooled reaction solution was diluted with ethyl acetate (30 mL) and filtered through celite. The filter cake was washed with ethyl acetate (30 mL). Water (50 mL) was added to the filtrate and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting residue was separated by silica gel column chromatography to obtain pure compound 8b (146 mg). MS (ESI) M / Z: 464.1 [M+Na + ].

[0279] Step 3: Trifluoroacetic acid (2 mL) was added dropwise to a stirred solution of 8b (146 mg, 0.33 mmol) in dichloromethane (2 mL) under an ice-water bath. The reaction solution was then slowly returned to room temperature and stirred for 2 hours. LC-MS showed that the main product was 8c and the starting material had been completely consumed. The reaction solution was rotary evaporated to remove dichloromethane and trifluoroacetic acid. Purified water (30 mL) was added to the crude residue and freeze-dried overnight to obtain crude product 8c (58 mg). MS (ESI) M / Z: 386.1 [M+H + ].

[0280] Step 4: To a stirred solution of A (50 mg, 0.1 mmol) in N,N-dimethylformamide (3 mL) at room temperature under argon was added 8c (57.9 mg, 0.15 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol), and N,N-diisopropylethylamine (64.5 mg, 0.5 mmol). The reaction mixture was slowly returned to room temperature and stirred under argon for 1 hour. LC-MS showed complete reaction of the starting material with the main product 8 (34%). Saturated aqueous sodium bicarbonate (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the resulting residue was separated by thin layer preparative chromatography to obtain pure 8 (2.07 mg + 16.31 mg, yield: 22%). MS (ESI) M / Z: 866.55 [M+H + ];864.30[MH - ]. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.51(d,J=5.2Hz,1H),8.79(d,J=7.6Hz,1H),8.41(d,J=4.0Hz,1H), 8.26(d,J=5.6Hz,1H),7.29-7.01(m,4H),6.89-6.44(m,1H),5.44-5.39(m,1H),5.28-5.08(m,1H),4.99-4. 94(m,1H),4.80-4.75(m,1H),4.44(s,2H),3.84-3.73(m,4H),3.65-3.59(m,5H),3.47-3.43(m,4H),2.90-2 .84(m,1H),2.75-2.60(m,4H),2.38-2.33(m,2H),2.23-2.17(m,2H),2.08-1.95(m,3H),1.65-1.53(m,4H).

[0281] Example 9

[0282] Referring to Example 2, the desired product 9 (2.83 mg) was obtained. MS (ESI) M / Z: 878.4 [M+H + ]; 1 H NMR (400MHz, CDCl3) δ9.61 (s, 1H), 8.47-8.41 (m, 2H), 8.32 (d, J = 8.0Hz, 2H), 7.22-7.17 (m, 1H), 7.04-6.97 (m,2H),6.80-6.73(m,2H),6.12(d,J=7.6Hz,1H),5.45(s,1H),5.35-5.17(m,2H),4.84-4.60(m,3H),4.40 (s,2H),4.10-4.07(m,1H),4.00-3.95(m,2H),3.81(s,3H),3.68-3.64(m,2H),3.61-3.56(m,2H),3.51-3. 48(m,2H),2.98-2.92(m,2H),2.88-2.67(m,4H),2.48-2.36(m,8H),2.12-2.09(m,2H),2.03-1.97(m,2H).

[0283] Example 10

[0284] Step 1: Dissolve ethyl 2-bromo-2-methylpropanoate (1.0 g, 5.13 mmol) in tetrahydrofuran (10 mL) at room temperature. Add cesium carbonate (3.34 g, 10.26 mmol) with stirring in an ice-water bath. After 20 minutes, slowly add propargyl alcohol (0.30 mL, 5.13 mmol). After 20 minutes, return the reaction mixture to room temperature and stir overnight under argon. Thin-layer chromatography (TLC) shows complete consumption of the bromide starting material and the formation of new spots. Add saturated aqueous ammonium chloride (approximately 20 mL) to the reaction mixture with stirring in an ice-water bath. The resulting mixture is extracted with ethyl acetate (3 × 30 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the resulting residue is purified by preparative thin-layer chromatography to yield 10a (200 mg). 1 H NMR (400MHz, CDCl3) δ4.27-4.15(m,4H),2.42(t,J=2.4Hz,1H),1.48(s,6H),1.33-1.24(m,3H).

[0285] The subsequent operation was carried out according to Example 5 to obtain the desired product 10 (4.6 mg). MS (ESI) M / Z: 880.5 [M+H+ ]. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=4.8Hz,1H),8.79(d,J=8.0Hz,1H),8.41(d,J=4.0Hz,1H), 8.26(d,J=5.6Hz,1H),7.28-7.00(m,4H),6.88-6.44(m,1H),5.43-5.08(m,2H),5.01-4.97(m,1H),4.77(d, J=17.2Hz,1H),4.37(s,2H),3.95-3.81(m,4H),3.64-3.59(m,5H),3.51-3.43(m,2H),2.91-2.85(m,1H),2 .72-2.58(m,2H),2.41-2.33(m,2H),2.24-2.19(m,2H),2.06-1.94(m,3H),1.80-1.50(m,4H),1.42(s,6H).

[0286] Example 11

[0287] Referring to Example 5, the desired product 11 (3.1 mg) was obtained. MS (ESI) M / Z: 866.4 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.2Hz,1H),8.79(d,J=8.0Hz,1H),8.41(d,J=4.0Hz,1H),8.26(d,J=5.6 Hz,1H),7.29-7.00(m,4H),6.88-6.44(m,1H),5.42-5.38(m,1H),5.28-5.08(m,1H),4.98-4.93(m,1H),4.80-4.75(m,1H) ,4.62-4.56(m,1H),4.52-4.37(m,2H),3.84-3.80(m,2H),3.75-3.72(m,1H),3.64-3.63(m,3H),3.59(s,1H),3.54-3.43( m,4H),2.92-2.84(m,1H),2.76-2.59(m,3H),2.49-2.15(m,4H),2.07-1.93(m,3H),1.66-1.49(m,4H),1.29-1.27(m,2H).

[0288] Example 12

[0289] Referring to Example 5, the desired product 12 (36.29 mg) was obtained. MS (ESI) M / Z: 852.4 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.2Hz,1H),8.85(s,2H),8.79(d,J=7.6Hz,1H),8.69(s,1H),8.41(d,J= 3.6Hz,1H),8.26(d,J=5.6Hz,1H),7.55-7.46(m,1H),7.20-7.01(m,4H),6.88-6.45(m,1H),5.41(dd,J=12.6,5.4Hz,1H) ,5.28-5.07(m,1H),5.00-4.93(m,1H),4.80-4.75(m,1H),4.54(s,2H),4.29(d,J=6.8Hz,2H),3.81(s,3H),3.63-3.57(m ,4H),3.55-3.30(m,1H),2.95-2.55(m,3H),2.40-2.35(m,2H),2.24-2.19(m,2H),2.06-1.93(m,2H),1.69-1.50(m,4H).

[0290] Example 13

[0291] Step 1: Dissolve B (1.0 g, 2.96 mmol) in N,N-dimethylformamide (10 mL) at room temperature under argon. Add tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.42 g, 5.91 mmol), cesium carbonate (1.93 g, 5.91 mmol), cuprous iodide (112 mg, 591.43 μmol), and bistriphenylphosphine palladium dichloride (207 mg, 295.72 μmol) in this order. The reaction mixture was stirred at 80°C under argon for 2 hours. LC-MS showed a small amount of starting material B remaining, and the main product was 13a. Cool the reaction mixture to room temperature, add water (100 mL), and extract with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated brine (3×50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting residue was separated by silica gel column chromatography to obtain 13a (1.03 g). 1H NMR (400MHz, CDCl3) δ8.26(s,1H),7.16(d,J=8.0Hz,1H),6.99(t,J=7.8Hz,1H),6.76(d,J=7.6Hz,1H),5.20(dd,J=12.6,5.4Hz,1H),4.4 6(s,2H),3.81-3.73(m,6H),3.16-3.09(m,2H),2.98-2.66(m,3H),2.34-2.17(m,1H),1.94-1.81(m,2H),1.60-1.52(m,2H),1.46(s,9H).

[0292] Step 2: Dissolve 13a (300 mg, 604.15 μmol) in dichloromethane (3 mL) under ice-water bath, and add trifluoroacetic acid (1.17 g, 12.08 mmol) with stirring. The reaction solution was slowly returned to room temperature and stirred for 2 hours. LC-MS showed that the starting material was completely consumed and 13b was the main product. The reaction solution was concentrated under reduced pressure to obtain 13b (236 mg, trifluoroacetate salt). 1 H NMR (400MHz, DMSO-d6) δ7.25-7.00(m,3H),5.40(dd,J=12.6,5.4Hz,1H),4.50(s,2H),3.72-3.67(m,1H),3.64(s,3H ),3.08-3.02(m,2H),2.93-2.83(m,1H),2.76-2.60(m,3H),2.04-2.00(m,1H),1.94-1.91(m,2H),1.53-1.45(m,2H).

[0293] Step 3: 13b (100 mg, 252.24 μmol) and p-nitrophenyl chloroformate (76 mg, 378.36 μmol) were dissolved in dichloromethane (3 mL) and triethylamine (76 mg, 756.72 μmol) was added at 0°C with stirring. The reaction mixture was stirred at room temperature under argon for 1 hour. LC-MS showed that the starting material disappeared. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture and extracted with dichloromethane (3×10 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting residue was purified by thin layer preparative chromatography to give 13c (77 mg). 1H NMR (400MHz, CDCl3) δ8.28-8.23(m,2H),8.20-8.13(m,1H),7.32-7.28(m,2H ),7.18(d,J=8.8Hz,1H),7.00(t,J=8.0Hz,1H),6.78(d,J=7.2Hz,1H),5.22- 5.17(m,1H),4.50(s,2H),3.98-3.80(m,3H),3.78(s,3H),3.59-3.38(m,2H) ,3.00-2.66(m,3H),2.29-2.18(m,1H),2.04-1.92(m,2H),1.83-1.71(m,2H).

[0294] Step 4: 13c (57 mg, 101.50 μmol) and A (61 mg, 121.81 μmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature and under argon protection, and potassium carbonate (42 mg, 304.51 μmol) was added with stirring. The reaction solution was then reacted overnight at 80 ° C under argon protection. LC-MS showed that a small amount of raw material remained and the main product was 13. After the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by thin layer preparative chromatography to give 13 (26.78 mg). MS (ESI) M / Z: 921.4 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.50(d,J=5.2Hz,1H),8.78(d,J=7.6Hz,1H),8.41-8.40(m,1H),8.27-8.25(m,1H ),7.29-7.01(m,4H),6.88-6.44(m,1H),5.43-5.37(m,1H),5.28-5.07(m,1H),5.02-4.92(m,1H),4.80-4.75(m,1H),4. 50(s,2H),3.83-3.69(m,3H),3.64-3.57(m,4H),3.49-3.36(m,3H),3.18-3.09(m,2H),3.08-3.01(m,2H),2.93-2.84(m ,3H),2.76-2.61(m,2H),2.42-2.32(m,2H),2.25-2.15(m,2H),2.05-1.87(m,5H),1.69-1.53(m,4H),1.48-1.39(m,2H).

[0295] Example 14

[0296] Step 1: To a stirred solution of N-Boc-3-hydroxyazetidine (10.1 g, 58.31 mmol) in tetrahydrofuran (100 mL) was added sodium hydride (60%, 2.80 g, 69.97 mmol) under ice-water bath. After stirring under ice-water bath for 0.5 hour, the reaction mixture was returned to room temperature and stirred for 0.5 hour. 3-Bromopropyne (8.32 g, 69.97 mmol, 6.03 mL) was added to the reaction mixture. The reaction mixture was then stirred at 60°C under argon overnight. LC-MS indicated the reaction was complete. The reaction mixture was cooled, placed in an ice-water bath, and quenched by the addition of saturated aqueous ammonium chloride (approximately 100 mL) with stirring. The resulting mixture was diluted with water (approximately 100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the resulting crude residue was separated by silica gel column chromatography to afford the desired product 14a (11.60 g). 1 H NMR (400MHz, DMSO-d6) δ4.39-4.32(m,1H),4.14(d,J=2.4Hz,2H),4.04-3.99(m,2H),3.71-3.67(m,2H),3.46(t,J=2.4Hz,1H),1.37(s,9H).

[0297] The subsequent reaction was carried out according to Example 13 to obtain the desired product 14 (25.4 mg). MS (ESI) M / Z: 893.2 [M+H + ]; 1H NMR (400MHz, CDCl3) δ9.63(s,1H),8.83(br,1H),8.49(d,J=10.0Hz,2H),8.32(d,J=7.6Hz,1H),7.17(dd,J=8.0,0.8Hz,1H),7.00(t,J=7.8 Hz,1H),6.92-6.64(m,2H),6.12(d,J=7.6Hz,1H),5.45(s,1H),5.22(dd,J=12.8,5.2Hz,1H),4.83-4.71(m,2H),4.48-4.39(m,3H),4.20-4. 16(m,2H),4.05-3.95(m,4H),3.78(s,3H),3.59(d,J=9.2Hz,1H),3.49(d,J=9.2Hz,1H),3.33-3.24(m,2H),3.22-3.12(m,2H),2.99-2.92(m ,1H),2.89-2.83(m,1H),2.81-2.67(m,1H),2.42-2.36(m,2H),2.31- 2.20(m,3H),2.12-2.09(m,1H),2.04-1.97(m,1H),1.57-1.51(m,4H).

[0298] Example 15

[0299] Referring to Example 2, the desired product 15 (9.02 mg) was obtained. MS (ESI) M / Z: 836.5 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.50(d,J=5.2Hz,1H),8.79(d,J=7.6Hz,1H),8.42-8.40(m,1H) ,8.26(d,J=5.6Hz,1H),7.28-6.97(m,4H),6.88-6.44(m,1H),5.42-5.36(m,1H),5.28-5.07(m,1H),5 .01-4.90(m,1H),4.80-4.74(m,1H),3.83-3.72(m,2H),3.65(s,3H),3.62-3.59(m,1H),3.45-3.39(m ,2H),2.94-2.85(m,1H),2.75-2.60(m,3H),2.39-2.13(m,9H),2.05-1.90(m,4H),1.84-1.44(m,8H).

[0300] Example 16

[0301] Referring to Example 13, the desired product 16 (134.24 mg) was obtained. MS (ESI) M / Z: 852.3 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.49(d,J=4.8Hz,1H),8.78(d,J=8.0Hz,1H),8.40(d,J=4.4Hz,1H),8.26(d,J =5.6Hz,1H),7.28-6.98(m,4H),6.88-6.44(m,1H),5.42-5.37(m,1H),5.28-5.07(m,1H),4.99-4.90(m,1H),4.80-4. 75(m,1H),4.23-4.19(m,2H),3.83-3.73(m,2H),3.64(s,3H),3.62-3.57(m,1H),3.46-3.30(m,5H),2.92-2.82(m,3H ),2.75-2.59(m,2H),2.35-2.30(m,2H),2.20-2.15(m,2H),2.07-1.92(m,3H),1.60-1.57(m,2H),1.53-1.51(m,2H).

[0302] Example 17

[0303] Referring to Example 1, the desired product 17 (72.51 mg) was obtained. MS (ESI) M / Z: 822.4 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.50(d,J=4.8Hz,1H),8.78(d,J=7.6Hz,1H),8.42(d,J= 3.6Hz,1H),8.26(d,J=5.6Hz,1H),7.28-6.98(m,4H),6.88-6.44(m,1H),5.42-5.37(m,1H),5. 28-5.07(m,1H),5.01-4.90(m,1H),4.80-4.75(m,1H),3.84-3.72(m,2H),3.65-3.59(m,5H),3 .50-3.40(m,1H),2.95-2.85(m,1H),2.76-2.54(m,7H),2.44-2.13(m,6H),2.07-1.52(m,9H).

[0304] Example 18

[0305] Referring to Example 14, the desired intermediate 18c (5.8 g) was obtained. 1 H NMR (400MHz, CDCl3) δ4.28-4.20(m,1H),4.18-4.11(m,2H),3.51-3.35(m,4H),2.44(t,J=2.4Hz 1H),2.10-1.89(m,2H),1.46(s,9H).

[0306] Step 4: A (100 mg, 200.59 μmol) and p-nitrophenyl chloroformate (61 mg, 300.88 μmol) were dissolved in dichloromethane (3 mL) under ice-water bath and stirring, and triethylamine (61 mg, 601.76 μmol) was added under ice-water bath and stirring. The reaction solution was then warmed to room temperature and stirred under argon for 1 hour. LC-MS showed that the starting material disappeared. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution and extracted with dichloromethane (3×10 mL). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by thin layer preparative chromatography to give 18d (85 mg). 1 H NMR(400MHz, CDCl3)δ9.62(s,1H),8.49-8.45(m,1H),8.43-8.41(m,1H),8.34-8 .31(m,1H),8.28-8.23(m,2H),7.31-7.28(m,2H),6.79(t,J=54.0Hz,1H),6.13(d ,J=8.0Hz,1H),5.46(s,1H),4.83-4.77(m,2H),4.01-3.96(m,2H),3.69-3.48(m, 6H),2.54-2.37(m,4H),2.13-2.09(m,1H),2.05-1.97(m,1H),1.82-1.77(m,4H).

[0307] Step 5: 18d (70 mg, 105.48 μmol) and 18c (61 mg, 158.22 μmol) were dissolved in dimethyl sulfoxide (1 mL) at room temperature and under argon protection, and N,N-diisopropylethylamine (136 mg, 1.05 mmol) was added with stirring. The reaction solution was then stirred at 100 ° C. under argon protection overnight. LC-MS showed that the main product was 18. The reaction solution was cooled to room temperature, saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, and then extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer preparative chromatography to give 18 (5.11 mg). MS (ESI) M / Z: 907.4 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=4.8Hz,1H),8.78(d,J=7.6Hz,1H),8.41-8.40(m,1H),8.26(d,J=5.6Hz,1H),7.29-7.01(m,4H ),6.88-6.44(m,1H),5.43-5.38(m,1H),5.28-5.07(m,1H),5.00-4.90 (m,1H),4.80-4.75(m,1H),4.54-4.44(m,2H),4.32-4.23(m,1H),3.85- 3.72(m,2H),3.68-3.51(m,5H),3.47-3.21(m,4H),3.18-2.81(m,5H),2.74-2.60( m,2H),2.38-2.27(m,2H),2.22-2.11(m,2H),2.08-1.83(m,5H),1.68-1.42(m,4H).

[0308] Example 19

[0309] Referring to Example 18, the desired product 19 (12.02 mg) was obtained. MS (ESI) M / Z: 907.5 [M+H + ]. 1H NMR (400MHz, CDCl3) δ9.73-9.20(m,2H),8.64-8.52(m,2H),8.32(d,J=6.8Hz,1H),7.19-7.16(m,1H),7.0 1-6.96(m,1H),6.91-6.63(m,2H),6.12(d,J=7.6Hz,1H),5.45(s,1H),5.32-5.22(m,1H),4.79(s,1H),4.6 9(t,J=8.0Hz,1H),4.55(t,J=16.0Hz,1H),4.40-4.33(m,1H),4.26-4.21(m,1H),3.97(s,2H),3.78(d,J= 1.2Hz,3H),3.66-3.40(m,6H),3.22-2.69(m,8H),2.34-2.2(m,4H),2.13-1.97(m,5H),1.53-1.47(m,3H).

[0310] Example 20

[0311] Referring to Example 12, the desired product 20 (1.96 mg) was obtained. MS (ESI) M / Z: 892.6 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.51(d,J=8.8Hz,1H),8.75(d,J=15.2Hz,1H),8.41(d,J=4.4Hz,1H),8.26 (d,J=5.2Hz,1H),7.00-7.29(m,4H),6.40-6.90(m,1H),5.35-5.45(m,1H),5.28(s,1H),5.05(s,1H),4.90-5.00( m,1H),4.75(d,J=13.6Hz,2H),4.38(s,2H),4.10(d,J=8.4Hz,3H),3.91(s,2H),3.80(s,2H),2.85-2.95(m,4H),2 .65-2.72(m,4H),2.32-2.40(m,2H),2.15-2.29(m,3H),2.00-2.10(m,3H),1.99-1.95(m,2H),1.19-1.63(m,4H).

[0312] Example 21

[0313] Step 1: At room temperature and under argon, B (300 mg, 891.84 μmol) was dissolved in N,N-dimethylformamide (3 mL). Propargyl alcohol (100 mg, 1.78 mmol), cesium carbonate (581 mg, 1.78 mmol), cuprous iodide (34 mg, 1.78 μmol), and bistriphenylphosphine palladium dichloride (62 mg, 89.18 μmol) were added sequentially. The reaction mixture was stirred at 80°C under argon for 2 hours. LC-MS showed a small amount of residual starting material B, and the main product was 21a. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to afford 21a (81 mg, yield: 29%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.15(d,J=7.6Hz,1H),7.08(d,J=8.0Hz,1H),7.02(t,J=7.6Hz,1H),5. 42-5.36(m,2H),4.36(d,J=6.0Hz,2H),3.65(s,3H),2.97-2.82(m,1H),2.77-2.57(m,2H),2.04-1.99(m,1H).

[0314] Step 2: Triethylamine (0.11 mL, 0.78 mmol) was added to a solution of 21a (80 mg, 0.26 mmol) and 4-nitrophenyl chloroformate (105 mg, 0.52 mmol) in dichloromethane (2.0 mL) in an ice-water bath and stirred. The reaction solution returned to room temperature after 10 minutes and stirred for 2 hours under argon protection. LC-MS showed that the reaction was complete. Saturated aqueous sodium bicarbonate solution (15 mL) was added to the reaction solution and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography and thin layer preparative chromatography to give 21b (38 mg). MS (ESI) M / Z: 479.1 [M+H + ]. 1H NMR (400MHz, CDCl3) δ8.32-8.29(m,2H),8.05(s,1H),7.43-7.40(m,2H),7.22-7.19(m,1H),7.04-6.99(m,1H),6.82 -6.79(m,1H),5.22-5.17(m,1H),5.14(s,2H),3.78(s,3H),2.99-2.93(m,1H),2.87-2.70(m,2H),2.26-2.22(m,1H).

[0315] Step 3: A (300 mg, 601.76 μmol) and 1-Boc-3-azetidinone (515 mg, 3.01 mmol) were dissolved in tetrahydrofuran (5 mL) under ice-water bath, and sodium triacetoxyborohydride (510 mg, 2.41 mmol) was added under ice-water bath and stirred. The reaction solution was then stirred at room temperature for 2 hours. LC-MS showed that the starting material was completely consumed and 21c was generated. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer preparative chromatography to give 21c (240 mg). MS (ESI) M / Z: 654.5 [M+H + ].

[0316] Step 4: Dissolve 21c (240 mg, 367.12 μmol) in dichloromethane (4 mL) under ice-water bath and add trifluoroacetic acid (418 mg, 3.67 mmol) with stirring. The reaction solution was slowly returned to room temperature and stirred for 1 hour. LC-MS showed that the starting material was completely consumed and 21d was the main product. The reaction solution was concentrated under reduced pressure to obtain 21d (80 mg, crude trifluoroacetate salt). 1 H NMR(400MHz,DMSO-d6)δ9.51(d,J=5.2Hz,1H),9.30-9.08(m,3H),8.79(d,J=8.4Hz,1H ),8.44(d,J=4.4Hz,1H),8.26(d,J=5.2Hz,1H),7.27-7.00(m,1H),6.88-6.45(m,1H), 5.27-5.08(m,1H),5.03-4.95(m,1H),4.79-4.74(m,1H),4.40-4.26(m,3H),4.20-4.0 8(m,2H),3.87-3.44(m,5H),2.49-2.44(m,1H),2.36-2.21(m,3H),2.08-1.64(m,7H).

[0317] Step 5: Disperse 21d (60 mg, 108.69 μmol), 21b (40 mg, 83.61 μmol) and potassium carbonate (35 mg, 250.83 μmol) in N,N-dimethylformamide (2 mL) at room temperature. The reaction solution was then heated to 60 ° C and stirred for 3 hours. LC-MS showed that a small amount of starting material remained and product was generated. The reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (10 mL) was added and extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with saturated brine (6×10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting residue was separated by thin layer preparative chromatography to give 21 (17.52 mg). MS (ESI) M / Z: 893.4 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.49(d,J=5.2Hz,1H),8.78(d,J=7.6Hz,1H),8.39(d,J=4.0Hz,1H ),8.25(d,J=5.6Hz,1H),7.28-7.00(m,4H),6.87-6.44(m,1H),5.42-5.38(m,1H),5.27-5.07(m,1H),4. 98-4.90(m,3H),4.79-4.75(m,1H),4.02-3.88(m,2H),3.82-3.70(m,4H),3.64-3.43(m,5H),3.09-3.03 (m,1H),2.93-2.83(m,1H),2.76-2.58(m,2H),2.34-2.14(m,8H),2.08-1.92(m,3H),1.69-1.56(m,4H).

[0318] Example 22

[0319] Step 1: Dissolve 3-butyn-1-ol (0.5 g, 7.13 mmol) in dichloromethane (10 mL) at room temperature. Add p-toluenesulfonyl chloride (1.63 g, 8.56 mmol) and pyridine (850 mg, 10.70 mmol) sequentially with stirring in an ice-water bath. The reaction mixture is then stirred at room temperature for 16 hours. Thin-layer chromatography indicates complete reaction of the starting material. Add saturated aqueous ammonium chloride (20 mL) to the reaction mixture, followed by extraction with ethyl acetate (2 × 50 mL). The combined organic phases are washed with saturated brine (3 × 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated, and the resulting crude residue is separated by silica gel column chromatography to yield the desired product 22a (860 mg). 1H NMR (400MHz, CDCl3) δ7.80(d,J=7.6Hz,2H),7.36(d,J=8.0Hz,2H),4.10(t,J=7.0Hz,2H),2.57-2.52(m,2H),2.45(s,3H),1.99(t,J=2.8Hz,1H).

[0320] Step 2: 22a (201.8 mg, 0.90 mmol) was dissolved in N,N-dimethylformamide (4 mL) at room temperature, and A (300 mg, 0.60 mmol) and cesium carbonate (586.5 mg, 1.80 mmol) were added with stirring. The reaction solution was then stirred at 60°C overnight. LC-MS showed that the starting material was completely reacted. Water (30 mL) was added to the cooled reaction solution and then extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated sodium bicarbonate aqueous solution (2×30 mL), saturated brine (2×30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude residue was separated by silica gel column chromatography to obtain the desired product 22b (123 mg). MS (ESI) M / Z: 551.4 [M+H + ]; 1 H NMR (400MHz, CDCl3) δ9.61 (s, 1H), 8.43 (t, J = 8.4Hz, 2H), 8.32 (d, J = 7.6Hz, 1H), 6.78 (t,J=54.0Hz,1H),6.13(d,J=7.6Hz,1H),5.46(s,1H),4.81(d,J=10.4Hz,1H),4.75-4 .67(m,1H),4.02-3.94(m,2H),3.62-3.44(m,2H),2.61(t,J=7.6Hz,2H),2.55-2.35(m ,8H),2.33-2.24(m,2H),2.14-2.09(m,1H),1.99(t,J=2.6Hz,2H),1.78-1.70(m,5H).

[0321] Step 3: 22b (123 mg, 0.22 mmol) and B (50 mg, 0.15 mmol) were dissolved in dry N,N-dimethylformamide (2 mL) at room temperature under argon. Cesium carbonate (122.2 mg, 0.38 mmol), bistriphenylphosphine palladium dichloride (16 mg, 0.022 mmol), and cuprous iodide (9.0 mg, 0.045 mmol) were added sequentially under argon. The reaction was then stirred at 80°C under argon for 5 hours. LC-MS indicated the formation of product 22. The cooled reaction mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). Saturated aqueous sodium bicarbonate (10 mL) was added to the filtrate, followed by extraction with ethyl acetate (2 × 20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (5 × 20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude residue was separated by preparative thin-layer chromatography to yield the desired product 22 (6.9 mg). MS (ESI) M / Z: 808.6 [M+H + ]; 1 H NMR (400MHz, CDCl3) δ9.61 (s, 1H), 8.43 (t, J = 10.8Hz, 2H),8.32(d,J=8.0Hz,1H),8.10(s,1H),7.12(d,J=8.0Hz,1H),7.00-6.94(m,1H),6. 78(t,J=54.6Hz,1H),6.71(d,J=8.0Hz,1H),6.13(t,J=7.6Hz.1H),5.46(s,1H),5.25 -5.16(m,1H),4.83-4.68(m,2H),4.01-3.95(m,2H),3.80(s,3H),3.62-3.48(m,2H), 2.99-2.96(m,1H),2.88-2.70(m,2H),2.68(s,4H),2.50-2.35(m,11H),1.75(s,4H).

[0322] Example 23

[0323] Referring to Example 16, the desired product 23 (20.25 mg) was obtained. MS (ESI) M / Z: 838.4 [M+H + ]; 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.2Hz,1H),8.78(d,J=7.6Hz,1H),8.41(d,J=4.0Hz,1H),8.2 6(d,J=5.6Hz,1H),7.29-7.01(m,4H),6.88-6.44(m,1H),5.43-5.38(m,1H),5.28-5.07(m,1H),5.01-4.94(m, 3H),4.77(d,J=15.2Hz,1H),3.84-3.72(m,2H),3.65-3.59(m,5H),3.47-3.39(m,3H),3.39-3.32(m,1H),2.94 -2.85(m,1H),2.76-2.60(m,2H),2.43-2.37(m,2H),2.26-2.20(m,2H),2.08-1.95(m,3H),1.67-1.57(m,4H).

[0324] Example 24

[0325] Step 1: Dissolve 4-pentynoic acid (2 g, 19.04 mmol) and tert-butanol (21.16 g, 285.46 mmol) in dichloromethane (40 mL) at room temperature. Add dicyclohexylcarbodiimide (DCC, 6.31 g, 30.59 mmol) and 4-dimethylaminopyridine (DMAP, 0.5 g, 4.08 mmol) with stirring in an ice-water bath. The reaction mixture was then stirred at room temperature overnight. Thin-layer chromatography indicated complete reaction of the starting material. Dilute hydrochloric acid (0.5 M, 50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (2 × 100 mL). The combined organic phases were washed with saturated brine (3 × 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude residue was separated by silica gel column chromatography to yield the desired product 24a (1.27 g). 1 H NMR (400MHz, CDCl3) δ2.45(s,4H),1.97(s,1H),1.46(s,9H).

[0326] The subsequent steps were carried out according to Example 8 to obtain the desired product 24 (17.05 mg). MS (ESI) M / Z: 836.6 [M+H + ]. 1H NMR (400MHz, CDCl3) δ11.11(s,1H),9.50(d,J=5.2Hz,1H),8.79(d,J=7.6Hz,1H),8.41(d,J=3.6Hz,1H) ,8.26(t,J=5.6Hz,1H),7.29-6.95(m,4H),6.89-6.44(m,1H),5.43-5.37(m,1H),5.28-5.07(m,1H),5.0 3-4.95(m,1H),4.80-4.75(m,1H),3.84-3.72(m,2H),3.65-3.59(m,4H),3.50-3.30(m,4H),2.92-2.84 (m,1H),2.74-2.59(m,7H),2.42-2.30(m,2H),2.25-2.19(m,2H),2.09-1.90(m,3H),1.70-1.50(m,4H).

[0327] Example 25

[0328] Referring to Example 24, the desired product 25 (2.25 mg) was obtained. MS (ESI) M / Z: 850.6 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.51(d,J=5.2Hz,1H),8.80(d,J=7.2Hz,1H),8.42(d,J=2.4Hz,1H ),8.28(d,J=4.8Hz,1H),7.28-6.97(m,4H),6.89-6.45(m,1H),5.44-5.35(m,1H),5.28-5.08(m,1H),5. 01-4.95(m,1H),4.80-4.75(m,1H),3.84-3.72(m,3H),3.68-3.55(m,4H),3.47-3.33(m,5H),2.92-2.60 (m,6H),2.40-2.30(m,2H),2.24-2.18(m,1H),2.05-1.95(m,4H),1.83-1.79(m,2H),1.66-1.50(s,4H).

[0329] Example 26

[0330] Step 1: To a stirred solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (1.0 g, 4.97 mmol) in dichloromethane (20 mL) was added Dess-Martin oxidant (4.22 g, 9.94 mmol) under an ice-water bath. The reaction mixture was returned to room temperature after 10 minutes and stirred under argon for 1 hour. Thin layer chromatography showed that the reaction was complete. The reaction mixture was filtered through celite. The filter cake was washed with ethyl acetate (30 mL), and the combined filtrate was added with water and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to obtain 26a (567 mg). 1 H NMR (400MHz, CDCl3) δ9.77 (s, 1H), 4.13 (t, J = 8.6Hz, 2H), 3.59-3.55 (m, 2H), 2.99-2.82 (m, 3H), 1.43 (s, 9H).

[0331] Step 2: To a stirred solution of 26a (630 mg, 3.23 mmol) in methanol (10 mL) was added dimethyl (1-diazo-2-oxopropyl)phosphonate (682 mg, 3.55 mmol) and potassium carbonate (670 mg, 4.85 mmol) at room temperature. The reaction was stirred at room temperature under argon overnight. Thin-layer chromatography indicated complete reaction of the starting material. Water (30 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford 26b (600 mg). 1 H NMR (400MHz, DMSO-d6) δ3.89 (brs, 2H), 3.55 (brs, 2H), 2.85 (t, J = 2.6Hz, 1H), 2.70-2.62 (m, 1H), 2.43-2.40 (m, 2H), 1.37 (s, 9H).

[0332] The subsequent steps were carried out according to Example 18 to obtain the desired product 26 (14.70 mg). MS (ESI) M / Z: 877.3 [M+H + ]; 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.50(d,J=5.6Hz,1H),8.79(d,J=8.0Hz,1H),8.41(d,J=4.0Hz,1H),8. 26(d,J=5.6Hz,1H),7.29-6.98(m,4H),6.89-6.44(m,1H),5.42-5.37(m,1H),5.28-5.08(m,1H),5.00-4.92( m,1H),4.80-4.75(m,1H),4.04-3.99(m,2H),3.83-3.70(m,5H),3.63-3.59(m,5H),3.47-3.43(m,1H),3.20- 3.11(m,4H),2.77-2.72(m,3H),2.39-2.33(m,2H),2.22-2.16(m,2H),2.04-1.95(m,3H),1.58-1.50(m,5H).

[0333] Example 27

[0334] Referring to Example 26, the desired product 27 (6.33 mg) was obtained. MS (ESI) M / Z: 905.4 [M+H + ]. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.51(d,J=5.2Hz,1H),8.79(d,J=7.6Hz ,1H),8.41(d,J=4.0Hz,1H),8.26(d,J=5.6Hz,1H),7.30-6.97(m,4H),6.89-6 .44(m,1H),5.42-5.37(m,1H),5.28-5.08(m,1H),5.00-4.95(m,1H),4.80-4. 75(m,1H),3.84-3.72(m,2H),3.64-3.43(m,7H),3.13-3.04(m,4H),2.95-2.84 (m,1H),2.77-2.60(m,4H),2.41-2.33(m,2H),2.24-2.16(m,2H),2.08-1.95(m,4H),1.79-1.58(m,7H),1.38-1.25(m,3H).

[0335] Example 28

[0336] Step 1: 2-(Propan-2-en-1-yloxy)tetrahydro-2H-pyran (312 mg, 2.22 mmol), B (300 mg, 0.9 mmol), cesium carbonate (876.6 mg, 2.7 mmol), cuprous iodide (618 mg, 0.09 mmol), and bis(triphenylphosphine)palladium dichloride (60 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (6 mL) at room temperature. The reaction system was evacuated and purged with nitrogen several times. The reaction solution was stirred in an oil bath at 85°C for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 28a (140 mg). MS (ESI) M / Z: 398.1 [M+H + ]. 1 H NMR (400MHz, CDCl3) δ8.04(s,1H),7.18(d,J=7.5Hz,1H),6.98(t,J=7.9Hz,1H),6.75(d,J=7.8Hz,1H),5.19(dd,J=12.4,5.2Hz,1H),4.89( t,J=3.4Hz,1H),4.53(d,J=3.6Hz,2H),3.93–3.84(m,1H),3.79(d,J=4.4Hz,3H),3.60–3.53(m,1H),1.85–1.73(m,2H),1.67–1.50(m,9H).

[0337] Step 2: 28a (140 mg, 0.352 mmol) and p-toluenesulfonic acid (72 mg, 0.704 mmol) were dissolved in methanol (5 mL). The reaction system was purged with nitrogen and stirred at 25 ° C for 3 hours. After TLC monitoring showed that the starting material disappeared, dichloromethane (30 mL) was added to the reaction solution to dilute the reaction solution. The reaction solution was washed with water (30 mL × 3) three times, and the organic phase was extracted. The organic phase was washed with saturated brine (300 mL × 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 28b (70 mg). MS (ESI) M / Z: 314.1 [M+H + ]. 1H NMR (400MHz, DMSO) δ11.12(s,1H),7.15(d,J=7.7Hz,1H),7.10–7.06(m,1H),7.02(t,J=7.8Hz,1H),5 .40(dd,J=12.7,5.3Hz,1H),4.36(s,2H),2.96–2.83(m,1H),2.65(s,2H),1.99(s,1H),1.17(s,1H).

[0338] Step 3: 28b (70 mg, 0.22 mmol) was dissolved in ethyl acetate (5 mL) to replace nitrogen in the reaction system and manganese dioxide (350 mg, 2.2 mmol) was slowly added to the reaction solution and stirred at room temperature overnight. After TLC monitoring showed that the starting material disappeared, ethyl acetate (20 mL) was added to the reaction solution to dilute the reaction solution, and then filtered to obtain a filtrate. The organic phase was first washed with saturated brine (20 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 28c (55 mg). MS (ESI) M / Z: 312.1 [M+H + ].

[0339] Step 4: (S)-pyrrolidin-3-ylmethanol (1.5 g, 14.5 mmol), di-tert-butyl dicarbonate (4.6 g, 22 mmol), 4-dimethylaminopyridine (180 mg, 1.45 mmol), and triethylamine (3.0 g, 29 mmol) were dissolved in dichloromethane (10 mL) at room temperature. The reaction system was evacuated and replaced with nitrogen several times. The reaction solution was stirred in an oil bath at 25°C for 12 hours. After LC-MS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 28d (1.8 g).

[0340] Step 5: 28d (300 mg, 1.5 mmol) and triethylamine (450 mg, 4.5 mmol) were dissolved in dichloromethane (5 mL) at room temperature. The reaction system was cooled to zero degrees and methylsulfonyl chloride (258 mg, 2.25 mmol) was slowly added dropwise, and then vacuumed and replaced with nitrogen several times. The reaction solution was stirred in an oil bath at 25 degrees for 12 hours. After LC-MS monitoring showed that the starting material disappeared, water (30 mL) was added to the reaction solution to quench the reaction. The mixed solution was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. The organic phase was first washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 28e (340 mg).

[0341] Step 6: Dissolve 28e (309 mg, 0.99 mmol), A (450 mg, 0.9 mmol), potassium iodide (372 mg, 2.7 mmol), and potassium carbonate (150 mg, 0.9 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction system was evacuated and replaced with nitrogen several times. The reaction solution was stirred in an oil bath at 90°C for 12 hours. After LC-MS monitoring showed the disappearance of the starting material, water (30 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 28f (270 mg). MS (ESI) M / Z: 583.1 [M+H+].

[0342] Step 7: 28f (270 mg, 0.39 mmol) was dissolved in dioxane (3 mL) at room temperature, followed by the dropwise addition of dioxane hydrochloride (3 mL) at 0°C. The reaction was stirred in an oil bath at 25°C for 2 hours. After LCMS monitoring indicated the disappearance of the starting material, the product was concentrated under reduced pressure and the pH was adjusted to 7-8. The product was then prepared by reverse phase chromatography to afford 28f (170 mg). MS (ESI) M / Z: 583.1 [M+H+].

[0343] Step 8: Dissolve 28g (300mg, 0.9mmol), cesium carbonate (876.6mg, 2.7mmol), cuprous iodide (618mg, 0.09mmol), and bis(triphenylphosphine)palladium dichloride (60mg, 0.09mmol) in N,N-dimethylformamide (6mL) at room temperature. The reaction system was evacuated and replaced with nitrogen several times. The reaction solution was stirred in an oil bath at 85°C for 3 hours. After LC-MS monitoring showed the disappearance of the starting material, water (30mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (30mL x 3). The organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 28 (140mg). MS (ESI) M / Z: 398.1 [M+H+]. 1H NMR (400MHz, CDCl3) δ8.04(s,1H),7.18(d,J=7.5Hz,1H),6.98(t,J=7.9Hz,1H),6.75(d,J=7.8Hz,1H),5.19(dd,J=12.4,5.2Hz,1H),4.89( t,J=3.4Hz,1H),4.53(d,J=3.6Hz,2H),3.93–3.84(m,1H),3.79(d,J=4.4Hz,3H),3.60–3.53(m,1H),1.85–1.73(m,2H),1.67–1.50(m,9H).

[0344] Example 29

[0345] Step 1: Dissolve (1R,3R)-methyl 3-hydroxycyclobutane-1-carboxylate (5.0 g, 38.4 mmol) in dry tetrahydrofuran (32 mL) and place in an ice-water bath. After the reaction system is cooled to 0°C, lithium aluminum hydride (2.5 M, 30.7 mL) is slowly added dropwise to the reaction mixture under a nitrogen atmosphere. The reaction is stirred at 0°C for 3 hours. After TLC monitoring shows the disappearance of the starting material, tetrahydrofuran (300 mL) is added to the reaction mixture to dilute it. Then, Na2SO4·10H2O is slowly added to quench the excess lithium aluminum hydride. A large amount of white solid is produced in the reaction mixture, which is filtered and the filtrate is concentrated under reduced pressure. The resulting mixture is purified by silica gel column chromatography to yield 29a (2.7 g). 1 H NMR (400MHz, DMSO) δ4.86 (d, J=6.3Hz, 1H), 4.46 (t, J=5.4Hz, 1H), 4.16–4.09 (m, 1H), 3.35(dd,J=7.0,5.5Hz,2H),2.18–2.05(m,1H),2.01–1.92(m,2H),1.88–1.78(m,2H).

[0346] Step 2: Dissolve 29a (2.5 g, 24.5 mmol) and imidazole (5.0 g, 73.5 mmol) in dichloromethane (30 mL). The reaction system was purged with nitrogen and placed in an ice-water bath. After the reaction system was cooled to 0°C, tert-butyldiphenylsilyl chloride (8.1 g, 29.4 mmol) was slowly added dropwise to the reaction solution under a nitrogen atmosphere. The reaction was stirred at 25°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, dichloromethane (30 mL) was added to the reaction solution to dilute it. The reaction solution was then washed with water (30 mL x 3). The organic phase was extracted and washed with saturated brine (300 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 29b (2.7 g). 1H NMR (400MHz, DMSO) δ7.65–7.54(m,5H),7.54–7.36(m,5H),4.92(d,J=6.3Hz,1H),4.15(dd,J=13.7,6. 8Hz,1H),3.61(d,J=6.5Hz,2H),2.33–2.21(m,1H),2.09–2.00(m,2H),1.95–1.85(m,2H),1.00(s,9H).

[0347] Step 3: Dissolve 29b (220 mg, 0.65 mmol) in dry tetrahydrofuran (3.5 mL), replace the nitrogen atmosphere in the reaction system, and place it in an ice-water bath. After cooling the reaction system to 0°C, sodium hydride (52 mg, 1.30 mmol) was slowly added to the reaction solution under a nitrogen atmosphere. After stirring the reaction at 0°C for 1 hour, propargyl bromide (153.4 mg, 1.29 mmol) was slowly added dropwise to the reaction system. The reaction was allowed to slowly return to room temperature and stirred overnight. After TLC monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 29c (190 mg). 1 H NMR (400MHz, DMSO) δ7.74–7.52(m,4H),7.52–7.37(m,6H),4.27–4.13(m,1H),4.00(d,J=2.4Hz,2H),3.63(d ,J=6.1Hz,2H),3.36(t,J=2.4Hz,1H),2.41–2.29(m,1H),2.12–2.04(m,2H),2.04–1.93(m,2H),1.01(s,9H).

[0348] Step 4: Dissolve 29c (190 mg, 0.50 mmol) in tetrahydrofuran (3 mL) at room temperature, then slowly add tetrabutylammonium fluoride (1.0 M, 1.0 mL) to the reaction mixture. Stir the reaction mixture at room temperature for 2 hours. After LC-MS monitoring shows the disappearance of the starting material, saturated aqueous ammonium chloride (15 mL) is added to the reaction mixture to quench the mixture. The mixture is extracted with ethyl acetate (15 mL x 3). The organic phases are combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to afford 29d (70 mg). 1H NMR (400MHz, DMSO) δ4.56(t,J=5.3Hz,1H),4.15–4.10(m,1H),4.00(d,J=2.4Hz,2H),3.42–3.34(m,3H),2.28–2.14(m,1H),2.04–1.88(m,4H).

[0349] Step 5: Dissolve 29d (31.1 mg, 0.22 mmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (50.0 mg, 0.15 mmol), cesium carbonate (344.3 mg, 0.75 mmol), cuprous iodide (2.8 mg, 0.015 mmol), and bis(triphenylphosphine)palladium dichloride (10.5 mg, 0.015 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature. Evacuate the reaction system and replace with nitrogen several times. Stir the reaction mixture in an oil bath at 85°C for 3 hours. After LC-MS monitoring indicated the disappearance of the starting material, quench the reaction with water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 29e (12 mg). 1 H NMR(400MHz,DMSO)δ11.12(s,1H),7.18(d,J=7.6Hz,1H),7.14–7.09(m,1H),7.0 3(t,J=7.9Hz,1H),5.40(dd,J=12.7,5.3Hz,1H),4.58(t,J=5.3Hz,1H),4.43(s, 0.3H),4.33(s,1.7H),4.28–4.20(m,1H),3.64(s,3H),3.39(dd,J=6.5,5.5Hz,2 H),2.96–2.82(m,1H),2.77–2.59(m,2H),2.28–2.18(m,1H),2.08–1.97(m,5H).

[0350] Step 6: 29e (110 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL) at room temperature. Triethylamine (85 mg, 0.84 mmol) and p-methylsulfonyl chloride (47.8 mg, 0.42 mmol) were added at 0°C, and the reaction solution was stirred at room temperature for two hours. After LC-MS monitoring showed that the starting material disappeared, water (30 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with dichloromethane (30 mL×3), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 29f (100 mg). MS (ESI) M / Z: 476.2 [M+H + ].

[0351] Step 7: At room temperature, 29f (100 mg, 0.21 mmol) and A (115.0 mg, 0.23 mmol) were dissolved in N,N-dimethylformamide (1.5 mL). Potassium carbonate (86.9 mg, 0.63 mmol) was then added. The reaction system was evacuated and replaced with nitrogen several times. The reaction solution was stirred at 50 ° C for 18 hours. After LC-MS monitoring showed that the starting material disappeared, water (30 mL) was added to the reaction solution to quench it. The mixed solution was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product 29 (8.8 mg). MS (ESI) M / Z: 878.3 [M+H + ]. 1H NMR (400MHz, DMSO) δ11.12(s,1H),9.49(d,J=5.4Hz,1H),8.78(d,J=7.7Hz,1H),8.39(d,J=4.0Hz ,1H),8.25(d,J=5.6Hz,1H),7.31–6.97(m,4H),6.87(d,J=7.8Hz,0.5H),6.45(d,J=7.8Hz,0.5H) ,5.4(dd,J=12.7,5.4Hz,1H),5.27(s,0.5H),5.07(s,0.5H),4.98–4.87(m,1H),4.77(d,J=16.2H z,1H),4.34(s,2H),4.31–4.21(m,1H),3.82(d,J=9.9Hz,2H),3.74(d,J=7.5Hz,1H),3.63(s,3H), 3.63–3.57(m,2H),3.47–3.42(m,1H),2.95–2.84(m,1H),2.77–2.71(m,1H),2.71–2.65(m,1 H),2.35–2.27(m,6H),2.23–2.11(m,3H),2.07–1.93(m,7H),1.58(dd,J=16.5,12.2Hz,4H).

[0352] Example 30

[0353] Referring to Example 29, the desired product 30 (8.5 mg) was obtained. MS (ESI) M / Z: 878.4 [M+H + ]. 1H NMR (400MHz, DMSO) δ11.12(s,1H),9.50(d,J=5.3Hz,1H),8.78(d,J=7.7Hz,1H ),8.39(d,J=4.0Hz,1H),8.25(d,J=5.6Hz,1H),7.29–6.97(m,4H),6.87(d,J=7 .9Hz,0.5H),6.45(d,J=7.8Hz,0.5H),5.40(dd,J=12.6,5.3Hz,1H),5.27(s,0. 5H),5.07(s,0.5H),4.98–4.88(m,1H),4.77(d,J=16.0Hz,1H),4.43(s,2H),3. 85–3.72(m,3H),3.63(d,J=3.8Hz,3H),3.59(s,1H),3.45(d,J=9.8Hz,0.5H), 3.33(s,0.5H),2.88(m,J=20.3,9.5Hz,1H),2.78–2.57(m,2H),2.31(m,J=12.5 ,5.1Hz,4H),2.22(s,1H),2.19–2.12(m,2H),2.10–1.90(m,6H),1.79(m,J=10. 7Hz,2H),1.64(m,2H),1.58(m,3H),1.46(m,J=12.9Hz,4H),1.25–1.18(m,2H).

[0354] Example 31

[0355] Step 1: Methyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (5.0 g, 31.6 mmol) was dissolved in dry tetrahydrofuran (50 mL) and placed in an ice-water bath. After the reaction system was cooled to 0°C, lithium aluminum hydride (2.5 M, 25.2 mL) was slowly added dropwise to the reaction mixture under a nitrogen atmosphere. The reaction was stirred at 0°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, tetrahydrofuran (300 mL) was added to the reaction mixture to dilute it. Then, Na2SO4·10H2O was slowly added to quench the excess lithium aluminum hydride. A large amount of white solid was produced in the reaction mixture, which was filtered and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 31a (2.6 g). 1H NMR (400MHz, DMSO) δ4.44(d,J=4.4Hz,1H),4.34(t,J=5.3Hz,1H),3.32–3.24(m,1H),3.18(t,J=5.8Hz ,2H),1.88–1.75(m,2H),1.74–1.61(m,2H),1.31–1.16(m,1H),1.15–0.98(m,2H),0.94–0.76(m,2H).

[0356] Step 2: Dissolve 31a (2.3 g, 17.7 mmol) and imidazole (3.6 g, 53.1 mmol) in dichloromethane (40 mL). The reaction system was purged with nitrogen and placed in an ice-water bath. After the reaction system was cooled to 0°C, tert-butyldiphenylsilyl chloride (5.8 g, 21.2 mmol) was slowly added dropwise to the reaction solution under a nitrogen atmosphere. The reaction was stirred at 25°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, dichloromethane (50 mL) was added to the reaction solution to dilute it. The reaction solution was then washed with water (50 mL x 3 times). The organic phase was extracted and washed with saturated brine (300 mL x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to yield 31b (3.8 g). 1 H NMR(400MHz,MeOD)δ7.72–7.58(m,4H),7.47–7.32(m,6H),3.52–3.38(m,3H),1.98–1.9 1(m,2H),1.90–1.74(m,2H),1.53–1.40(m,1H),1.32–1.25(m,2H),1.11–0.94(m,11H).

[0357] Step 3: Dissolve 31b (3.5 g, 9.5 mmol) in dry tetrahydrofuran (3.5 mL), replace the nitrogen atmosphere in the reaction system, and place it in an ice-water bath. After cooling the reaction system to 0°C, sodium hydride (1.1 g, 28.4 mmol) was slowly added to the reaction solution under a nitrogen atmosphere. After stirring the reaction at 0°C for 1 hour, propargyl bromide (3.4 g, 28.4 mmol) was slowly added dropwise to the reaction system. The reaction was allowed to slowly return to room temperature and stirred overnight. After TLC monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding saturated aqueous ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 31c (2.0 g).

[0358] Step 4: Dissolve 31c (1.8 g, 4.4 mmol) in tetrahydrofuran (20 mL) at room temperature, then slowly add tetrabutylammonium fluoride (1.0 M, 8.8 mL) to the reaction mixture. Stir the reaction mixture at room temperature for 2 hours. After LC-MS monitoring shows the disappearance of the starting material, saturated aqueous ammonium chloride (20 mL) is added to the reaction mixture for quenching. The mixture is extracted with ethyl acetate (20 mL x 3). The organic phases are combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to afford 31d (670 mg). 1 H NMR (400MHz, DMSO) δ4.38(t,J=5.3Hz,1H),4.13(d,J=2.4Hz,2H),3.37–3.33(m,1H),3.33–3.25(m,1H),3.24 –3.14(m,2H),2.03–1.93(m,2H),1.78–1.65(m,2H),1.35–1.22(m,1H),1.15–1.02(m,2H),0.96–0.80(m,2H).

[0359] Step 5: Dissolve 31d (364.9 mg, 2.25 mmol), B (500.0 mg, 1.5 mmol), cesium carbonate (2.4 g, 7.5 mmol), cuprous iodide (28.5 mg, 0.15 mmol), and bis(triphenylphosphine)palladium dichloride (105.1 mg, 0.15 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction system was evacuated and replaced with nitrogen several times. The reaction solution was sealed and stirred in an oil bath at 85°C for 3 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was quenched by adding water (200 mL). The mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield 31e (300 mg). 1H NMR (400MHz, DMSO) δ11.12(s,1H),7.17(d,J=7.7Hz,1H),7.11(d,J=7.0Hz,1H),7.03 (t,J=7.9Hz,1H),5.40(dd,J=12.7,5.3Hz,1H),4.46(s,2H),3.64(s,3H),3.50–3.37( m,1H),3.30(s,1H),3.20(m,2H),2.97–2.81(m,1H),2.79–2.61(m,2H),2.11–2.00(m, 3H),1.75(d,J=11.6Hz,2H),1.37–1.25(m,1H),1.16–1.06(m,1H),0.99–0.77(m,2H).

[0360] Step 6: 31e (270 mg, 0.63 mmol) was dissolved in dichloromethane (8 mL) at room temperature. Triethylamine (318.8 mg, 3.1 mmol) and p-methylsulfonyl chloride (291.9 mg, 2.5 mmol) were added at 0°C, and the reaction solution was stirred at room temperature for two hours. After LC-MS monitoring showed that the starting material disappeared, water (30 mL) was added to the reaction solution to quench the mixture. The mixed solution was extracted with dichloromethane (30 mL×3), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 31f (160 mg). MS (ESI) M / Z: 504.0 [M+H + ].

[0361] Step 7: At room temperature, 31f (160 mg, 0.32 mmol) and A (207.2 mg, 0.42 mmol) were dissolved in N,N-dimethylformamide (4 mL). Potassium carbonate (176.6 mg, 1.28 mmol) was then added. The reaction system was evacuated and replaced with nitrogen several times. The reaction solution was stirred at 50 ° C for 18 hours. After LC-MS monitoring showed that the starting material disappeared, water (30 mL) was added to the reaction solution to quench it. The mixed solution was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phases were first washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to give the final product 31 (18.9 mg). MS (ESI) M / Z: 906.8 [M+H + ]. 1H NMR (400MHz, DMSO) δ11.12(s,1H),9.49(d,J=5.2Hz,1H),8.78(d,J=7.7Hz,1H),8.39(d,J=3.9Hz,1H),8.25(d,J=5.7Hz,1H),7.41–6.92(m,4 H),6.87(d,J=7.9Hz,0.5H),6.45(d,J=7.7Hz,0.5H),5.40(dd,J=12.7,5.3Hz,1H),5.28(s,0.5H),5.08(s,0.5H),5.00–4.86(m,1H),4.77(d ,J=16.4Hz,1H),4.46(s,2H),3.87–3.69(m,2H),3.64(s,3H),3.63–3. 54(m,1H),3.50–3.39(m,2H),2.95–2.83(m,1H),2.79–2.58(m,2H),2. 37–2.10(m,8H),2.05–1.93(m,7H),1.78(d,J=11.9Hz,2H),1.61(d,J= 22.8Hz,4H),1.52–1.38(m,1H),1.21–1.07(m,2H),0.95–0.76(m,2H).

[0362] Example 32

[0363] Referring to Example 31, the desired product 32 (12.39 mg) was obtained. MS (ESI) M / Z: 906.5 [M+H + ]. 1H NMR (400MHz, DMSO) δ11.12(s,1H),9.50(d,J=5.3Hz,1H),8.78(d,J=7.7Hz,1H ),8.39(d,J=4.0Hz,1H),8.25(d,J=5.6Hz,1H),7.29–6.97(m,4H),6.87(d,J=7 .9Hz,0.5H),6.45(d,J=7.8Hz,0.5H),5.40(dd,J=12.6,5.3Hz,1H),5.27(s,0. 5H),5.07(s,0.5H),4.98–4.88(m,1H),4.77(d,J=16.0Hz,1H),4.43(s,2H),3. 85–3.72(m,3H),3.63(d,J=3.8Hz,3H),3.59(s,1H),3.45(d,J=9.8Hz,0.5H), 3.33(s,0.5H),2.88(m,J=20.3,9.5Hz,1H),2.78–2.57(m,2H),2.31(m,J=12.5 ,5.1Hz,4H),2.22(s,1H),2.19–2.12(m,2H),2.10–1.90(m,6H),1.79(m,J=10. 7Hz,2H),1.64(m,2H),1.58(m,3H),1.46(m,J=12.9Hz,4H),1.25–1.18(m,2H).

[0364] Example 33

[0365] Referring to Example 4, the desired product 33 (2.4 mg) was obtained. MS (ESI) M / Z: 892.4 [M+H + ]. 1H NMR (400MHz, DMSO) δ11.12(s,1H),9.49(d,J=5.2Hz,1H),8.79(d,J=7.7Hz,1H), 8.39(d,J=3.8Hz,1H),8.26(d,J=5.6Hz,1H),7.19–7.08(m,2.5H),7.03(t,J=7.9 Hz,1.4H),6.87(d,J=7.8Hz,0.49H),6.45(d,J=7.8Hz,0.53H),5.40(dd,J=12.6, 5.4Hz,1H),5.27(s,0.5H),5.08(s,0.5H),4.97–4.87(m,1H),4.77(d,J=15.5Hz, 1H),4.47–4.41(m,2H),3.82(d,J=9.9Hz,1.4H),3.74(d,J=7.2Hz,1H),3.65–3.6 3(m,3.64H),3.59(s,1H),3.48–3.39(m,1H),3.29(s,1H),2.93–2.84(m,1H),2.7 5–2.60(m,2H),2.46–2.42(m,1H),2.38–2.23(m,5H),2.07–1.98(m,3H),1.94–1. 86(m,2H),1.75(d,1H),1.65–1.56(m,3H),1.49–1.42(m,2H),1.27–1.21(m,1H).

[0366] Example 34

[0367] Referring to Example 3, the desired product 34 (13.58 mg) was obtained. MS (ESI) M / Z: 919.2 [M+H + ]. 1H NMR (400MHz, DMSO) δ11.12(s,1H),9.49(d,J=5.4Hz,1H),8.78(d,J=7.7Hz,1H),8.39(d,J=4.0Hz,1H),8.25(d,J=5.6Hz,1H),7.30–6.96(m,4 H),6.87(d,J=8.0Hz,0.5H),6.45(d,J=7.8Hz,0.5H),5.39(dd,J=12.8,5.2Hz,1H),5.27(s,0.5H),5.07(s,0.5H),4.99–4.88(m,1H),4.77(d ,J=17.4Hz,1H),3.84–3.72(m,2H),3.65(d,J=3.6Hz,3H),3.60(d,J=11.7Hz,1H),3.45(d,J=10.3Hz,1H),3.11(d,J=10.0Hz,2H),2.97–2.83 (m,1H),2.77–2.60(m,3H),2.39–2.27(m,5H),2.17(t,J=10.3Hz,6H), 2.09–1.86(m,4H),1.79–1.58(m,6H),1.43(s,6H),1.18–1.03(m,2H).

[0368] Example 35

[0369] Step 1: Dissolve sodium hydride (8.6 g, 38.4 mmol) in dry tetrahydrofuran (50 mL). Displace the reaction system with nitrogen and place it in an ice-water bath. Cool the reaction system to 0°C. Slowly add 1,4-dioxaspiro[4.5]decan-8-one (5.0 g, 32.0 mmol dissolved in 10 mL of tetrahydrofuran) to the reaction solution under a nitrogen atmosphere. Stir the reaction at 0°C for 1 hour. Cool the reaction solution to -20°C and slowly add ethyl 2-(dimethoxyphosphoryl)acetate (8.6 g, 38.4 mmol dissolved in 8 mL of tetrahydrofuran) dropwise to the reaction system. Return the reaction to room temperature and stir for 2.5 hours. After TLC monitoring showed the disappearance of the starting material, water (500 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (500 mL × 3 times). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide 35a (4.4 g). 1H NMR(400MHz,DMSO)δ5.45–5.32(m,1H),4.05(dt,J=12.3,4.2Hz,2H),3.86(s,4H ),2.97(s,2H),2.20–2.07(m,4H),1.65(t,J=6.5Hz,2H),1.17(t,J=7.1Hz,3H).

[0370] Step 2: 35a (4.0 g, 17.6 mmol) and palladium on carbon (4.0 g, 17.6 mmol) were dissolved in ethanol (25 mL) and the reaction system was stirred under a hydrogen atmosphere at room temperature for 3 hours. After TLC monitoring showed the disappearance of the starting material, ethanol (100 mL) was added to the reaction solution to dilute the reaction solution. The black solid was filtered through a Buchner funnel, the filter cake was rinsed twice with ethanol, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 35b (2.2 g). MS (ESI) M / Z: 229.1 [M+H + ].

[0371] Step 3: Dissolve 35b (2.2 g, 9.6 mmol) in dry tetrahydrofuran (30 mL) and place in an ice-water bath. After the reaction system is cooled to 0°C, lithium aluminum hydride (2.5 M, 7.7 mL) is slowly added dropwise to the reaction solution under a nitrogen atmosphere. The reaction is stirred at 0°C for 3 hours. After TLC monitoring shows the disappearance of the starting material, tetrahydrofuran (300 mL) is added to the reaction solution to dilute it. Then, Na2SO4·10H2O is slowly added to quench the excess lithium aluminum hydride. A large amount of white solid is produced in the reaction solution. The filtrate is filtered and concentrated under reduced pressure. The resulting mixture is purified by silica gel column chromatography to obtain 35c (1.45 g). The mixture is then evaporated to dryness under reduced pressure. 1 H NMR (400MHz, DMSO) δ4.31(t,J=5.1Hz,1H),3.83(s,4H),3.47–3.37(m,2H),1.63(d,J=10.1Hz,4H),1.47–1.28(m,5H),1.18–1.04(m,2H).

[0372] Step 4: Dissolve oxalyl chloride (0.2 mL, 2.42 mmol) in dry dichloromethane (3 mL). The reaction system was purged of nitrogen and placed in a dry ice-acetone bath. After cooling the reaction system to -78°C, dimethyl sulfoxide (0.35 mL, 4.84 mmol dissolved in 3 mL dichloromethane) was slowly added to the reaction solution under a nitrogen atmosphere. After stirring the reaction at -78°C for 0.5 hour, 35c (300 mg, 1.61 mmol dissolved in 3 mL dichloromethane) was slowly added dropwise to the reaction system. The reaction was stirred at -78°C for 1 hour. After TLC monitoring showed the disappearance of the starting material, triethylamine (12 mL) was added to the reaction solution and stirred at room temperature for 0.5 hour. Water (50 mL) was then added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 35d (250 mg, yield 84.4%). 1 H NMR (400MHz, DMSO) δ9.65 (t, J=2.0Hz, 1H), 3.83 (s, 4H), 2.33 (dd, J=6.8, 2.0Hz, 2H),1.92–1.78(m,1H),1.69–1.57(m,4H),1.53–1.39(m,2H),1.27–1.12(m,2H).

[0373] Step 5: 35d (250 mg, 1.36 mmol) and potassium carbonate (563.1 mg, 4.08 mmol) were dissolved in methanol (5 mL) at room temperature. Dimethyl (1-diazo-2-oxo-propanol)-phosphonate (313.0 mg, 4.08 mmol) was then added, and the reaction mixture was stirred at room temperature for 18 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure and quenched by adding water (30 mL) to the residue. The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 35e (220 mg, 89.8% yield). 1 H NMR (400MHz, DMSO) δ3.83 (s, 4H), 2.77 (t, J = 2.7Hz, 1H), 2.09 (dd, J = 6.5, 2.7Hz, 2H), 1.73–1.61 (m, 4H), 1.50–1.38 (m, 3H), 1.30–1.20 (m, 2H).

[0374] Step 6: 35e (167.1 mg, 0.93 mmol), B (200.0 mg, 0.62 mmol), cesium carbonate (1.0 g, 3.1 mmol), cuprous iodide (11.8 mg, 0.062 mmol), and bis(triphenylphosphine)palladium dichloride (43.5 mg, 0.062 mmol) were dissolved in N,N-dimethylformamide (16 mL) at room temperature. The reaction system was evacuated and replaced with nitrogen several times. The reaction solution was sealed and stirred in an oil bath at 85°C for 3 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction solution was quenched by the addition of water (200 mL). The mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 35f (100 mg). MS (ESI) M / Z: 438.3 [M+H + ].

[0375] Step 7: 35f (100 mg, 0.23 mmol) was dissolved in dichloromethane / acetone (4 mL / 1 mL) at room temperature, and then iron (III) chloride hexahydrate (216.5 mg, 0.8 mmol) was slowly added to the reaction solution. The reaction solution was stirred at room temperature overnight. After LC-MS monitoring showed that the starting material disappeared, sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution to quench the mixture. The mixture was extracted with dichloromethane (20 mL×3 times), and the organic phases were combined. The organic phases were first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 35g (62 mg). MS (ESI) M / Z: 394.0 [M+H + ].

[0376] Step 8: At room temperature, 35 g (60 mg, 0.15 mmol) was dissolved in a mixture of tetrahydrofuran and N,N-dimethylformamide (0.8 mL / 0.4 mL). A (83.4 mg, 0.17 mmol) and potassium acetate (16.2 mg, 0.17 mmol) were then added to the reaction mixture. The reaction system was evacuated and replaced with nitrogen several times. The reaction mixture was stirred at 25°C for 2 hours. Sodium cyanoborohydride (18.9 mg, 0.30 mmol) was then slowly added to the reaction mixture. The reaction mixture was stirred at room temperature for another 2 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the final product 35 (12.0 mg). MS (ESI) M / Z: 876.5 [M+H + ]. 1 H NMR (400MHz, DMSO) δ11.11(s,1H),9.50(d,J=5.1Hz,1H),8.79(d,J=7.7Hz,1H) ,8.39(d,J=4.1Hz,1H),8.26(d,J=5.7Hz,1H),7.20–6.92(m,4H),6.87(d,J=7.9 Hz,0.5H),6.46(d,J=7.8Hz,0.5H),5.38(dd,J=12.7,5.4Hz,1H),5.28(s,0.5H ),5.08(s,0.5H),5.00–4.85(m,1H),4.77(d,J=16.4Hz,1H),3.85–3.71(m,2H), 3.66–3.57(m,4.5H),3.48–3.41(m,0.5H),3.29(s,2H),2.95–2.82(m,1H),2.78–2.57 (m,2H),2.40–2.26(m,6H),2.21–2.10(m,3H),2.08–1.74(m,6H),1.74–1.41(m,10H).

[0377] Example 36

[0378] Referring to Example 20, the desired product 36 (11.4 mg) was obtained. MS (ESI) M / Z: 892.4 [M+H + ]. 1H NMR (400MHz, DMSO) δ11.12(s,1H),9.50(d,J=5.1Hz,1H),8.79(d,J=7.7Hz,1H),8.41(d,J=4.1Hz,1H),8.26(d,J=5.7Hz,1H),7.35–6. 94(m,4H),6.87(d,J=7.9Hz,0.5H),6.46(d,J=7.7Hz,0.5H),5.40(dd,J=12.6,5.3Hz,1H),5.28(s,0.5H),5.08(s,0.5H),5.03–4.91(m ,1H),4.77(d,J=17.3Hz,1H),4.37(s,2H),4.23–4.13(m,1H),3.87–3.71(m,2H),3.64(s,3H),3.63–3.57(m,1.5H),3.52–3.37(m,2.5H ),3.26–3.17(m,1H),2.96–2.81(m,1H),2.77–2.60(m,2H),2.43–2.34(m,4H),2.26–2.18(m,5H),2.06–1.91(m,4H),1.65–1.50(m,4H)

[0379] Example 37

[0380] Referring to Example 1, the desired product 37 (2.44 mg) was obtained. MS (ESI) M / Z: 866.3 [M+H + ]; 1 H NMR (400MHz, CDCl3) δ9.61 (s, 1H), 8.69 (s, 1H), 8.54-8.27 (m, 3H), 7.18 (d, J = 7.9Hz, 1H), 6 .99(t,J=7.9Hz,1H),6.92-6.61(m,2H),6.12(d,J=7.5Hz,1H),5.49-5.18(m,2H),4.80-4. 60(m,1H),4.52-4.35(m,2H),3.99-3.94(m,3H),3.85-3.76(m,4H),3.54(dd,J=36.4,9.4H z,2H),3.02-2.57(m,7H),2.25(s,1H),2.09(s,1H),2.01-1.59(m,12H),1.30-1.20(m,4H).

[0381] Example 38

[0382] Referring to the above example, the desired product 38 (1.96 mg) was obtained. MS (ESI) M / Z: 892.1 [M+H + ]; 1 H NMR(400MHz, DMSO-d6)δ11.15(s,1H),10.03(s,1H),9.51(s,1H),8.80(s,1H),8.44(s, 1H),8.26(s,1H),7.20-6.99(m,5H),6.88-6.47(m,1H),5.50-5.05(m,2H) ,4.80-4.75(m,1H),4.43(s,2H),4.20-4.15(m,1H),3.88-3.55(m,5H),2. 89-2.66(m,8H),2.23-2.10(m,5H),2.03-1.88(m,10H),1.55-1.40(m,5H).

[0383] Example 39

[0384] Referring to the above example, the desired product 39 (1.22 mg) was obtained. MS (ESI) M / Z: 921.3 [M+H + ]; 1 H NMR(400MHz, Methanol-d4)δ9.74(s,1H),8.52(d,J=7.9Hz,1H),8.43-8.23(m,3H),7.50-7.32(m,3H),7.27-7.12(m,4H),7.11-6.68(m,2H),6.44(d, J=8.4Hz,1H),5.46-5.29(m,2H),4.73-4.45(m,3H),4.27-4.17(m,2H),4. 00-3.94(m,3H),3.83-3.63(m,6H),2.95-2.75(m,6H),2.23-1.85(m,11H).

[0385] Example 40

[0386] Referring to the above example, the desired product 40 (1.52 mg) was obtained. MS (ESI) M / Z: 906.2 [M+H] + ; 1H NMR(400MHz, Methanol-d4)δ8.51(d,J=7.8Hz,1H),8.41-8.26(m,3H),7.19-7.12(m,3H),7.10-6.97(m,2H),6.87(d, J=8.5Hz,1H),6.73(d,J=8.0Hz,1H),6.43(d,J=7.8Hz,1H),5.46-5.30(m,2H),4.79 (d,J=7.2Hz,1H),4.38(d,J=3.9Hz,2H),4.16-4.14(m,2H),3.93(d,J=3.9Hz,2H),3 .74(s,4H),3.73-3.62(m,2H),3.50(d,J=9.8Hz,1H),2.82-2.79(m,8H),2.58-2.53 (m,2H),2.23-2.13(m,3H),2.07(d,J=18.9Hz,2H),2.01-1.95(m,5H),1.56(s,3H).

[0387] Example 41

[0388] Referring to the above example, the desired product 41 (2.38 mg) was obtained. MS (ESI) M / Z: 921.3 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.50(d,J=6.0Hz,1H),8.78(d,J=7.7Hz,1H),8.40(d,J=4.8H z,1H),8.26(d,J=5.4Hz,1H),7.27-7.02(m,4H),6.88-6.43(m,1H),5.44-5.36(m,1H),5.28-5.06( m,1H),4.77(d,J=17.3Hz,1H),4.51(s,2H),4.26-4.15(m,1H),3.82-3.51(m,14H),3.03-2.83(m,3 H),2.78-2.60(m,3H),2.08-1.89(m,8H),1.81-1.71(m,2H),1.65-1.55(m,2H),1.45-1.36(m,2H).

[0389] Example 42

[0390] Referring to the above example, the desired product 42 (24.29 m, formate) was obtained. MS (ESI) M / Z: 893.2 [M+H + ];1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.56-9.44(m,1H),8.78(d,J=7.8Hz,1H),8.45-8.37(m,1H),8. 26(d,J=5.4Hz,1H),7.27-7.02(m,4H),6.89-6.43(m,1H),5.45-5.36(m,1H),5.28-5.07(m,1H),4.77 (d,J=17.4Hz,1H),4.47(s,2H),4.26-4.16(m,1H),4.14-4.05(m,2H),3.85-3.74(m,4H),3.70-3.53( m,8H),2.96-2.83(m,1H),2.78-2.58(m,3H),2.08-1.84(m,8H),1.81-1.67(m,2H),1.66-1.54(m,2H).

[0391] Example 43

[0392] Referring to the above example, the desired product 43 (4.1 mg) was obtained. MS (ESI) M / Z: 949.1 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.50(d,J=5.9Hz,1H),8.79(d,J=7.7Hz,1H),8.42(d,J=4.7Hz,1H),8.26(d,J= 5.7Hz,1H),7.25-7.00(m,4H),6.88-6.44(m,1H),5.41(dd,J=12.7,5.3Hz,1H),5.28-5.07(m,1H),4.77(d,J=16.4Hz ,1H),4.50(s,2H),4.22-4.18(m,1H),3.86-3.79(m,1H),3.74(d,J=7.9Hz,1H),3.65(s,3H),3.59(s,1H),3.45-3.30 (m,4H),3.14(s,4H),2.93-2.86(m,3H),2.80-2.58(m,3H),2.11-1.94(m,4H),1.94-1.75(m,8H),1.65-1.20(m,6H).

[0393] Example 44

[0394] Referring to the above example, the desired product 44 (11.14 mg) was obtained. MS (ESI) M / Z: 878.60 [M+H + ]; 1 H NMR (400MHz, CDCl3) δ10.39(s,1H),9.67(d,J=12.4Hz,1H),8.69-8.56(m,2H),8.33(dd,J=7.6,2.0Hz,1H),7.20(d,J=8.0Hz,1H), 7.00(s,1H),6.89-6.62(m,2H),6.12(d,J=7.6Hz,1H),5.44(s,1H),5.37-5.17(m,1H),4.80(s,1H),4.64-4.61(m,1H),4.52-4.46 (m,1H),4.32-4.22(m,1H),3.97(s,3H),3.80(d,J=6.8Hz,4H),3.58(d,J=9.6Hz,1H),3.49(d,J=9.6Hz,1H),3.39-3.20(m,2H),2. 95-2.80(m,4H),2.40-2.16(m,8H),2.11-2.08(m,2H),2.00-1.97(m,1H),1.46-1.43(m,2H),1.29-1.24(m,3H),1.07-0.84(m,2H).

[0395] Example 45

[0396] Referring to the above example, the desired product 45 (2.19 mg, formate salt) was obtained. MS (ESI) M / Z: 907.2 [M+H + ]; 1 H NMR (400MHz, CDCl3) δ9.60 (s, 1H), 8.42 (s, 2H), 8.31 (s, 1H), 8.21 (s, 1H), 7.17 (d, J = 8.0Hz, 1H), 6 .98(d,J=7.6Hz,1H),6.91-6.57(m,2H),6.15-6.11(m,1H),5.45(s,1H),5.36-5.18(m,2H),4.79( s,1H),4.33(s,3H),4.21(d,J=7.4Hz,1H),4.05-3.95(m,3H),3.77(s,3H),3.69(s,2H),3.65-3.4 5(m,4H),2.95-2.72(m,4H),2.50(s,1H),2.25-2.20(m,2H),2.15-1.95(m,7H),1.85-1.15(m,6H).

[0397] Example 46

[0398] Referring to the above example, the desired product 46 (14.13 mg) was obtained. MS (ESI) M / Z: 934.3 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.49(d,J=5.4Hz,1H),8.79(d,J=7.7Hz,1H),8.41(d,J=4.2Hz,1H),8.25(d,J=5.6 Hz,1H),7.22(d,J=26.4Hz,1H),7.17-7.11(m,2H),7.05-7.02(m,1H),6.88-6.44(m,1H),5.47-5.34(m,1H),5.28-5.08(m ,1H),4.77(d,J=17.9Hz,1H),4.47(s,2H),4.19(s,1H),3.86-3.70(m,2H),3.64(s,3H),3.62-3.57(m,1H),3.50-3.40(m ,1H),3.30-3.27(m,1H),2.95-2.80(m,1H),2.78-2.56(m,3H),2.36-2.25(m,3H),2.05-1.80(m,16H),1.57-1.10(m,9H).

[0399] Example 47

[0400] Referring to the above example, the desired product 47 (2.06 mg) was obtained. MS (ESI) M / Z: 813.3 [M+H + ]; 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),11.08(s,1H),9.24(s,1H),8.71(d,J=3.4Hz,1H),8.65(s,1H),8.60(s,1H ),8.22(d,J=9.2Hz,1H),8.12(s,1H),7.68(d,J=8.6Hz,1H),7.36(s,1H),7.32(dd,J=9.3,4.3Hz,1H),7.26(s,2 H),5.07(dd,J=12.8,5.2Hz,1H),4.49(s,1H),4.13(s,3H),4.08(s,2H),3.08-3.02(m,7H),2.98-2.79(m,1H),2 .69-2.55(m,2H),2.35-2.14(m,4H),2.06-1.95(m,5H),1.90-1.82(m,3H),1.65-1.50(m,4H),1.33-1.20(m,3H).

[0401] Example 48

[0402] Referring to the above example, the desired product 48 (2.07 mg) was obtained. MS (ESI) M / Z: 813.2 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.53(s,1H),9.38(dd,J=7.0,1.5Hz,1H),8.96(dd,J=4.2,1.5Hz,1H),8 .70(s,1H),8.68(s,1H),8.31(s,1H),7.65(d,J=8.5Hz,1H),7.35(dd,J=7.0,4.2Hz,1H),7.31(s,1H),7.23(d,J =8.6Hz,1H),7.11(s,1H),5.07(dd,J=12.9,5.4Hz,1H),4.37-4.33(m,1H),4.07-4.02(m,1H),4.02(s,3H),3.0 0-2.82(m,3H),2.65-2.33(s,5H),2.28-2.10(m,1H),2.05-1.80(m,11H),1.66-1.30(m,6H),1.25-1.16(m,4H).

[0403] Example 49

[0404] Referring to Example 31, the desired product 49 (23 mg) was obtained. MS (ESI) M / Z: 908.1 [M+H + ]; 1 H NMR (400MHz, DMSO) δ11.13(s,1H),9.50(d,J=5.2Hz,1H),8.79(d,J=7.7Hz,1H),8.42(s,1H),8.26(d,J=5.6Hz,1H),7.31–6.96(m,4H),6.87 (d,J=8.0Hz,0.5H),6.46(d,J=7.7Hz,0.5H),5.40(dd,J=12.6,5.3Hz,1H),5.27(s,0.5H),5.08(s,0.5H),4.96(s,1H),4.77(d,J=18.3Hz,1H ),4.48(s,2H),3.86–3.71(m,2H),3.66(s,3H),3.63–3.56(m,1.5H),3 .49–3.41(m,1.5H),2.95–2.82(m,1H),2.76–2.63(m,2H),2.37–2.25( m,4H),2.24–2.14(m,2H),2.11–1.88(m,7H),1.88–1.74(m,3H),1.68– 1.55(m,2H),1.49–1.39(m,1H),1.09–0.97(m,2H),0.81–0.68(m,2H).

[0405] Example 50

[0406] Referring to the above example, the desired product 50 (6 mg) was obtained. MS (ESI) M / Z: 905.6 [M+H + ]; 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.45(d,J=6,1H),8.78(d,J=7.6,1H),8.41(d,J=2.8,1H),8.26(d,J=5 .2,1H),7.14(t,J=6.6,3H),7.04-6.86(m,2H),6.46(d,J=8,1H),5.42-5.37(m,1H),5.28(s,1H),5.07(s,1H) ,4.97-4.95(m,1H),4.79-4.75(m,1H),3.81(s,1H),3.75-3.73(m,1H),3.67-3.59(m,5H),2.89-2.85(m,1H) ,2.73-2.61(m,3H),2.39-2.33(m,3H),2.23-2.18(m,2H),2.05-1.95(m,4H),1.61-1.45(m,5H),1.22(s,9H).

[0407] Example 51

[0408] Step 1: 4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1.22 g, 5.75 mmol) and acetone (10 mL) were added to a reaction flask with stirring. 1 M sodium hydroxide solution (5.8 mL, 5.8 mmol) was added dropwise at room temperature. After a clear solution formed, 4 M aqueous silver nitrate solution (1.5 mL, 6.0 mmol) was added and stirred at room temperature for 2 h. Filtered, the residue was washed with water, methyl tert-butyl ether, and acetone, and the solvent was drained to yield 51a (1.82 g).

[0409] Step 2: Add 51a (1.82 g, 5.75 mmol) to a reaction flask, replace the N2 atmosphere, add n-hexane (12 mL), and dropwise add liquid bromine (920 mg, 5.75 mmol). Stir for 4 hours. Filter the filtrate, and wash the residue with methyl tert-butyl ether (15 mL x 3) and saturated sodium bicarbonate solution (20 mL x 3). The organic phase is washed with brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to yield 51b (909 mg). 1 H NMR(400MHz,Chloroform-d)δ3.63(s,3H),2.29-2.19(m,6H),2.00-1.93(m,6H).

[0410] Step 3: 51b (13.3 g, 53.8 mmol), sodium hydroxide (12.9 g, 323 mmol), and water (300 mL) were added to a reaction flask. The reaction was incubated at 110°C for 24 h. After completion of the reaction, 4 M hydrochloric acid was added to adjust the pH to 3-4. EA (50 mL x 3) was added for extraction. The organic phase was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and spin-dried to afford 51c (4.5 g). 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),4.21(s,1H),1.79-1.72(m,6H),1.55-1.44(m,6H).

[0411] Step 4: Add 51c (4.5 g, 26.5 mmol) to a reaction flask, purge with nitrogen, and add anhydrous dichloromethane (10 mL) and anhydrous methanol (10 mL) until the solution becomes clear. Trimethylsilyldiazomethane (2 M, 53 mmol, 26.5 mL) is then added dropwise under a nitrogen atmosphere. The mixture is allowed to react at room temperature overnight. Upon completion of the reaction, compound 51d (2.0 g) is isolated by column chromatography. 1 H NMR(400MHz,Chloroform-d)δ3.63(s,3H),1.94-1.88(m,6H),1.70-1.62(m,6H).

[0412] Step 5: Add 51d (2.0 g, 10.9 mmol) to the reaction flask, purge the atmosphere with nitrogen, add anhydrous DMF (10 mL), and sodium hydride (60% wt, 872 mg, 21.8 mmol) and react at room temperature for 30 min. Then, add propargyl bromide (2.59 g, 21.8 mmol) and react at room temperature overnight. After completion, the reaction was quenched with water (30 mL) and extracted with EA (30 mL x 4). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and isolated by column chromatography to afford 51e (720 mg). 1 H NMR (400MHz, Chloroform-d) δ4.00 (d, J = 2.4Hz, 2H), 3.57 (s, 3H), 2.31 (t, J = 2.4Hz, 1H), 1.91-1.81 (m, 6H), 1.71-1.62 (m, 6H).

[0413] Step 6: 51e (100 mg, 0.45 mmol), LiOH (54 mg, 2.25 mmol), THF (2 mL), and water (0.4 mL) were added to a reaction flask and reacted at room temperature overnight. After completion of the reaction, 1 M dilute hydrochloric acid was added to adjust the pH to 3-4, and EA (10 mL x 3) was added for extraction. The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to give 51f (85 mg).1 H NMR (400MHz, DMSO-d6) δ12.05(s,1H),4.01(d,J=2.4Hz,2H),3.27(t,J=2.4Hz,1H),1.83–1.74(m,6H),1.66–1.57(m,6H).

[0414] Step 7: Add 51f (20 mg, 0.096 mmol) to the reaction flask, replace nitrogen, add anhydrous DMF (2 mL) and HATU (40 mg, 0.106 mmol), and react at room temperature for 30 min. Add A (48 mg, 0.096 mmol) and react at room temperature overnight. After the reaction is completed, water (10 mL) and EA (10 mL x 3) are added to extract the aqueous phase. The organic phase is washed with saturated brine (10 mL x 5), dried over anhydrous sodium sulfate, and spin-dried to obtain 51g (38 mg). [M+H] + =689.5

[0415] Step 8: Dissolve B (110 mg, 0.32 mmol), 51 g (450 mg, 0.65 mmol), cesium carbonate (212 mg, 0.65 mmol), CuI (12 mg, 0.06 mmol), and Pd(PPh3)2Cl2 (46 mg, 0.06 mmol) in ultra-dry DMF (3 mL) at room temperature, fully replace N2, and stir at 90°C for 12 hours. LC-MS monitoring. Quench with water (5 mL), extract with ethyl acetate (5 mL × 3 mL), combine the organic phases, dry over anhydrous sodium sulfate, and separate and purify by preparative TLC to obtain the desired product 51 (4.5 mg). MS (ESI) M / Z: 946.7 [M+H + ]; 1H NMR (400MHz, DMSO-d6) δ11.1(s,1H),9.50(d,J=5.2Hz,1H),8.78(d,J=8.0Hz,1H),8.41(d,J=4.0Hz,1H),8.25( d,J=5.2Hz,1H),7.28-7.02(m,4H),6.87-6.46(m,1H),5.41-5.37(m,1H),5.27-5.07(m,1H),4.99-4.95(m,1H), 4.79-4.75(m,1H),4.35(s,2H),3.83-3.72(m,2H),3.63-3.59(m,4H),3.51-3.43(m,4H),2.92-2.60(m,3H),2. 41-2.36(m,2H),2.24-2.19(m,3H),2.03-1.95(m,3H),1.92-1.88(m,6H),1.73-1.71(m,6H),1.59-1.53(m,4H).

[0416] Example 52

[0417] Step 1: Dissolve 51e (260 mg, 1.17 mmol) in ultra-dry THF (4 mL) at room temperature. Slowly add lithium aluminum hydride (1.75 mL, 1.75 mmol) at 0°C, and warm to room temperature with stirring for 3 h. After completion, the reaction was quenched with water and extracted with EA (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate to yield 170 mg (74.9%) of 52a.

[0418] Step 2: Dissolve 52a (170 mg, 0.87 mmol), B (300 mg, 0.62 mmol), cesium carbonate (395 mg, 1.24 mmol), CuI (24 mg, 0.12 mmol), and Pd(PPh3)2Cl2 (89 mg, 0.12 mmol) in ultra-dry DMF (5 mL) at room temperature, fully replace the nitrogen, and stir at 90°C for 4 hours. Monitor by LC-MS. Quench with water (5 mL), extract with ethyl acetate (5 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and separate and purify by preparative TLC to afford 120 mg of 52b. MS (ESI) M / Z: 452.3 [M+H + ].

[0419] Step 3: Dissolve 52b (120 mg, 0.26 mmol) in DCM (3 mL) at room temperature, add Dessmartin reagent (124 mg, 0.29 mmol), and stir at room temperature for 2 h. After completion of the reaction, the mixture was quenched with water and extracted with DCM (5 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative TLC to afford 90 mg (75.6%) of 52c. MS (ESI) M / Z: 450.1 [M+H] + .

[0420] Step 4: 52c (32 mg, 0.07 mmol) and A (32 mg, 0.07 mmol) were dissolved in DCM (3 mL) at room temperature, and NaBH(OAc)3 (18 mg, 0.08 mmol) was added. The mixture was stirred at room temperature for 16 h. LC-MS monitoring was performed. The mixture was quenched with water (5 mL), extracted with DCM (5 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and separated and purified by preparative TLC to obtain a crude product (30 mg). Subsequently, the desired product 52 (13.8 mg) was further separated and purified by high pressure preparative liquid chromatography. MS (ESI) M / Z: 932.8 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),9.55(d,J=5.2Hz,1H),8.82(d,J=7.6Hz,1H),8.43(d,J=4.0Hz,1H), 8.31(d,J=5.6Hz,1H),7.54-7.06(m,4H),6.92-6.49(m,1H),5.47-5.43(m,1H),5.33-5.12(m,1H),4.99-4. 92(m,1H),4.84-4.80(m,1H),4.38(s,2H),3.88-3.80(m,2H),3.69-3.65(m,5H),3.50-3.48(m,1H),2.98-2 .90(m,1H),2.81-2.67(m,2H),2.44-2.29(m,6H),2.23-1.93(m,8H),1.72-1.64(m,7H),1.59-1.47(m,7H).

[0421] Example 53

[0422] Referring to the above example, the desired product 53 (6.4 mg) was obtained. MS (ESI) M / Z: 905.7 [M+H + ]; 1H NMR(400MHz,Chloroform-d)δ9.63(s,1H),8.54(d,J=9.2Hz,2H),8.33(s,1H),7.14(d,J=8 .1Hz,1H),7.02–6.94(m,1H),6.76(d,J=7.6Hz,1H),6.13(s,1H),5.51(s,1H),5.20(d,J=40 .7Hz,1H),4.80(d,J=10.5Hz,1H),4.70(t,J=8.5Hz,1H),3.96(d,J=7.4Hz,2H),3.91–3.70 (m,4H),3.54(dd,J=33.2,14.8Hz,2H),3.18–2.57(m,8H),2.53–1.89(m,17H),1.64(s,6H).

[0423] Example 54

[0424] Referring to the above example, the desired product 54 (2.5 mg) was obtained. MS (ESI) M / Z: 919.6 [M+H + ]; 1 H NMR(400MHz, CDCl3)δ:9.46(s,1H),8.53-8.41(m,2H),8.35-8.24(m,1H),7.11-7.08(m,1H),6.93-6.87(m,1H) ),6.71-6.65(m,1H),6.05(d,J=2.8Hz,1H),5.38(s,1H),5.17-5.03(m,1H),4.76-4,60(m,2H),3.95-3.86(m, 2H),3.72(s,3H),3.57-3.37(m,4H),3.31-3.04(m,4H),2.96-2.83(m,5H), 2.81-2.61(m,2H),2.45-2.15(m,7H),2.06-1.91(m,5H),1.47-1.42(m,6H).

[0425] Example 55

[0426] Referring to the above example, the desired product 55 (16.1 mg) was obtained. MS (ESI) M / Z: 919.7 [M+H + ]; 1H NMR(400MHz,Chloroform-d)δ9.56(s,1H),8.57–8.35(m,2H),8.25(d,J=7.6Hz,1H),7.10 (d,J=7.5Hz,1H),6.95–6.87(m,1H),6.70(d,J=7.8Hz,1H),6.06(d,J=7.7Hz,1H),5.37(s ,1H),5.18(d,J=40.4Hz,1H),4.76–4.52(m,2H),3.90(s,2H),3.72(s,3H),3.54–3.40(m, 3H),3.29(s,1H),3.16–3.07(m,6H),3.00–2.72(m,6H),2.44–1.88(m,11H),1.45(s,6H).

[0427] Example 56

[0428] Step 1: Methyl 4-piperidinate (0.5 g, 3.49 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, and 3-chloro-3-methyl-1-butyne (0.53 g, 5.2 mmol) and TEA (881 mg, 8.73 mmol) were added, followed by stirring for 10 minutes. CuI (66 mg, 0.349 mmol) was added to the system and stirred for 0.5 h. The organic phase was then extracted three times with 40 mL of water and 80 mL of ethyl acetate, and dried over anhydrous sodium sulfate. Product 56a (470 mg) was obtained after spin drying. 1 H NMR (400MHz, Chloroform-d) δ3.61 (s, 3H), 2.99 (dt, J=11.7, 3.6Hz, 2H), 2.28–2.07 (m, 4H), 1.68 (qd, J=11.6, 3.7Hz, 2H), 1.33 (s, 6H).

[0429] Step 2: 56a (100 mg, 0.48 mmol), B (100 mg, 0.29 mmol), Pd(PPh3)2Cl2 (37 mg, 0.05 mmol), CuI (10 mg, 0.05 mmol), and cesium carbonate (360 mg, 1.1 mmol) were dissolved in DMF (2 mL) at room temperature and stirred at 90°C for 1 hour. After the reaction was completed, the crude product was filtered through celite and purified by preparative TLC to give product 56b (90 mg). MS (ESI) M / Z: 467.2 [M+H + ].

[0430] Step 3: 56b (47 mg, 0.1 mmol) was dissolved in a THF / MeOH = 1 / 1 (6 mL) mixed solvent at room temperature, and LiOH (36 mg, 1.5 mmol) was added. The reaction solution was stirred at 40°C for 1 h, and then 40 mL of dichloromethane was added. After filtering off the excess salt, 56c (25 mg) was purified by preparative TLC. MS (ESI) M / Z: 453.3 [M+H + ].

[0431] Step 4: 56c (20 mg, 0.044 mmol) and HATU (18.5 mg, 0.048) were added to 0.5 mL of dichloromethane at room temperature and stirred at room temperature for 5 minutes. Then, A (22 mg, 0.044 mmol) and TEA (13 mg, 0.13 mmol) were dissolved in dichloromethane (0.5 mL) and added to the reaction system and stirred at 40°C for 2 hours. After completion of the reaction, the desired product 56 (13.3 mg) was obtained by purification by preparative TLC. MS (ESI) M / Z: 933.6 [M+H + ]; 1 H NMR(400MHz,Chloroform-d)δ9.53(s,1H),8.50(s,1H),8.35(d,J=10.0Hz,1H),8.24(s,1 H),7.11(s,1H),6.92(s,1H),6.69(s,1H),6.06(s,1H),5.37(s,1H),5.13(s,1H),4.69(d ,J=21.9Hz,2H),3.90(s,2H),3.71(s,3H),3.47(d,J=38.1Hz,4H),3.27(s,1H),3.19(s,2 H), 2.76 (d, J = 69.2Hz, 4H), 2.34 (d, J = 37.0Hz, 8H), 1.83 (d, J = 80.8Hz, 10H), 1.43 (s, 6H).

[0432] Example 57

[0433] Referring to the above example, the desired product 57 (2.5 mg) was obtained. MS (ESI) M / Z: 900.5 [M+H + ]; 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),9.49(d,J=5.2Hz,1H),8.78(d,J=7.6Hz,1H),8.39(d,J=4.0Hz,1H),8.25(d,J=5.2Hz,1H ),7.24(d,J=8.4Hz,2H),7.14(dd,J=26.4,7.8Hz,2H),7.02(dt,J=7.6,3.6Hz,3H),6.86(d,J=7.8Hz,1H),6.45(d,J=7.6Hz,1H) ,5.38(dd,J=12.8,5.4Hz,1H),5.27(s,1H),5.11(d,J=7.4Hz,2H),5.07(s,1H),4.98–4.88(m,1H),4.77(d,J=17.2Hz,1H),3.82 (d,J=10.4Hz,2H),3.74(d,J=7.6Hz,1H),3.66–3.56(m,2H),3.45(s,2H),3.39–3.36(m,2H),2.87(t,J=14.8Hz,1H),2.68–2.59 (m,2H),2.33(d,J=8.8Hz,4H),2.16(d,J=19.6Hz,3H),1.99(dd,J=20.8,10.3Hz,3H),1.62(d,J=23.2Hz,4H),1.23(s,2H).

[0434] Example 58

[0435] Referring to the above example, the desired product 58 (1.8 mg) was obtained. MS (ESI) M / Z: 877.7 [M+H + ]; 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.51(d,J=5.6Hz,1H),8.79(d,J=7.8Hz ,1H),8.41(d,J=4.2Hz,1H),8.26(d,J=5.6Hz,1H),7.15(dd,J=13.2,8.0Hz,2 H),7.03(t,J=7.8Hz,1H),6.87(d,J=8.0Hz,1H),6.46(d,J=8.0Hz,1H),5.40( dd,J=12.4,5.6Hz,1H),4.98(t,J=8.4Hz,1H),4.78(d,J=17.2Hz,1H),3.82(d ,J=9.6Hz,1H),3.67(s,2H),3.60(s,1H),3.49(d,J=19.2Hz,4H),3.17(s,2H) ,2.88(d,J=17.2Hz,2H),2.80–2.70(m,1H),2.61(s,1H),2.39(t,J=10.0Hz,2 H),2.33(t,J=2.0Hz,1H),2.22(t,J=10.0Hz,2H),2.00(dd,J=19.6,10.1Hz,3 H),1.59(d,J=18.0Hz,2H),1.51(s,1H),1.25(d,J=10.7Hz,6H),0.86(s,1H).

[0436] Example 59

[0437] Referring to the above example, the desired product 59 (5.3 mg) was obtained. MS (ESI) M / Z: 891.6 [M+H + ]; 1 H NMR(400MHz, CDCl3)δ9.55(s,1H),8.47-8.39(m,2H),8.27–8.25(m,1H),7.13-7.11(m,1H),6. 92(t,J=8Hz,1H),6.84-6.57(m,2H),6.05(d,J=7.6Hz,1H),5.38(s,1H),5.16-5.12(m,1H),4. 76–4.66(m,2H),3.93-3.89(m,2H),3.82-3.75(m,5H),3.56-3.50(m,2H),3.44-3.29(m,5H),3 .10–2.97(m,2H),2.90-2.64(m,4H),2.36-2.24(m,4H),2.18–2.08(m,4H),2.05–1.98(m,5H).

[0438] Example 60

[0439] Referring to the above example, the desired product 60 (8.0 mg) was obtained. MS (ESI) M / Z: 891.6 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.3Hz,1H),8.79(d,J=7.8Hz,1H),8.42(d,J=4.1Hz,1H),8.26(d,J=5.5Hz,1H) ,8.13(s,0.6H),7.17(dd,J=18.6,7.3Hz,3H),7.08–7.00(m,1H),6.87(d,J=7.9Hz,0.5H),6.46(d,J=7.8Hz,0.5H),5.40(dd,J= 12.7,5.4Hz,1H),5.18(d,J=79.8Hz,1H),4.99(q,J=7.7Hz,1H),4.77(d,J=17.9Hz,1H),4.02(s,2H),3.78(d,J=25.0Hz,2H),3. 63(d,J=23.6Hz,5H),3.52–3.43(m,4H),3.11–2.80(m,4H),2.79–2.58(m,3H),2.46–2.30(m,3H),2.29–2.12(m,3H),2.06–1.91 (m,4H),1.72–1.50(m,4H).

[0440] Example 61

[0441] Referring to the above example, the desired product 61 (2.1 mg) was obtained. MS (ESI) M / Z: 906.7 [M+H + ]; 1H NMR(400MHz,Chloroform-d)δ9.60(s,1H),8.47–8.41(m,2H),8.32(d,J=7.6Hz,1H),8.22(s,1H),7.15(d,J=7.6Hz,1H),7.00(t,J=7.6Hz,1H),6. 79(s,1H),6.77(d,J=2.8Hz,1H),6.12(d,J=7.6Hz,1H),5.46(s,1H),5.2 0(dd,J=12.4,5.2Hz,1H),4.81(d,J=11.2Hz,1H),4.68(p,J=8.4Hz,1H), 4.44(s,2H),3.97(d,J=9.2Hz,2H),3.81(s,1H),3.77(s,3H),3.58(d,J= 9.2Hz,1H),3.49(d,J=9.2Hz,1H),2.89–3.01(m,3H),2.89–2.68(m,4H), 2.51(s,2H),2.36–2.45(m,1H),2.32–2.21(m,5H),1.78–1.86(m,4H),1. 58–1.73(m,4H),1.36–1.47(m,2H),1.21–1.30(m,1H),0.95–1.15(m,2H).

[0442] Example 62

[0443] Referring to the above example, the desired product 62 (63.1 mg) was obtained. MS (ESI) M / Z: 905.7 [M+H + ]; 1H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.3Hz,1H),8.78(dd,J=7.7 ,1.0Hz,1H),8.40(d,J=4.0Hz,1H),8.26(d,J=5.6Hz,1H),7.27(s,0.3H),7.1 9–7.06(m,2.6H),7.05–6.99(m,1.3H),6.87(d,J=7.9Hz,0.5H),6.45(d,J=7. 8Hz,0.5H),5.40(dd,J=12.7,5.4Hz,1H),5.28(s,0.5H),5.07(s,0.5H),4.99 –4.87(m,1H),4.77(d,J=16.5Hz,1H),4.50–4.35(m,2H),3.85–3.70(m,2H), 3.67–3.57(m,4H),3.50–3.39(m,3H),3.17(d,J=5.2Hz,1H),2.96–2.84(m,1H ),2.78–2.66(m,1H),2.68–2.59(m,1H),2.43–2.20(m,7H),2.20–2.10(m,4H) ,2.07–2.00(m,2H),1.99–1.89(m,3H),1.71–1.54(m,4H),1.52–1.38(m,1H).

[0444] Example 63

[0445] Referring to the above example, the desired product 63 (1.93 mg) was obtained. MS (ESI) M / Z: 877.5 [M+H + ]; 1H NMR (400MHz, CD3OD) δ8.52-8.48(m,1H),8.36-8.30(m,2H),7.19-7.17(m,1H),7.13-7.10(m,1H),7.07-7.03(m,1H), 6.90-6.72(m,1H),6.43(d,J=2.8Hz,1H),5.44(s,1H),5.36-5.32(m,1H),3.94-3.92(m,1H),3.77(s,3H),3.74-3.72( m,1H),3.70-3.68(m,2H),3.52-3.47(m,2H),3.13-3.12(m,1H),3.03-2.96(m,1H),2.93-2.73(m,6H),2.53-2.52(m,3 H),2.43-2.39(m,7H),2.32-2.27(m,2H),2.20-2.17(m,1H),2.09-2.05(m,3H),1.77-1.70(m,4H),1.60-1.53(m,1H).

[0446] Example 64

[0447] Referring to the above example, the desired product 64 (4.4 mg) was obtained. MS (ESI) M / Z: 825.1 [M+H + ]; 1 H NMR (400MHz, CDCl3) δ11.22(s,1H),8.82(s,1H),8.37(s,2H),8.25(s,1H),8.08(s,1H),7.96(d,J=9.0Hz,1 H),7.18-7.15(m,2H),7.04-6.94(m,2H),6.76(d,J=7.8Hz,1H),5.20(dd,J=12.4,5.2Hz,1H),4.35(s,2H),4 .27(s,3H),3.99-3.96(m,1H),3.77(s,3H),3.06-2.64(m,4H),2.61-2.53(m,3H),2.43-2.30(m,3H),2.25- 2.22(m,2H),2.12-2.07(m,5H),2.00-1.87(m,4H),1.85-1.78(m,2H),1.53-1.51(m,1H),1.37-1.33(m,2H).

[0448] Example 65

[0449] Referring to the above example, the desired product 65 (6.7 mg) was obtained. MS (ESI) M / Z: 811.0 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),11.13(s,1H),10.71(brs,1H),8.99(d,J=3.8Hz,1H),8.66(s,1H),8.59(s,1H),8.45(d,J=9 .2Hz,1H),8.38(s,1H),7.69(dd,J=9.2,4.5Hz,1H),7.31(s,1H),7.20(d,J=7.8Hz,1H),7.13(d,J=7.7Hz,1H),7.04(t,J=7.9Hz,1H ),5.43(dd,J=12.7,5.4Hz,1H),5.28-5.18(m,1H),4.37(s,2H),4.14(s,3H),4.10-3.95(m,1H),3.65(s,3H),3.38-3.17(m,3H),3. 15-3.06(m,2H),3.01-2.82(m,3H),2.76-2.60(m,3H),2.48-2.30(m,4H),2.27-2.13(m,1H),2.12-1.84(m,6H),1.82-1.68(m,2H).

[0450] Example 66

[0451] Referring to the above example, the desired product 66 (19 mg) was obtained. MS (ESI) M / Z: 904.4 [M+H + ]; 1H NMR (400MHz, CDCl3) δ9.60 (s, 1H), 8.40 (d, J = 6.8Hz, 2H), 8.32 (d, J = 7.6Hz, 1H), 7.16 (d, J = 7.2Hz, 1H), 6.99 (t, J=7.6Hz,1H),6.90-6.58(m,2H),6.12(d,J=7.6Hz,1H),5.44(s,1H),5.20(dd,J=12.4,5.2Hz,1H),4.79(s,1H), 4.39(s,2H),4.06-3.92(m,3H),3.90-3.72(m,5H),3.68-3.45(m,5H),2.96-2.94(m,1H),2.87-2.71(m,4H),2. 35-2.24(m,3H),2.17-2.09(m,4H),2.00-1.92(m,4H),1.78-1.69(m,4H),1.68-1.66(m,2H),1.56-1.37(m,4H).

[0452] Example 67

[0453] Referring to the above example, the desired product 67 (5.3 mg) was obtained. MS (ESI) M / Z: 813.4 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.19(s,1H),11.07(s,1H),9.01-8.96(m,1H),8.78(s,1H),8.47(s,1H),8.46-8.42( m,1H),7.98(s,1H),7.66(d,J=8.4Hz,1H),7.56(dd,J=9.2,4.5Hz,1H),7.38(s,1H),7.33-7.29(m,1H),7.26-7 .21(m,1H),5.07(dd,J=12.8,5.4Hz,1H),4.65-4.54(m,1H),4.13(s,3H),4.09-3.99(m,2H),3.29(s,1H),3.0 8-2.76(m,4H),2.41-2.30(m,4H),2.21-1.93(m,8H),1.85-1.72(m,6H),1.67-1.61(m,2H),1.40-1.33(m,4H).

[0454] Example 68

[0455] Referring to the above example, the desired product 68 (40 mg) was obtained. MS (ESI) M / Z: 934.3 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),9.49(d,J=5.2Hz,1H),8.78(d,J=7.6Hz,1H),8.41(d,J=4.4Hz,1H),8.25 (d,J=5.6Hz,1H),7.26-6.98(m,4H),6.88-6.44(m,1H),5.41(dd,J=12.6,5.4Hz,1H) ,5.17(d,J=80.8Hz,1H),4.77(d,J=17.6Hz,1H),4.49(s,2H),4.19-4.16(m,1H),3.8 4-3.72(m,2H),3.65-3.56(m,5H),3.49-3.43(m,1H),2.94-2.85(m,2H),2.77-2.61( m,3H),2.33-1.75(m,14H),1.66-1.49(m,4H),1.44-1.20(m,6H),1.14-0.93(m,4H).

[0456] Example 69

[0457] Referring to the above example, the desired product 69 (1 mg) was obtained. MS (ESI) M / Z: 851.2 [M+H + ]; 1H NMR (400MHz, CDCl3) δ9.60(s,1H),8.42(d,J=6.4Hz,2H),8.31(d,J=7.6Hz,1H),8.11(d,J=4.8Hz,1H),7.18(d,J=7.6Hz,1H),6 .99(t,J=8.0Hz,1H),6.91-6.63(m,2H),6.12(d,J=7.6Hz,1H),5.46(s,1H),5.36-5.33(m,1H),5.22-5.17(m,1H),4.82-4.79( m,1H),4.40(s,2H),4.07-3.95(m,3H),3.79(s,3H),3.57(d,J=9.2Hz,1H),3.49(d,J=9.2Hz,1H),3.43(d,J=6.0Hz,2H),2.98- 2.71(m,3H),2.26-2.20(m,1H),2.12-1.85(m,8H),1.67-1.61(m,1H),1.49-1.45(m,1H),1.39-1.30(m,4H),1.12-0.98(m,4H).

[0458] Example 70

[0459] Referring to the above example, the desired product 70 (19 mg) was obtained. MS (ESI) M / Z: 850.4 [M+H + ]; 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),9.50(d,J=5.2Hz,1H),8.78(d,J=8.0Hz,1H),8.40(d,J=3.6Hz,1H), 8.25(d,J=5.6Hz,1H),7.28-7.01(m,4H),6.88-6.44(m,1H),5.45-5.36(m,1H),5.28-5.07(m,1H),5.02-4. 94(m,1H),4.80-4.74(m,1H),3.85-3.72(m,4H),3.65-3.59(m,5H),3.51-3.43(m,2H),2.93-2.85(m,1H),2 .72-2.60(m,2H),2.44-2.38(m,2H),2.27-2.21(m,2H),2.05-1.95(m,3H),1.76-1.64(m,4H),1.51(s,6H).

[0460] Example 71

[0461] Step 1: Dissolve methyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (4.3 g, 27.2 mmol) in dry tetrahydrofuran (40 mL). The reaction system was purged with nitrogen and placed in an ice-water bath. After cooling the reaction system to 0°C, sodium hydride (1.3 g, 32.6 mmol) was slowly added to the reaction solution under a nitrogen atmosphere. After stirring the reaction at 0°C for 1 hour, propargyl bromide (3.88 g, 32.6 mmol) was slowly added dropwise to the reaction system. The reaction was allowed to return to room temperature and stirred for 3 hours. After TLC monitoring indicated the disappearance of the starting material, the reaction solution was quenched by adding saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give P1(71a) (140 mg) and P2(72a) (200 mg).

[0462] P1 1 H NMR (400MHz, CDCl3) δ4.15 (t, J = 5.0Hz, 2H), 3.75–3.69 (m, 1H), 3.67 (s, 3H), 2.44–2.32 (m,2H),1.94–1.79(m,4H),1.70–1.64(m,2H),1.60–1.51(m,2H).

[0463] P2 1 H NMR (400MHz, CDCl3) δ4.19 (d, J=2.4Hz, 2H), 3.67 (s, 3H), 3.47 (tt, J=10.5, 4.1Hz, 1H), 2.41 (t, J= 2.4Hz,1H),2.28(tt,J=11.7,3.7Hz,1H),2.15–2.02(m,4H),1.55–1.44(m,2H),1.33–1.26(m,2H).

[0464] Step 2: 71a (200 mg, 1.1 mmol) was dissolved in 4 mL of tetrahydrofuran / water (0.8 mL) at room temperature. Lithium hydroxide (230 mg, 5.49 mmol) was added, and the reaction system was stirred at 50°C overnight. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was extracted with ethyl acetate (30 mL x 2). The aqueous phase was adjusted to pH 3-4 with 1 M hydrochloric acid and then extracted with ethyl acetate (30 mL x 2) to provide intermediate 71b (160 mg, light yellow solid). 1H NMR (400MHz, DMSO) δ12.04(s,1H),4.13(t,J=3.9Hz,2H),3.35(m,J=2.4Hz,2H),2.15(tt,J=1 1.5,3.6Hz,1H),2.00–1.94(m,2H),1.91–1.83(m,2H),1.38–1.28(m,2H),1.21–1.12(m,2H).

[0465] Step 3: Dissolve 71b (101 mg, 0.554 mmol), intermediate A (230 mg, 0.462 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (263 mg, 0.693 mmol) in N,N-dimethylformamide (4 mL), add N,N-diisopropylethylamine (150 mg, 1.155 mmol), and the reaction system is stirred at room temperature for one hour.

[0466] After TLC monitoring showed the disappearance of the starting material, 30 mL of ethyl acetate was added to the reaction solution, and the mixture was extracted with water (30 mL × 3 times). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 71c (150 mg). MS (ESI) M / Z: 663.3 [M+H + ].

[0467] Step 4: Dissolve 71c (150 mg, 0.226 mmol), intermediate B (92 mg, 0.271 mmol), cesium carbonate (220 mg, 0.679 mmol), cuprous iodide (5 mg, 0.0226 mmol), and bis(triphenylphosphine)palladium dichloride (16 mg, 0.0226 mmol) in N,N-dimethylformamide (4 mL) at room temperature. The reaction system was evacuated and replaced with nitrogen several times. The reaction solution was stirred in an oil bath at 85°C for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction solution was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the final product 71 (5.6 mg). MS (ESI) M / Z: 920.1 [M+H + ]; 1H NMR (400MHz, DMSO) δ11.10(s,1H),9.50(d,J=5.2Hz,1H),8.79(d,J=7.7Hz,1H),8.4 2(d,J=4.1Hz,1H),8.26(d,J=5.6Hz,1H),7.31–7.09(m,3H),7.03(dd,J=9.8,5.9Hz, 1H),6.87(d,J=7.9Hz,0.5H),6.46(d,J=7.8Hz,0.5H),5.40(dd,J=12.7,5.4Hz,1H) ,5.28(s,0.5H),5.08(s,0.5H),4.99(d,J=7.0Hz,1H),4.77(d,J=16.0Hz,1H),4.47( s,2H),3.80(t,J=16.7Hz,2H),3.65(s,3H),3.61(d,J=10.7Hz,1.5H),3.45(d,J=9. 3Hz,3.5H),3.37(s,2H),2.93–2.84(m,1H),2.77–2.68(m,1H),2.65(t,J=5.4Hz,1H) ,2.40(s,2H),2.23(t,J=9.3Hz,2H),2.12–2.02(m,4H),2.01–1.91(m,2H),1.67(s,3 H),1.59(s,2H),1.51(s,1H),1.40(dd,J=25.0,11.6Hz,2H),1.27(d,J=10.9Hz,2H).

[0468] Example 72

[0469] Referring to Example 71, the desired product 72 (6.9 mg) was obtained. MS (ESI) M / Z: 920.3 [M+H + ]; 1H NMR (400MHz, DMSO) δ11.10 (s, 1H), 9.50 (d, J = 5.2Hz, 1H), 8.79 (d, J = 7.8Hz, 1H),8.41(d,J=4.1Hz,1H),8.26(d,J=5.6Hz,1H),7.19–7.00(m,4H),6.87( d,J=7.9Hz,0.5H),6.46(d,J=7.7Hz,0.5H),5.40(dd,J=12.7,5.4Hz,1H),5 .28(s,0.5H),5.08(s,0.5H),4.99(s,1H),4.77(d,J=15.3Hz,1H),4.45(s,2 H),3.82(d,J=8.9Hz,2H),3.74(d,J=7.7Hz,0.5H),3.64(s,3H),3.58(d,J= 11.3Hz,1.5H),3.45(d,J=9.8Hz,3H),3.37(s,2H),2.88(dd,J=20.6,9.4Hz, 1H),2.75–2.62(m,3H),2.40(t,J=9.3Hz,2H),2.23(t,J=10.0Hz,2H),2.08 –1.85(m,6H),1.66(s,2H),1.58(d,J=9.8Hz,3H),1.52(s,2H),1.41(s,2H).

[0470] Biological Activity Test Example

[0471] The control molecule used in this test example is KT-474, which was prepared based on the preparation method of compound I-417 in patent WO2020113233A1. Its structure is as follows:

[0472] Test Example 1: Degradation of IRAK4 in SU-DHL-2 and OCI-LY3 cells by compounds

[0473] (1) Experimental purpose

[0474] Flow cytometry was used to detect the degradation level of IRAK4 protein in SU-DHL-2 cell line by the compounds.

[0475] (2) Experimental materials

[0476] Fix Buffer I, BD Phosflow TM ,557870

[0477] Perm III buffer, BD Phosflow TM ,558050

[0478] LIVE / DEAD TM Fixable Violet Dead Cell Stain Kit, Thermo Fisher, L34966

[0479] Alexa Fluor 647 Mouse anti-Human IRAK4 Clone L29-525(RUO), BD Phosflow TM ,560315

[0480] (3) Experimental instruments

[0481] Flow cytometer, BD, model: BD LSRFortessa

[0482] (4) Experimental methods

[0483] Step 1: SU-DHL-2 cell lines were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% double antibody.

[0484] Step 2: On day 1, seed 100 μL of cells per well in a 96-well plate at a density of 2*10^5. Dissolve the compound in DMSO to a final concentration of 10 mM and add it to the cells using a 1:5 dilution series of 10 dilutions in culture medium, achieving a maximum final concentration of 2 μM. A well containing cells supplemented with 0.1% DMSO serves as a positive control. Incubate the cells in a 37°C, 5% CO₂ incubator for 24 hours.

[0485] Step 3: After centrifugation, wash the cells with FACS buffer. TM Fixable Blue Dead Cell Stain Kit was used to distinguish live and dead cells, and PE Mouse Anti-Human CD14 was used to stain the surface of monocytes. The cells were incubated at 4°C for 30 minutes.

[0486] Step 4: After centrifugation, wash the cells with FACS buffer. Add a volume of Fix buffer I equal to the volume of cultured cells and fix the cells at 37°C for 10 minutes.

[0487] Step 5: After centrifugation, wash the cells with FACS buffer. Add 150 μL of Perm III reagent and incubate at 4°C for 30 minutes to permeabilize the cell membrane. After centrifugation, wash the cells with FACS buffer.

[0488] Step 6: Stain the cells with Alexa Fluor 647 Mouse anti-Human IRAK4 Antibody and incubate at 4°C for 1 hour. Perform flow cytometric analysis.

[0489] (5) Data processing

[0490] Flow cytometry data were analyzed using FlowJo software. 50 (half maximal degradation concentration) was calculated using Prism 8.0.2 (GraphPad).

[0491] (6) Experimental results

[0492] The results of the degradation activity of the compounds of the examples of the present disclosure on IRAK4 are shown in Table 1.

[0493] The Dmax of the compounds of the embodiments of the present disclosure on SU-DHL-2 and OCI-LY3 cells is generally above 50%, and can reach up to about 90%.

[0494] The results showed that the compounds of the embodiments of the present disclosure had good degradation activity against IRAK4 targets in SU-DHL-2 and OCI-LY3 cells.

[0495] Table 1. IRAK4 degradation results in SU-DHL-2 and OCI-LY3 cells.

[0496] Test Example 2: Degradation of IRAK4 in human PBMC by compounds

[0497] (1) Experimental purpose

[0498] Flow cytometry was used to detect the degradation level of IRAK4 in monocytes of human peripheral blood mononuclear cells (hPBMCs).

[0499] (2) Experimental materials

[0500] Fix Buffer I, BD Phosflow TM ,557870

[0501] Perm III buffer, BD Phosflow TM ,558050

[0502] LIVE / DEAD TMFixable Blue Dead Cell Stain Kit, for UV excitation, Thermo Fisher, L34962

[0503] PE Mouse Anti-Human CD14, BD Pharmingen TM ,555398

[0504] Alexa Fluor 647 Mouse anti-Human IRAK4 Clone L29-525(RUO), BD Phosflow TM ,560315

[0505] (3) Experimental instruments

[0506] Flow cytometer, BD, model: BD LSRFortessa

[0507] (4) Experimental methods

[0508] After thawing, the frozen hPBMCs were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% Pen+Strep and revived at 37°C for 1 hour.

[0509] On day 1, cells were seeded in 96-well plates at a concentration of 2*10<5> per well in 100 μL.

[0510] The compound was dissolved in DMSO to a final concentration of 10 mM, diluted 10 times in culture medium at a concentration gradient of 1:5, and added to the cells to achieve a maximum final concentration of 2 μM. A well containing 0.1% DMSO was used as a positive control.

[0511] Incubate at 37°C in a 5% CO2 incubator for 24 hours.

[0512] After centrifugation, cells were washed with FACS buffer.

[0513] Using LIVE / DEAD TM Fixable Blue Dead Cell Stain Kit was used to distinguish live and dead cells, and PE Mouse Anti-Human CD14 was used to stain the surface of monocytes. The cells were incubated at 4°C for 30 minutes.

[0514] After centrifugation, cells were washed with FACS buffer.

[0515] Add Fix buffer I in a volume equal to the volume of cultured cells and fix the cells at 37°C for ten minutes.

[0516] After centrifugation, cells were washed with FACS buffer.

[0517] Add 150ul Perm III reagent and incubate at 4°C for 30 minutes to permeabilize the cells.

[0518] After centrifugation, cells were washed with FACS buffer.

[0519] Cells were stained with Alexa Fluor 647 Mouse anti-Human IRAK4 Antibody and incubated at 4°C for 1 hour.

[0520] Flow cytometric analysis was performed using a flow cytometer.

[0521] (5) Data processing method

[0522] Flow cytometry data were analyzed using FlowJo software. 50 Calculations were performed using Prism 8.0.2 (GraphPad).

[0523] (6) Experimental results

[0524] The results of the degradation activity of the compounds of the examples of the present disclosure on IRAK4 are shown in Table 2.

[0525] The results showed that the compounds of the embodiments of the present disclosure had good degradation activity on the IRAK4 target in human PBMC cells.

[0526] Table 2. IRAK4 degradation results in human PBMC cells

[0527] Test Example 3: Inhibition of compound on secretion of inflammatory factors induced by human PBMC

[0528] (1) Experimental purpose

[0529] The effect of PROTAC small molecules on TLR and IL-1-induced IRAK4 downstream PBMC cell inflammatory factors was detected based on the CBA (micro-sample multi-indicator flow cytometry) method

[0530] (2) Experimental materials

[0531] (3) Experimental instruments

[0532] Flow cytometer, BD, model: BD LSRFortessa

[0533] (4) Experimental methods

[0534] Step 1: Human PBMC recovery

[0535] Step 2: Adjust the PBMC cell density to 1E6 / mL, seed 1640 PBMCs in 150 μL of complete culture medium in a 96-well plate, and incubate at 37°C for 1 h.

[0536] Step 3: Inoculate 50 μL of serially diluted small molecule drugs (working concentration: 10000 nM, 1:3 dilution) onto the plate in a 37°C incubator for 8 hours.

[0537] Step 4: Add 10 μL of stimulants respectively, with the final concentration of LPS being 100 ng / mL, the final concentration of R848 being 1 μg / mL, and the final concentration of IL-1β being 100 ng / mL.

[0538] Step 5: CBA Assay: Use Hu IL-6 CBA Flex Set A7 and Hu TNF-CBA Flex Set D9 to measure the concentrations of IL-6 and TNF-α in the cell culture supernatant.

[0539] Step 6: Prepare the standard: 2500 pg / mL, 1250 pg / mL, ... 0.1:2 gradient dilution, 10 concentrations.

[0540] Step 7: Resuspend the mixed capture beads in capture bead diluent (1:50), add cell culture supernatant (50 μL) and incubate at room temperature for 10 minutes.

[0541] Step 8: Add the detection reagent prepared in the detection diluent and incubate at room temperature in the dark for 3 hours. At the end of the incubation, wash once with wash buffer and resuspend for testing.

[0542] (5) Data processing

[0543] IL-6 and TNFa concentrations were calculated using the standard curve method. Data show IC 50 Calculations were performed using Prism 8.0.2

[0544] (6) Experimental results

[0545] The results of the inhibition of the secretion of inflammatory factors induced by the compounds of the examples of the present disclosure on human PBMC are shown in Tables 3 and 4.

[0546] The results show that the compounds of the embodiments of the present disclosure can effectively inhibit the secretion of inflammatory factors and have potential value in treating inflammatory diseases.

[0547] Table 3-1. LPS, R848, and IL-1β induce TNFα secretion in human PBMC cells

[0548] Table 3-2. LPS, R848, and IL-1β induce TNFα secretion in human PBMC cells

[0549] Table 4-1. LPS, R848, and IL-1β induce IL-6 secretion in human PBMC cells

[0550] Table 4-2. LPS, R848, and IL-1β induce IL-6 secretion in human PBMC cells

[0551] Test Example 4: Inhibition of hERG potassium channels by compounds

[0552] (1) Experimental purpose

[0553] The effects of compounds on hERG potassium channel (human Ether-a-go-go Related Gene potassium channel) currents were tested using the whole-cell manual voltage clamp electrophysiology method.

[0554] (2) Experimental materials

[0555] Sodium chloride (NaCl) Sigma S7653, potassium chloride (KCl) Sigma P9333, magnesium chloride (MgCl2) Sigma M1028

[0556] Calcium chloride (CaCl2) Sigma 21115, glucose (Glucose) Sigma G7528, HEPES Sigma H3375, EGTA Sigma E3889, sodium hydroxide (NaOH) Sinopharm 10019718, potassium hydroxide (KOH) Sinopharm 10017018;

[0557] CHO-hERG cell line (Chinese Hamster Ovary): Chinese hamster ovary cells stably expressing hERG channels

[0558] Extracellular solution formula (mM): 140NaCl, 5KCl, 1CaCl2, 1.25MgCl2, 10HEPES and 10Glucose, adjusted to pH 7.4 with NaOH.

[0559] Intracellular solution formula (mM): 140KCl, 1MgCl2, 1CaCl2, 10EGTA and 10HEPES, adjusted to pH 7.2 with KOH.

[0560] (3) Experimental instruments

[0561] Patch clamp amplifier (Multiclamp 700B, Axon, USA)

[0562] Digital-to-analog converter (DigiData 1440A, Axon, USA)

[0563] Inverted microscope (IX71, Olympus, Japan )

[0564] Rapid drug delivery system (RSC-200, Bio-Logic, France)

[0565] Micromanipulator (MX7600R, Syskiyou, USA)

[0566] Electrode pulling apparatus (P-97, Sutter, USA)

[0567] Glass electrode (BF150-86-10, Sutter, USA)

[0568] Anti-vibration table and shielding net (63-534, TMC, USA)

[0569] Data acquisition and analysis software (pClamp, Axon, USA)

[0570] CO2 incubator (HERAcell 150i, Thermo, USA)

[0571] Biological safety cabinet (MODEL 1384, Thermo, USA)

[0572] Water purifier (Milli Q, Millipore, USA)

[0573] (4) Experimental methods

[0574] (4.1) Cell culture and treatment

[0575] CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes in a 37°C, 5% CO2 incubator. The cells were passaged every 48 hours at a 1:5 ratio. The culture medium consisted of 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 μg / mL G418 (Invitrogen), and 100 μg / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated, the cells were rinsed once with extracellular medium, and then digested with 0.25% Trypsin-EDTA (Invitrogen) solution at room temperature for 3-5 minutes. The digestion medium was aspirated, the cells were resuspended in extracellular medium, and then transferred to a dish for electrophysiological recording.

[0576] (4.2) Compound preparation

[0577] On the day of testing, prepare the compound to a 10 mM stock solution in DMSO, dilute to 1 mM with DMSO, and then dilute 1000-fold in extracellular fluid to the desired final concentration. For the positive control compound, cisapride, prepare 10 μL of a 150 μM cisapride DMSO stock solution to 4990 μL of extracellular fluid and dilute 500-fold to a final concentration of 300 nM. The DMSO content in the final test concentration does not exceed 0.2%, as this concentration of DMSO has no effect on hERG potassium channels.

[0578] (4.3) Electrophysiological recording process

[0579] hERG potassium channel currents were recorded using the whole-cell voltage-clamp technique at room temperature in CHO cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch clamp amplifier by inserting them into the amplifier headstage. Clamp voltage and data recording were controlled and recorded by a computer using pClamp software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -100 mV. To elicit hERG potassium currents (I hERG ), a step voltage was applied from -100 mV to +20 mV for 2 s, followed by repolarization to -50 mV for 1 s before returning to -100 mV. This voltage stimulus was applied every 5 s, and drug administration was initiated after confirming the stability of the hERG potassium current (1 min). Compounds were administered for at least 1 minute to steady state of action or for a maximum of 3 minutes at each test concentration, and at least two cells (n≥2) were tested at each concentration.

[0580] (5) Data processing

[0581] Data analysis and processing were performed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1–(I / Io)] × 100%

[0582] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0583] (6) Experimental results

[0584] Table 5. Inhibition results of hERG potassium channels

[0585] Note: @1uM refers to the concentration of the test compound.

[0586] The experimental results show that the compounds of the examples disclosed herein have no obvious inhibitory activity on hERG, indicating that the compounds disclosed herein have good safety.

[0587] Test Example 5: In vivo pharmacokinetics determination of compounds

[0588] Experiment 1:

[0589] C57BL / 6 mice were used as test animals to study the pharmacokinetic behavior of the disclosed compounds in the plasma of mice after oral administration at a dose of 100 mg / kg.

[0590] 1. Experimental Plan

[0591] 1.1 Investigational Drugs:

[0592] Embodiments 13, 22, and 31 of the present disclosure.

[0593] 1.2 Experimental animals

[0594] C57BL / 6, male, animals were transferred from the animal reserve bank of the experimental institution (999M-018).

[0595] 1.3 Administration:

[0596] Three male C57BL / 6 mice were used. The animals were fasted overnight (10–14 hours) prior to dosing and had free access to water. Four hours after dosing, the PO dose was 100 mg / kg in a 20 mL / kg dosing volume.

[0597] 1.4 Experimental Equipment

[0598] Centrifuge (5810R) was purchased from Eppendorf, pipettes were purchased from Eppendorf, and vortexer was purchased from Scientific Industries.

[0599] 1.5 Sample collection

[0600] After administration, 0.03 mL of venous blood was collected from mice at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in EDTA-K2 tubes, centrifuged at 6800 rpm for 5 minutes at 2-8°C, and the plasma was separated and stored at -80°C.

[0601] 1.6 Sample processing

[0602] 1) 10 μL of plasma sample was added to 200 μL of methanol for precipitation, mixed and centrifuged at 18000 g for 10 minutes.

[0603] 2) The supernatant solution after treatment was taken and the concentration of the test compound was analyzed by LC / MS / MS.

[0604] 1.7 Liquid phase analysis

[0605] Liquid phase conditions: Shimadzu LC-30AD pump

[0606] Mass spectrometry conditions: AB Sciex API 5500 mass spectrometer

[0607] Column: Phenomenex Kinetex 2.6μm C18 50 3.0mm

[0608] Mobile phase: Liquid A is 0.1% formic acid in water, Liquid B is 0.1% formic acid in acetonitrile

[0609] Flow rate: 0.6 mL / min

[0610] Elution time: gradient elution 0-1.6 minutes.

[0611] 2. Experimental Results and Analysis

[0612] The main pharmacokinetic parameters were calculated using WinNonlin 8.0.

[0613] The experimental results show that the compounds of the present invention have good pharmacokinetic properties.

[0614] Table 6. Pharmacokinetic parameters of some compounds of the present disclosure in mice after oral administration

[0615] Experiment 2:

[0616] 1.1 Investigational Drugs:

[0617] This disclosure discloses embodiment 52.

[0618] 1.2 Experimental animals

[0619] C57BL / 6J, male, purchased from JH Laboratory Animal Co.LTD. Qualification No.: SCXK(SH)2022-0009 20220009007223

[0620] 1.3 Administration:

[0621] Two male C57BL / 6 mice were given free access to food and water. The PO dose was 100 mg / kg in a 10 mL / kg volume.

[0622] 1.4 Experimental Equipment

[0623] Centrifuge (5810R) was purchased from Eppendorf, pipettes were purchased from Eppendorf, and vortexer was purchased from Scientific Industries.

[0624] 1.5 Sample collection

[0625] After administration, 0.025 mL of venous blood was collected from mice at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in EDTA-K2 tubes, centrifuged at 2000 g for 5 minutes at 4°C, and the plasma was separated and stored at -70°C.

[0626] 1.6 Sample processing

[0627] 1) 5 μL of plasma sample was added to 100 μL of acetonitrile for precipitation, mixed and centrifuged at 5800 rpm for 10 minutes.

[0628] 2) The supernatant solution after treatment was taken and analyzed by LCMS / MS to determine the concentration of the test compound.

[0629] 1.7 Liquid phase analysis

[0630] Liquid chromatography-mass spectrometry instrument: LCMS / MS-45 (Triple Quad 6500+)

[0631] Chromatographic column: Waters BEH C18 (2.1×50mm, 1.7μm)

[0632] Mobile phase: Liquid A is H2O-0.025% FA-1mM NH4OAc, Liquid B is MeOH-0.025% FA-1mM NH4OAc

[0633] Flow rate: 0.6 mL / min

[0634] Elution time: gradient elution 0-2.5 minutes.

[0635] 2. Experimental Results and Analysis

[0636] The main pharmacokinetic parameters were calculated using WinNonlin 8.2. The pharmacokinetic parameters of oral administration to mice are shown in Table 7 below. The experimental results show that the disclosed compound 52 has good pharmacokinetic properties.

[0637] Table 7. Pharmacokinetic parameters of some compounds of the present disclosure in mice after oral administration

[0638] Experiment 3:

[0639] 1.1 Investigational Drugs:

[0640] Embodiments 13, 22, 31 and 52 of the present disclosure.

[0641] 1.2 Experimental animals

[0642] Healthy male Beagle dogs, weighing about 8-10 kg, 3 per group.

[0643] 1.3 Experimental plan:

[0644] Beagle dogs (3 dogs / group) were gavaged with 2.5 mg / kg of the compound in a volume of 5 mL / kg, prepared with 10% DMSO + 50% PEG400 + 40% Water (w / v), without food fasting and with free access to water.

[0645] 0.5-0.8 mL of venous blood was collected 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after oral administration, placed in a K2EDTA tube, and centrifuged at 4°C to separate plasma. The concentration of the compound in the plasma was determined by liquid chromatography-tandem mass spectrometry.

[0646] 1.4 Experimental results:

[0647] The main pharmacokinetic parameters were calculated using WinNonlin. The pharmacokinetic parameters of the oral drug for dogs are shown in Table 8 below. The experimental results show that the compounds of the examples of the present disclosure have good pharmacokinetic properties.

[0648] Table 8. Pharmacokinetic parameters of some compounds of the present disclosure in dogs after oral administration

[0649] Test Example 6: Evaluation of the efficacy of compounds on IL-33-induced acute inflammation in mice

[0650] (1) Experimental purpose

[0651] IL-33 is a member of the IL-1 cytokine family and a ligand for IL-1 receptor-like 1 or ST2. IL-33 transgenic mice, which specifically express IL-33 in keratinocytes, spontaneously develop AD (atopic dermatitis)-like eczema, suggesting that the IL-33 pathway plays a key role in AD. An acute inflammatory mouse model induced by intraperitoneal injection of IL-33 was used to investigate the effects of compounds on inflammatory responses through the IL-1R signaling pathway.

[0652] (2) Experimental materials and methods

[0653] Experimental animals: SPF male C57BL / 6J mice aged 6-8 weeks.

[0654] Compound preparation: 10% DMSO + 50% PEG400 + 40% sterile water for injection. Prepare by dissolving the compound in DMSO, then adding PEG400 and sterile water for injection, and adjusting the solution with 6N hydrochloric acid until clear.

[0655] Preparation of IL-33 inducer: Prepare recombinant mouse IL-33 powder into a 1 μg / μL stock solution. Add 3960 μL of PBS to 40 μL of the 1 μg / μL IL-33 solution and mix thoroughly by inversion to obtain 4 mL of a 1 μg / 100 μL IL-33 solution. Prepare and use immediately.

[0656] Compound Administration and IL-33 Inflammation Induction: Mice were randomly divided into groups based on body weight and orally administered twice daily with a final dose of 15 mg / kg, 50 mg / kg, or 150 mg / kg of compound. Four hours after the last dose of compound, mice were intraperitoneally injected with 1 μg of IL-33 in 100 μl of PBS to induce inflammation.

[0657] Termination, Sample Collection, and Data: Plasma, peritoneal lavage fluid, and spleen were collected for subsequent sample parameter analysis.

[0658] The experiment was terminated 8 hours after the last administration. The mice were anesthetized and blood was collected from the heart. After anticoagulation with EDTA-K2, the blood samples were centrifuged at 3500 rpm for 15 minutes to obtain the upper plasma layer. The euthanized mice were disinfected by soaking in 75% alcohol for 3 minutes in a sterile clean bench. 2.5 mL of 4°C pre-cooled PBS was injected intraperitoneally. The mouse abdomen was massaged for 5 minutes. The mouse abdominal skin was cut open with sterile scissors and sterile forceps to expose the peritoneum. The sternum was lifted at the xiphoid process with sterile forceps, and the peritoneum was cut 1 mm at the xiphoid process. 2 A small opening was used to insert a pipette into the peritoneal cavity, gently pipetting and aspirating 2 mL of lavage fluid. The fluid was then aliquoted into 1.5 mL centrifuge tubes and stored at -80°C. ELISA was used to assay the expression of inflammatory factors in mouse plasma and peritoneal lavage fluid, and LC-MS was used to assay the expression of IRAK4 protein in mouse spleen.

[0659] (3) Experimental results and analysis

[0660] Table 9. Endpoint plasma and tissue drug concentrations

[0661] The results in Table 9 show that the concentrations of Example 22 in plasma and spleen at a dose of 50 mpk reached the same level as that of KT-474 at a dose of 150 mpk, indicating that Example 22 has a lower dosage.

[0662] Figure 1 shows the concentration-dependent reduction of inflammatory factors in mouse plasma and peritoneal lavage fluid after three PO doses of Example 22. When the plasma drug concentrations were comparable, Example 22 had a better anti-inflammatory effect than KT474.

[0663] Figure 2 shows the in vivo degradation of IRAK4 in mouse spleens after three PO doses of Example 22. At comparable spleen drug concentrations, Example 22 at 50 mpk showed 2-3 times better degradation than KT-474 at 150 mpk.

[0664] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. A bifunctional compound represented by general formula (I), its isomer, its deuterated product or a pharmaceutically acceptable salt thereof, in, Ring C is phenyl, 5-6 membered heteroaryl, 9-10 membered fused heteroaryl; R 1 Selected from -CN, -NR 1a R 1b 、-OH、halogen、C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, 7-9 membered bridged heterocyclyl, 6-10 membered fused heterocyclyl, 3-6 membered cycloalkyl-NH-, phenyl, 5-6 membered heteroaryl, 9-10 membered fused heteroaryl, wherein the heterocyclyl, bridged heterocyclyl, fused heterocyclyl, cycloalkyl, heteroaryl, fused heteroaryl are optionally substituted by one or more Rx, wherein Rx is selected from -NH2, -NR 1a R 1b 、-CN、-OH、halogen、C 1-6 Alkyl, halogenated C 1-6 alkyl; R 1a , R 1b are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl-C 1-6 Alkyl-, 3-6 membered heterocyclic group, 3-6 membered heterocyclic group-C 1-6 alkyl-; m is selected from 0, 1, 2, 3, 4; Ring B is selected from 5-6 membered heteroaryl, 9-10 membered fused heteroaryl; R 2 Selected from H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; q is selected from 0, 1, 2, 3, 4; Lx is -C(O)-NR La -; R La Selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, 3-6 membered cycloalkyl; Ring A is selected from a divalent group optionally substituted by one or more Rz: 7-11 membered spirocycloalkyl, 7-11 membered spiroheterocyclyl, 7-9 membered subbridged cycloalkyl, 7-9 membered subbridged heterocyclyl, wherein Rz is selected from halogen, -OH, -NH2, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl; L is -(B 1 )n1-(B 2 )n2-(B 3 )n3-; B 1 C 1-6 An alkylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n1 is selected from 0, 1; B 2 Selected from the following divalent rings optionally substituted with one or more Ry: C 3-6 Cycloalkylene, C 5-8 a 4-6 membered heterocyclyl group, a 6-8 membered heterocyclyl group, a phenylene group, a 6-8 membered heterocycloalkenyl group, wherein Ry is selected from oxo, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl; n2 is selected from 0, 1; B 3 Selected from saturated or unsaturated C 1-6 An alkylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n3 is selected from 0, 1; R a , R b are independently selected from H, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and R a , R b Not at the same time H; Alternatively, R on the same carbon atom a , R b Together with the carbon atom to which it is connected, it forms a 3-6 membered cycloalkyl group or a 3-6 membered heterocyclic group; R c Selected from H, C 1-6 alkyl; Degradons are ligands that bind to E3 enzymes.

2. The bifunctional compound, its isomer, its deuterated product or its pharmaceutically acceptable salt according to claim 1, characterized in that: The bifunctional compound is shown in the following formula (IA): Among them, R 1 Selected from -CN, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heterocyclic group, 7-9 membered bridged heterocyclic group, 6-10 membered fused heterocyclic group, 3-6 membered cycloalkyl-NH-, wherein the heterocyclic group, bridged heterocyclic group, fused heterocyclic group, cycloalkyl are optionally substituted by one or more Rx, wherein Rx is selected from -NH2, -OH, halogen, C 1-4 Alkyl, halogenated C 1-4 alkyl; m is selected from 0, 1, 2, 3, 4; R 2 Selected from C 1-4 Alkyl, halogenated C 1-4 alkyl; Ring A is selected from the following divalent groups: 7-11 membered spirocycloalkylene, 7-11 membered spiroheterocyclylene, 7-9 membered bridged cycloalkylene, 7-9 membered bridged heterocyclylene; L is selected from -(B 1 )n1-(B 2 )n2-(B 3 )n3-; B 1 Selected from C 1-3 An alkylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n1 is selected from 0, 1; B 2 Selected from the following divalent rings optionally substituted with one or more Ry: C 3-6 Cycloalkylene, C 5-8 a 4-6 membered heterocyclyl group, a 6-8 membered heterocyclyl group, a phenylene group, a 6-8 membered heterocycloalkenyl group, wherein Ry is selected from oxo, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl; n2 is selected from 0, 1; B 3 Selected from saturated or unsaturated C 1-6 An alkylene chain, wherein any methylene unit thereof is optionally substituted with -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S-; n3 is selected from 0, 1; R a , R b are independently selected from H, deuterium, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, and R a , R b Not at the same time H; Alternatively, R on the same carbon atom a , R b Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group; R c Selected from H, C 1-4 alkyl.

3. The bifunctional compound according to claim 1 or 2, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: It meets one or more of the following conditions: (1) The heteroatoms in the heterocyclic group, bridged heterocyclic group, fused heterocyclic group, heteroaryl group, fused heteroaryl group, and spiro heterocyclic group are each independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is each independently 1, 2, 3, or 4; (2)R 1 Selected from -CN, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered heterocyclic group, 7-9 membered bridged heterocyclic group, 6-10 membered fused heterocyclic group, 3-6 membered cycloalkyl-NH-; (3) Rx is selected from -NH2 or C 1-6 alkyl; (4) m is selected from 1 or 2, preferably 1; (5) Ring B is a 5-6 membered heteroaryl group; (6)R 2 C 1-6 Alkyl or halogenated C 1-6 Alkyl, preferably halogenated C 1-6 alkyl; (7)q is 1; (8) Lx is -C(O)-NR La -*, where the * end is connected to ring B; (9)L, -(B 3 )n3-end is connected to the degradon; (10) Ring A is selected from the following unsubstituted divalent groups: 7-11 membered spirocycloalkylene, 7-11 membered spiroheterocyclylene, 7-9 membered bridged cycloalkylene, 7-9 membered bridged heterocyclylene.

4. The bifunctional compound according to any one of claims 1 to 3, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: R 1 is selected from 7-9 membered bridged heterocyclic groups.

5. The bifunctional compound according to any one of claims 1 to 3, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: R 1 Selected from -F, -CH3, -CN, -CHF2, -CF3, -OCH3, Best m is selected from 1 or 2.

6. The bifunctional compound according to any one of claims 1 to 5, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: R 2 Selected from -CH3, -CH2F, -CHF2, -CF3; preferably -CHF2.

7. The bifunctional compound according to any one of claims 1 to 6, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: Ring A is selected from 7-9 membered nitrogen-containing spiroheterocyclic groups.

8. The bifunctional compound according to any one of claims 1 to 6, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: Ring A is selected from The "a" end represents the end connected to L in the general formula (IA); Preferably, ring A is selected from 9. The bifunctional compound according to any one of claims 1 to 8, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: L is selected from -B 1 -B 2 -B 3 -, or -B 1 -B 3 -, or -B 2 -B 3 -; Preferably, L is selected from -B 1 -B 2 -B 3 -; More preferably, -B 3 - end is connected to the degradation sub-substrate; Alternatively, L is selected from -B 3 -.

10. The bifunctional compound according to any one of claims 1 to 9, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: It meets one or more of the following conditions: (1)B 1 Selected from C 1-3 Alkylene chain, 1-2 methylene units of which are optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-; preferably, 1 methylene unit is optionally replaced by -C(O)-; (2)B 3 Selected from unsaturated C 2-6 An alkylene chain in which 1-2 methylene units are optionally replaced by -O-, -C(O)-, -C(R a )(R b )-; the alkylene chain is connected to the degradation unit through the alkynyl end; preferably, one methylene unit is optionally replaced by -O-; (3)R a , R b are independently selected from H, deuterium, -CH3; and R a , R b are not H at the same time; or, R on the same carbon atom a , R b Together with the carbon atom to which it is attached, it forms a cyclopropyl or cyclobutyl group; (4)R c Selected from H, -CH3; preferably H; (5)B 2 Selected from the following groups: Best Preferably, B 2 Selected from the following groups: Where the b end is connected to -(B 3 )n3-connected; preferably 11. The bifunctional compound according to any one of claims 1 to 10, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: B 1 Selected from C 1-3 Alkylene chain, 1-2 methylene units of which are optionally replaced by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-replaced; B 3 Selected from unsaturated C 2-6 An alkylene chain in which 1-2 methylene units are optionally replaced by -O-, -C(O)-, -C(R a )(R b )-replaced; the alkylene chain is connected to the degradation sub-agent via the alkynyl end; R a , R b are independently selected from H, deuterium, -CH3; and R a , R b are not H at the same time; or, R on the same carbon atom a , R b Together with the carbon atom to which it is attached, it forms a cyclopropyl or cyclobutyl group; R c Selected from H, -CH3; B 2 Selected from the following groups:

12. The bifunctional compound according to any one of claims 1 to 11, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: B 3 Selected from C 2-6 An alkynylene chain, wherein 1-2 methylene units are optionally replaced by -O-, -C(O)-; the alkynylene chain is connected to the degradon via the alkynyl end; preferably, B 3 Select C with only one terminal triple bond 2-6 More preferably, B 3 Select C with only one terminal triple bond 2-4 Alkyne chain.

13. The bifunctional compound according to any one of claims 1 to 12, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: B 1 Selected from -CH2-, -CD2-, -C(O)-; B 2 Selected from the following divalent rings: C 5-6 Cycloalkylene, C 6-8 A 6-membered cycloalkylene group, a 6-membered heterocyclylene group, a 6- to 8-membered heterocyclylene group; B 3 Selected from 14. The bifunctional compound according to any one of claims 1 to 13, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: L is selected from Preferably, L is selected from More preferably, the alkynyl end of L is linked to the degron.

15. The bifunctional compound according to any one of claims 1 to 14, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: It meets one or more of the following conditions: (1) Each 9-10 membered fused heteroaryl group is a pyrazolopyrimidinyl group, for example (2) each halogen is fluorine, chlorine, bromine or iodine, for example fluorine; (3) Each C 1-6 Alkyl is C 1-4 Alkyl groups, such as methyl; (4) Each C 1-6 Alkoxy is C 1-4 Alkoxy groups, such as methoxy; (5) The heteroatoms in each 3-6 membered heterocyclic group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1 or 2, for example: (6) The heteroatoms in each 7-9 membered bridged heterocyclic group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1 or 2, for example: (7) The heteroatoms in each 6-10 membered fused heterocyclic group are independently selected from one, two or three of N, O and S, and the number of heteroatoms is independently 1 or 2, for example: (8) each 3-6 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclohexyl; (9) Each 5-6 membered heteroaryl group is pyrazolyl, for example (10) Each 7-11 membered spirocycloalkylene group is (11) Each 7-11 membered spiroheterocyclic group is (12) Each 7-9 membered sub-bridged cycloalkyl group is (13) Each 7-9 membered sub-bridged heterocyclic group is (14) Each C 1-6 The alkylene chain is C 1-4 an alkylene chain, such as methylene or ethylene; (15) Each C 3-6 Cycloalkylene is (16) Each C 5-8 The cycloalkylene bridge is (17) Each 4-6 membered heterocyclylene group is (18) Each 6-8 membered sub-bridged heterocyclic group is (19) Each 6- to 8-membered heterocycloalkenylene group is (20) Each saturated or unsaturated C 1-6 The alkylene chain is unsaturated C 3-6 Alkyne chain, preferably 16. The bifunctional compound according to any one of claims 1 to 15, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: The bifunctional compound has a structure shown in the following general formula: Ring A and Ring L are as defined in any one of claims 1 to 15.

17. The bifunctional compound as shown below, its isomer, its deuterated product or its pharmaceutically acceptable salt:

18. A bifunctional compound represented by the following formula (IB), its isomer, its deuterated product or a pharmaceutically acceptable salt thereof, in, Ring A and L are as defined in any one of claims 1 to 15; Ring B is selected from 8-10 membered fused heteroaryl; L1 is selected from -N(R d )-C(O)- or -C(O)-N(R d )-; R d Selected from H, C 1-4 alkyl; R 3 Selected from C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 alkyl; p is selected from 0, 1, 2, 3; R 4 Selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, 7-9 membered bridged heterocyclic group; q is selected from 0, 1, 2, 3, 4; LBM is selected from 19. The bifunctional compound according to claim 18, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: Ring B is selected from 20. The bifunctional compound according to claim 18 or 19, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: R 3 Selected from -CH3, -CH2CH3, -OCH3, -OCH2CH3; p is selected from 0, 1, 2.

21. The bifunctional compound according to any one of claims 18 to 20, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: The bifunctional compound has the structure shown below: Wherein ring A and ring L are as defined in any one of claims 1-15.

22. The bifunctional compound according to any one of claims 18 to 21, its isomer, its deuterated product or its pharmaceutically acceptable salt, characterized in that: The bifunctional compound has the structure shown below:

23. A pharmaceutical composition comprising the bifunctional compound according to any one of claims 1 to 22, its isomer, its deuterated product or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients; Preferably, in the pharmaceutical composition, the content of the compound, its isomer, its deuterated substance or its pharmaceutically acceptable salt is 1%-95%; Preferably, in the pharmaceutical composition, the pharmaceutically acceptable excipients include one or more of fillers, disintegrants, binders, glidants, and lubricants.

24. Use of the bifunctional compound according to any one of claims 1 to 22, its isomer, its deuterated product or its pharmaceutically acceptable salt, or the composition according to claim 23 in the preparation of a medicament for preventing and / or treating diseases mediated by IRAK4; Preferably, the IRAK4-mediated related diseases are selected from immune inflammatory diseases; Preferably, the IRAK4-mediated related diseases are selected from hidradenitis suppurativa, rheumatoid arthritis, atopic dermatitis, lupus erythematosus, gouty arthritis, psoriasis, asthma, chronic obstructive pulmonary disease, polyposis sinusitis, and inflammatory bowel disease.

25. A compound represented by formula (Z), its isomer, its deuterated product or a pharmaceutically acceptable salt thereof: in, Ring A is as defined in any one of claims 1 to 15.

26. A compound represented by formula (X), its isomer, its deuterated product or a pharmaceutically acceptable salt thereof: in, L is B 1-1 -B 2 -B 3-1 -; B 1-1 is hydroxy, amino, carboxyl or hydroxy-substituted C 1-3 alkyl; B 3-1 C 1-3 An alkylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(R a )(R b )-、-N(R c )-, -S- replaced; R a , R b are independently selected from H, deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, and R a , R b Not at the same time H; B 2 As defined in any one of claims 1 to 15.

27. The compound shown below, its isomer, its deuterated substance or its pharmaceutically acceptable salt:

28. Use of the compound according to claim 25 or 26, its isomer, its deuterated product or its pharmaceutically acceptable salt in the preparation of an IRAK4 degrader; preferably, the IRAK4 degrader is the bifunctional compound according to claim 1, its isomer, its deuterated product or its pharmaceutically acceptable salt.

29. Use of the compound according to claim 27, its isomer, its deuterated product or its pharmaceutically acceptable salt in the preparation of an IRAK4 degrader.

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