IRAK4 degrading agent and use thereof

Abstract

The present invention relates to an IRAK4 degrading agent and uses thereof, and more particularly to a bifunctional compound represented by the following formula (I), an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, and the use of such a compound in the treatment of related diseases mediated by IRAK4. [Formula 1] JPEG2026508341000215.jpg35169

Description

Detailed Description of the Invention

[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. This application cites the above Chinese patent applications in their entirety.

[0002] [Technical Field] The present disclosure belongs to the field of medicine, and specifically relates to compounds that bind to interleukin-1 receptor-associated kinase 4 (IRAK4), their isomers, their deuterated derivatives, or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, methods for preparing them, and pharmaceutical uses thereof.

[0003] [Background technology] Proteolysis-targeting chimeras (PROTACs) technology is a new drug development technology that has emerged in recent years. Unlike traditional small molecule protein inhibitors, PROTACs target proteins by delivering them to the proteasome for complete degradation, thus overturning the traditional definition of a drug. Compared with traditional small molecule inhibitors, PROTACs offer many advantages, such as converting targets from "undruggable" to "undruggable," eliminating the need for "space-occupancy driving," and solving the problem of drug resistance.

[0004] PROTACs are bifunctional conjugate molecules consisting of three parts: a ligand structure (TBM, a small molecule inhibitor or common functional group that can recognize the target protein) that targets the target protein on one end; a ligand structure that can recruit a proteolytic system such as an E3 ligase on the other end; and a linker in the middle that connects the two ligands. After binding to the target protein (TBM), the PROTAC molecule brings the target protein and E3 ligase in close proximity, allowing the E3 to ubiquitinate the target protein (an E2 enzyme bound to the E3 ligase brings the TBM into sufficient proximity to carry out polyubiquitination). The ubiquitinated target protein is then degraded by the proteasome pathway. There are over 600 E3 ubiquitin ligases in humans, but only about 10 have been developed as protein degraders (e.g., CRBN, VHL, IAP, MDM2, DCAF15, DCAF16, and RNF114). CRBN and VHL are the most widely used E3 ligases, possessing the broadest range of action domains among these E3 ligases, allowing them to flexibly and efficiently degrade a variety of target proteins. Their relatively widespread expression patterns enable high-level systemic degradation.

[0005] Interleukin-1 receptor-associated kinase 4 (IRAK-4), a member of the IRAK family of intracellular serine-threonine kinases, mediates inflammatory signaling pathways via activation of Toll-like receptors (TLRs) and IL-1 receptors (IL-1Rs), playing an important bridging role in innate immune signaling pathways. IRAK4 is recruited by MyD88 and activated by forming the myddosome, which activates downstream IRAK1 / 2. This leads to IRAK1 / 2 becoming hyperphosphorylated, dissociating from the complex, and binding to TRAF6. The activated TRAF6 complex triggers downstream signaling pathways, producing pro-inflammatory factors (e.g., NF-κB, CREB, AP-1, and IRFs). IRAK4 inhibition may play an important role in the development and progression of inflammatory diseases. Currently, no inhibitors against 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 primarily targets IRAK4 through its heterobifunctional molecule, binding to IRAK4 and recruiting an E3 ubiquitin ligase, which "tags" IRAK4 for degradation via the proteasome degradation system. KT-474 is primarily intended for the treatment of IL-1R / TLR-driven diseases such as atopic dermatitis (HS) and hidradenitis suppurativa (AD), as well as rheumatoid arthritis (RA), and other inflammatory diseases. Preclinical studies have demonstrated potent anti-inflammatory activity. Results from a Phase I clinical trial in healthy patients demonstrated that a single dose of KT-474 dose-dependently reduced levels of IRAK4 and various pro-inflammatory cytokines, with a favorable safety profile and tolerability.

[0007] Although there are currently IRAK4 degraders under investigation for the treatment of inflammatory diseases, there is still significant uncertainty before these products are launched. Clinically, there is still a lack of structural diversity, therapeutic differentiation, and safe drugs. Therefore, continuing the development of new IRAK4 degraders to increase the variety of clinical samples and improve patient accessibility remains of great clinical significance.

[0008] Summary of the Invention The present disclosure provides bifunctional compounds that target IRAK4 (i.e., IRAK4-targeting protac molecules), which can effectively recruit IRAK4 to E3 ubiquitin ligases for degradation.

[0009] The bifunctional compound targeting IRAK4, i.e., the IRAK4 degrader, described in the present disclosure is a triad compound comprising a targeting structure, a linker, and a degrader, and is represented by formula (X). [ka] In this triad, the targeting moiety can specifically bind to a target protein, such as an IRAK protein, and is covalently connected to a linker. The linker is a linking group between the targeting moiety and the degrader, with one end covalently bonded to the targeting moiety and the other end covalently bonded to the degrader. The degrader can bind to a ubiquitin ligase, such as an E3 ubiquitin ligase, and is covalently bonded to the linker.

[0010] Specifically, in a first aspect, the present disclosure provides a bifunctional compound represented by the following general formula (I), an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof: [ka] provided that ring C is phenyl, a 5- or 6-membered heteroaryl, or a 9- or 10-membered fused heteroaryl; R 1 -CN, -NR 1a R 1b, -OH, halogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 is selected from alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 7- to 9-membered bridged heterocyclyl, 6- to 10-membered fused heterocyclyl, 3- to 6-membered cycloalkyl-NH-, phenyl, 5- to 6-membered heteroaryl, and 9- to 10-membered fused heteroaryl, wherein the heterocyclyl, bridged heterocyclyl, fused heterocyclyl, cycloalkyl, heteroaryl, and fused heteroaryl are optionally substituted with one or more Rx, and the Rx is selected from -NH2, -NR 1a R 1b , -CN, -OH, halogen, C 1-6 Alkyl, HaloC 1-6 alkyl, R 1a , R 1b are independently H, C 1-6 Alkyl, HaloC 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C 1-6 Alkyl-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-C 1-6 alkyl-, m is selected from 0, 1, 2, 3, and 4; Ring B is selected from 5- to 6-membered heteroaryl and 9- to 10-membered fused heteroaryl; R 2 H, halogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, Hydroxy C 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 alkoxy; q is selected from 0, 1, 2, 3, and 4; Lx is -C(O)-NR La - and R La is H, C 1-6 Alkyl, HaloC 1-6 alkyl, 3- to 6-membered cycloalkyl; Ring A is a divalent group optionally substituted with one or more Rz selected from the group consisting of 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridged cycloalkylene, and 7- to 9-membered bridged heterocyclylene, wherein Rz is selected from halogen, —OH, —NH2, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 selected from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl; L is -(B 1 )n1-(B 2 )n2-(B 3 )n3-, B 1 is C 1-6 an alkylene chain, any methylene unit of which is optionally —O—, —C(O)—, —C(R a )(R b )-, -N(R c )-, -S-, and n1 is selected from 0 and 1; B 2 is a divalent ring optionally substituted by one or more Ry: 3-6 Cycloalkylene, C 5-8 Ry is selected from the group consisting of bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene, and 6- to 8-membered heterocycloalkenylene, and Ry is selected from the group consisting of oxo, halogen, C 1-6 Alkyl, HaloC 1-6 alkyl; n2 is selected from 0 and 1; B 3 is saturated or unsaturated C 1-6 alkylene chains, any methylene unit of which is optionally selected from -O-, -C(O)-, -C(R a )(R b )-, -N(R c )-, -S-, and n3 is selected from 0 and 1; R a , R b are independently H, deuterium, halogen, and C 1-6 Alkyl, HaloC 1-6 alkyl, and Ra , R b is not H at the same time, Alternatively, R on the same carbon atom a , R b together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl; R c is H, C 1-6 alkyl, Degradants are ligands that bind to E3 enzymes.

[0011] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated derivative, or its pharmaceutically acceptable salt has a structure represented by formula (IA): [ka] However, R 1 -CN, halogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 alkoxy, 5- to 6-membered heterocyclyl, 7- to 9-membered bridged heterocyclyl, 6- to 10-membered fused heterocyclyl, 3- to 6-membered cycloalkyl-NH-, wherein the heterocyclyl, bridged heterocyclyl, fused heterocyclyl, cycloalkyl is optionally substituted with one or more Rx, and the Rx is selected from -NH2, -OH, halogen, C 1-4 Alkyl, HaloC 1-4 alkyl, m is selected from 0, 1, 2, 3, and 4; R 2 is C 1-4 Alkyl, HaloC 1-4 alkyl, Ring A is selected from the following divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridged cycloalkylene, and 7- to 9-membered bridged heterocyclylene; L is -(B 1 )n1-(B 2 )n2-(B 3 )n3-, B 1 is C 1-3 alkylene chains, any methylene unit of which is optionally selected from -O-, -C(O)-, -C(R a )(R b )-, -N(R c )-, -S-, and n1 is selected from 0 and 1; B 2 is a divalent ring optionally substituted by one or more Ry: 3-6 Cycloalkylene, C 5-8 Ry is selected from the group consisting of bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene, and 6- to 8-membered heterocycloalkenylene, and Ry is selected from the group consisting of oxo, halogen, C 1-4 Alkyl, HaloC 1-4 alkyl; n2 is selected from 0 and 1; B 3 is saturated or unsaturated C 1-6 alkylene chains, wherein any methylene unit thereof is optionally selected from -O-, -C(O)-, -C(R a )(R b )-, -N(R c )-, -S-, and n3 is selected from 0 and 1; R a , R b are independently H, deuterium, halogen, and C 1-4 Alkyl, HaloC 1-4 alkyl, and R a , R b is not H at the same time, Alternatively, R on the same carbon atom a , R b together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; R c is H, C 1-4 alkyl.

[0012] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated form or its pharmaceutically acceptable salt. [ka] However, R 1 -CN, halogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 alkoxy, 5- to 6-membered heterocyclyl, 7- to 9-membered bridged heterocyclyl, 6- to 10-membered fused heterocyclyl, 3- to 6-membered cycloalkyl-NH-, wherein the heterocyclyl, bridged heterocyclyl, fused heterocyclyl, cycloalkyl is optionally substituted with one or more Rx, and the Rx is selected from -NH2, -OH, halogen, C 1-4 Alkyl, HaloC 1-4 alkyl, m is selected from 0, 1, 2, 3, and 4; R 2 is C 1-4 Alkyl, HaloC 1-4 alkyl, Ring A is selected from the following divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridged cycloalkylene, and 7- to 9-membered bridged heterocyclylene; L is -(B 1 )n1-(B 2 )n2-(B 3 )n3-, B 1 is C 1-3 alkylene chains, any methylene unit of which is optionally selected from -O-, -C(O)-, -C(R a )(R b )-, -N(R c )-, -S-, and n1 is selected from 0 and 1; B 2 is a divalent ring optionally substituted by one or more Ry: 3-6 Cycloalkylene, C 6-8 Ry is selected from the group consisting of bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene, and 6- to 8-membered heterocycloalkenylene, and Ry is selected from the group consisting of oxo, halogen, C 1-4 Alkyl, HaloC 1-4alkyl; n2 is selected from 0 and 1; B 3 is saturated or unsaturated C 1-6 alkylene chains, wherein any methylene unit thereof is optionally selected from -O-, -C(O)-, -C(R a )(R b )-, -N(R c )-, -S-, and n3 is selected from 0 and 1; R a , R b are independently H, deuterium, halogen, and C 1-4 Alkyl, HaloC 1-4 alkyl, and R a , R b is not H at the same time, Alternatively, R on the same carbon atom a , R b together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; R c is H, C 1-4 alkyl.

[0013] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated form or its pharmaceutically acceptable salt. [ka] However, R 1 -CN, halogen, C 1-4 Alkyl, HaloC 1-4 Alkyl, C 1-4 alkoxy, 5- to 6-membered heterocyclyl, 7- to 9-membered bridged heterocyclyl, 6- to 10-membered fused heterocyclyl, 3- to 6-membered cycloalkyl-NH-, wherein the heterocyclyl, bridged heterocyclyl, fused heterocyclyl, cycloalkyl is optionally substituted with one or more Rx, and the Rx is selected from -NH2, -OH, halogen, C 1-4 Alkyl, HaloC 1-4 alkyl, m is selected from 0, 1, 2, 3, and 4; R 2 is C 1-4 Alkyl, HaloC 1-4 alkyl, Ring A is selected from the following divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridged cycloalkylene, and 7- to 9-membered bridged heterocyclylene; L is -(B 1 )n1-(B 2 )n2-(B 3 )n3-, B 1 is C 1-3 alkylene chains, any methylene unit of which is optionally selected from -O-, -C(O)-, -C(R a )(R b )-, -N(R c )-, -S-, and n1 is selected from 0 and 1; B 2 is a divalent ring optionally substituted by one or more Ry: 3-6 Cycloalkylene, C 6-8 Ry is selected from the group consisting of oxo, halogen, C 1-4 Alkyl, HaloC 1-4 alkyl; n2 is selected from 0 and 1; B 3 is saturated or unsaturated C 1-6 alkylene chains, wherein any methylene unit thereof is optionally selected from -O-, -C(O)-, -C(R a )(R b )-, -N(R c )-, -S-, and n3 is selected from 0 and 1; R a , R b are independently H, halogen, or C 1-4 Alkyl, HaloC 1-4 alkyl, and R a , R b is not H at the same time, Alternatively, R on the same carbon atom a , R btogether with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; R c is H, C 1-4 alkyl.

[0014] In another preferred embodiment, the heteroatoms in the heterocyclyl, bridged heterocyclyl, fused heterocyclyl, heteroaryl, fused heteroaryl, and spiroheterocyclyl 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.

[0015] In another preferred embodiment, R 1 -CN, halogen, C 1-6 Alkyl, HaloC 1-6 Alkyl, C 1-6 It is selected from alkoxy, 3- to 6-membered heterocyclyl, 7- to 9-membered bridged heterocyclyl, 6- to 10-membered fused heterocyclyl, and 3- to 6-membered cycloalkyl-NH-.

[0016] In another preferred embodiment, R 1 is selected from 7- to 9-membered bridged heterocyclyl.

[0017] In another preferred embodiment, R 1 -F, -CH3, -CN, -CHF2, -CF3, -OCH3, [ka] is selected from m is selected from 1 or 2.

[0018] In another preferred embodiment, R 1 teeth, [ka] is selected from.

[0019] In another preferred embodiment, Rx is -NH2 or C 1-6 alkyl.

[0020] In another preferred embodiment, m is selected from 1 or 2, preferably 1.

[0021] In another preferred embodiment, ring B is a 5-6 membered heteroaryl.

[0022] In another preferred embodiment, R 2 is C 1-6 Alkyl or haloC 1-6 alkyl, preferably haloC 1-6 It is alkyl.

[0023] In another preferred embodiment, R 2 is selected from —CH3, —CH2F, —CHF2, —CF3.

[0024] In another preferred embodiment, R 2 is selected from -CHF2.

[0025] In another preferred embodiment, q is 1.

[0026] In another preferred embodiment, Lx is —C(O)—NR La -*, where the * end is connected to ring B.

[0027] In another preferred embodiment, ring A is selected from the following unsubstituted divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridged cycloalkylene, and 7- to 9-membered bridged heterocyclylene.

[0028] In another preferred embodiment, ring A is a 7-9 membered nitrogen-containing spiroheterocyclylene.

[0029] In another preferred embodiment, ring A is [ka] and the "a" end represents the end connected to L in general formula (IA).

[0030] In another preferred embodiment, ring A is [ka] is selected from.

[0031] In another preferred embodiment, L is -(B 3 ) The n3-terminus is linked to a degradant.

[0032] In another preferred embodiment, L is -B 1 -B 2 -B 3 - or -B 1 -B 3 - or -B 2 -B 3 -, preferably -B 3 The -end is linked to a decomposer.

[0033] In another preferred embodiment, L is -B 1 -B 2 -B 3 -, preferably -B 3 The -end is linked to a decomposer.

[0034] In another preferred embodiment, L is -B 3 - is selected from.

[0035] In another preferred embodiment, B 1 is C 1-3 alkylene chains, one to two of which are optionally -O-, -C(O)-, -C(R a )(R b )-, -N(R c)-, preferably one methylene unit is optionally replaced by -C(O)-.

[0036] In another preferred embodiment, B 3 is unsaturated C 2-6 alkylene chains, wherein one to two methylene units are optionally selected from -O-, -C(O)-, -C(R a )(R b )-, the alkylene chain is connected to a decomposer via the alkynyl terminus, preferably one methylene unit is optionally replaced by -O-.

[0037] In another preferred embodiment, R a , R b are each independently selected from H, deuterium, and —CH3, and R a , R b is not H at the same time, Alternatively, R on the same carbon atom a , R b together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl.

[0038] In another preferred embodiment, R c is selected from H, —CH 3 , preferably H.

[0039] In another preferred embodiment, B 2 is the group: [ka] is selected from, preferably [ka] is.

[0040] In another preferred embodiment, B 2 is the group: [ka] wherein the b terminus is selected from -(B 3 )n3-, preferably [ka] is.

[0041] In another preferred embodiment, B 1 is C 1-3 alkylene chains, one to two of which are optionally -O-, -C(O)-, -C(R a )(R b )-, -N(R c )- and replaced by B 3 is unsaturated C 2-6 alkylene chains, wherein one to two methylene units are optionally selected from -O-, -C(O)-, -C(R a )(R b )-, and the alkylene chain is connected to a decomposer via an alkynyl terminus, R a , R b are each independently selected from H, deuterium, and —CH3, and R a , R b is not H at the same time, Alternatively, R on the same carbon atom a , R b together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, R c is selected from H, -CH3, B 2 is the group: [ka] is selected from.

[0042] In another preferred embodiment, B 1 is C 1-3alkylene chains, one to two of which are optionally -O-, -C(O)-, -C(R a )(R b )-, -N(R c )- and replaced by B 3 is unsaturated C 2-6 alkylene chains, wherein one to two methylene units are optionally selected from -O-, -C(O)-, -C(R a )(R b )-, and the alkylene chain is connected to a decomposer via an alkynyl terminus, R a , R b are each independently selected from H and -CH3, and R a , R b is not H at the same time, Alternatively, R on the same carbon atom a , R b together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, R c is selected from H, -CH3, B 2 is the group: [ka] where B is selected from 2 The method of describing the groups does not limit the order of linkage to the groups on both sides.

[0043] In another preferred embodiment, B 2 is the group: [ka] is selected from.

[0044] In another preferred embodiment, B 2 is the group: [ka] is selected from.

[0045] In another preferred embodiment, R a , R b are each independently selected from deuterium.

[0046] In another preferred embodiment, wherein B 3 is C 2-6 An alkynylene chain is selected from an alkynylene chain, wherein one to two methylene units are optionally replaced by -O-, -C(O)-, and the alkynylene chain is linked to a decomposer via the alkynyl terminus.

[0047] In another preferred embodiment, wherein B 3 is a C with only one triple bond at the end 2-6 An alkynylene chain is selected from an alkynylene chain, wherein one to two methylene units are optionally replaced by -O-, -C(O)-, and the alkynylene chain is linked to a decomposer via the alkynyl terminus.

[0048] In another preferred embodiment, wherein B 3 is a C with only one triple bond at the end 2-4 An alkynylene chain is selected from an alkynylene chain, wherein one to two methylene units are optionally replaced by -O-, -C(O)-, and the alkynylene chain is linked to a decomposer via the alkynyl terminus.

[0049] In another preferred embodiment, B 1 is selected from -CH2-, -CD2-, and -C(O)-; B 2 is the following bivalent ring: C 5-6 Cycloalkylene, C 6-8 selected from bridged cycloalkylene, 6-membered heterocyclylene, and 6- to 8-membered bridged heterocyclylene; B 3 teeth, [ka] is selected from.

[0050] In another preferred embodiment, L is [ka] JPEG2026508341000021.jpg236169 JPEG2026508341000022.jpg26169, and preferably the alkynyl terminus of L is linked to a decomposer.

[0051] In another preferred embodiment, L is [ka] JPEG2026508341000024.jpg95169, and preferably the alkynyl terminus of L is linked to a decomposer.

[0052] In another preferred embodiment, L is [ka] Preferably, the alkynyl terminus of L is linked to a degradant.

[0053] In another preferred embodiment, L is [ka] Preferably, the alkynyl terminus of L is linked to a degradant.

[0054] In another preferred embodiment, L is [ka] Preferably, the alkynyl terminus of L is linked to a degradant.

[0055] In another preferred embodiment, L is [ka] Preferably, the alkynyl terminus of L is linked to a degradant.

[0056] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated derivative, or its pharmaceutically acceptable salt has a structure represented by the following general formula: [ka] Rings A, L are as defined in any one of the preceding embodiments.

[0057] In another preferred embodiment, each 9- to 10-membered fused heteroaryl is pyrazolopyrimidinyl, for example: [ka] is.

[0058] In another preferred embodiment, each halogen is fluorine, chlorine, bromine or iodine, for example fluorine.

[0059] In another preferred embodiment, each C 1-6 Alkyl is C 1-4 It is alkyl, for example, methyl.

[0060] In another preferred embodiment, each C 1-6 Alkoxy is C 1-4 Alkoxy, for example, methoxy.

[0061] In another preferred embodiment, the heteroatoms in each 3- to 6-membered heterocyclyl are each independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is each independently 1 or 2, for example, [ka] is.

[0062] In another preferred embodiment, the heteroatoms in each 7- to 9-membered bridged heterocyclyl are each independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is each independently 1 or 2, for example, [ka] is.

[0063] In another preferred embodiment, the heteroatoms in each 6- to 10-membered fused heterocyclyl are each independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is each independently 1 or 2, for example, [ka] is.

[0064] In another preferred embodiment, each 3- to 6-membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclohexyl.

[0065] In another preferred embodiment, each 5- to 6-membered heteroaryl is pyrazolyl, for example: [ka] is.

[0066] In another preferred embodiment, each 7- to 11-membered spirocycloalkylene is [ka] is.

[0067] In another preferred embodiment, each 7- to 11-membered spiroheterocyclylene is [ka] is.

[0068] In another preferred embodiment, each 7- to 9-membered bridged cycloalkylene is [ka] is.

[0069] In another preferred embodiment, each 7- to 9-membered bridged heterocyclylene is [ka] is.

[0070] In another preferred embodiment, each C 1-6 The alkylene chain is C 1-4 It is an alkylene chain, for example methylene or ethylene.

[0071] In another preferred embodiment, each C 3-6 Cycloalkylene is [ka] is.

[0072] In another preferred embodiment, each C 5-8 The bridged cycloalkylene is [ka] is.

[0073] In another preferred embodiment, each 4- to 6-membered heterocyclylene is [ka] is.

[0074] In another preferred embodiment, each 6- to 8-membered bridged heterocyclylene is [ka] is.

[0075] In another preferred embodiment, each 6- to 8-membered heterocycloalkenylene is [ka] is.

[0076] In another preferred embodiment, each saturated or unsaturated C 1-6 The alkylene chain is an unsaturated C 3-6 an alkynylene chain, for example [ka] is.

[0077] Any substituents and any groups in the technical solutions described in the present disclosure can be combined with each other to form a new complete technical solution, and the formed new technical solution has the same or similar technical effect as the solution described in the present disclosure, and all are included in the scope of the present disclosure.

[0078] The above technical solutions of the present disclosure can be combined and defined with each other, and any new solutions formed are also included in the scope of the present disclosure.

[0079] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated form or its pharmaceutically acceptable salt is selected from the following compounds: [ka] JPEG2026508341000046.jpg255168 JPEG2026508341000047.jpg239169 JPEG2026508341000048.jpg255166 JPEG2026508341000049.jpg247169 JPEG2026508341000050.jpg238169 JPEG2026508341000051.jpg196169

[0080] In another preferred embodiment, the bifunctional compound, its isomer, its deuterated form or its pharmaceutically acceptable salt is selected from the following compounds: [ka]

[0081] A second aspect of the present disclosure further provides a compound according to the following formula (IB), an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof: [ka] wherein ring B is selected from 8- to 10-membered fused heteroaryls; L1 is -N(R d )-C(O)- or -C(O)-N(R d )-selected from R d is H, C 1-4 alkyl, R 3 is C 1-4 Alkyl, C 1-4 Alkoxy, HaloC 1-4 alkyl, p is selected from 0, 1, 2, and 3; R 4 is C 1-4 Alkyl, HaloC 1-4 alkyl, and 7- to 9-membered bridged heterocyclyl; q is selected from 0, 1, 2, 3, and 4; LBM is [ka] is selected from Rings A and L are as defined in any one embodiment of the first aspect of the present disclosure.

[0082] In another embodiment of the present disclosure, ring B is [ka] is selected from.

[0083] In another embodiment of the present disclosure, R 3 is selected from -CH3, -CH2CH3, -OCH3, -OCH2CH3, and p is selected from 0, 1, and 2.

[0084] In another embodiment of the present disclosure, the bifunctional compound, its isomer, its deuterated form, or its pharmaceutically acceptable salt has the structure shown below: [ka] wherein rings A and L are as defined in any one of the above embodiments.

[0085] In another embodiment of the present disclosure, the compound of formula (IB), its isomer, its deuterated form or its pharmaceutically acceptable salt is [ka] is selected from.

[0086] In a third aspect of the present disclosure, a pharmaceutical composition is provided comprising a compound described in any one of the schemes of the first and second aspects of the present disclosure, its isomer, its deuterated derivative, or a pharmaceutically acceptable salt thereof, 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 biologically suitable for use in an organism. The selection of a particular excipient depends on the administration method or the type and condition of the disease intended for treatment of a particular patient. Examples of pharmaceutically acceptable excipients include, but are not limited to, conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonicity agents, thickeners, emulsifiers, adhesives, lubricants, stabilizers, wetting agents, emulsification enhancers, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, antioxidants, etc. Flavoring agents, preservatives, sweeteners, etc. can be added to the pharmaceutical formulation composition as needed.

[0087] In another preferred embodiment, the content of the compound, its isomer, its deuterated derivative, or its pharmaceutically acceptable salt in the pharmaceutical composition is 1% to 95%.

[0088] In some embodiments of the present disclosure, in the pharmaceutical composition, the pharmaceutically acceptable excipients comprise one or more of a filler, a disintegrant, an adhesive, a glidant, and a lubricant.

[0089] In a fourth aspect, the present disclosure provides use of a compound according to any one of the first and second aspects of the present disclosure, an isomer thereof, a deuterated form thereof, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament, the medicament being used for the prevention and / or treatment of an associated disease mediated by IRAK4.

[0090] In another preferred embodiment, the IRAK4-mediated related disease is selected from immunoinflammatory diseases.

[0091] 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, sinusitis with nasal polyps, and inflammatory bowel disease.

[0092] In a fifth aspect of the present disclosure, there is further provided a method for treating an IRAK4-mediated related disease, comprising administering a therapeutically effective amount of a compound according to any one of the embodiments of the first aspect of the present disclosure, its isomer, its deuterated form, or a pharmaceutically acceptable salt thereof to a subject, said subject primarily referring to a human.

[0093] In another preferred embodiment, the IRAK4-mediated related disease is selected from immunoinflammatory diseases.

[0094] 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, sinusitis with nasal polyps, and inflammatory bowel disease.

[0095] In a sixth aspect of the present disclosure, there is provided the following compound, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof: [ka] wherein ring A is as defined in any one of the above embodiments.

[0096] In another preferred embodiment, the compound of formula (Z), its isomer, its deuterated form, or its pharmaceutically acceptable salt is selected from the following structures: [ka] In another preferred embodiment, the compound of formula (Z), its isomer, its deuterated form, or its pharmaceutically acceptable salt is selected from the following structures: [ka]

[0097] In a seventh aspect of the present disclosure, there is provided a compound of formula (X), an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof: [ka] However, L is B 1-1 -B 2 -B 3-1 - and B 1-1 is hydroxy, amino, carboxyl, or C substituted by hydroxy 1-3 is alkyl, B 3-1 is C 1-3 an alkylene chain, any methylene unit of which is optionally —O—, —C(O)—, —C(R a )(R b )-, -N(R c )-, -S-, and R a , R b are independently H, deuterium, halogen, and C 1-6 Alkyl, HaloC 1-6 alkyl, and R a , R b But at the same time, it's not H, B 2 is as defined in the first aspect of this disclosure.

[0098] In another preferred embodiment, the compound of formula (X), its isomer, its deuterated form, or its pharmaceutically acceptable salt is selected from the following structures: [ka] JPEG2026508341000063.jpg58169

[0099] In an eighth aspect of the present disclosure, there is provided the following compound, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof: [ka]

[0100] A ninth aspect of the present disclosure further includes use of a compound described in the sixth or seventh aspect, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof in the manufacture of an IRAK4 decomposing agent, and preferably, the IRAK4 decomposing agent is as described in the first aspect of the present disclosure.

[0101] A tenth aspect of the present disclosure further includes use of a compound according to the eighth aspect, an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof in the manufacture of an IRAK4 decomposing agent.

[0102] [Explanation and definition] In this disclosure, unless otherwise explained, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. In order to better understand this disclosure, definitions of some terms are provided below. If the definitions of terms provided in this disclosure are inconsistent with the meanings that are commonly understood by those skilled in the art, the definitions and interpretations of terms provided in this disclosure shall prevail.

[0103] In the present disclosure, the term "E3 enzyme" includes enzymes belonging to the E3 family disclosed in the prior art, such as CRBN, VHL, MDM2, IAPs, TRIM24, DCAF15, DCAF16, and RNF114. Specific ligands for E3 ligases have the structures shown in the literature (Jaeseok Lee, et al., Discovery of E3 Ligase Ligands for Target Protein Degradation Molecules, 2022, 27(19):6515).

[0104] The term "pharmaceutically acceptable salt" refers to compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment and are suitable for contact with the tissues of humans and animals without appreciable toxicity, irritation, allergic response or other problem or complication and present a reasonable benefit / risk ratio.

[0105] The term "pharmaceutically acceptable salts" refers to derivatives prepared with relatively non-toxic acids or bases from compounds of the present disclosure. These salts can be prepared during the synthesis, isolation, or purification of the compounds, or the free form of the purified compound can be reacted with the appropriate acid or base. When a compound contains a relatively acidic functional group, it can be reacted with alkali metal or alkaline earth metal hydroxides or organic amines to form base addition salts, including cations based on alkali and alkaline earth metals, and non-toxic ammonium, quaternary ammonium, and amine cations, as well as salts of amino acids. When a compound contains a relatively basic functional group, it can be reacted with organic or inorganic acids to form acid addition salts.

[0106] The term "effective prophylactic or therapeutic amount" refers to that amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof sufficient to treat a disorder, at a reasonable benefit / risk ratio applicable to any medical treatment and / or prophylaxis. It should be recognized, however, that the total daily usage of the compound of Formula I or a pharmaceutically acceptable salt thereof and compositions of the present disclosure should be decided by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend on a variety of factors, including the disease and severity of the disease being treated, the activity of the specific compound used, the specific composition 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 used, the duration of treatment, drugs used in combination with or concomitantly with the specific compound used, and similar factors known in the medical arts.

[0107] The term "isomer" as used herein includes geometric and stereoisomers, such as atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemates and other mixtures thereof, and all mixtures thereof are within the scope of this 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 points of hydrogen attachment due to the displacement of one or more double bonds; for example, a ketone and its enol form are keto-enol tautomers. The term "diastereomer" refers to a stereoisomer in which the molecules have two or more chiral centers and are not mirror images of each other. The term "cis-trans isomer" refers to different spatial configurations in which double bonds or single bonds of ring carbon atoms cannot freely rotate. The term "atropisomer" refers to stereoisomers that can be separated due to hindered or very slow rotation of single bonds.

[0108] Stereoisomers of the compounds of the present disclosure can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, enantiomers of specific compounds of the present disclosure can be prepared by asymmetric catalysis or chiral-assisted derivatization techniques. Alternatively, compounds of a single configuration can be obtained from a mixture by chiral resolution techniques. Alternatively, they can be prepared directly from chiral starting materials. Separation of optically pure compounds in the present disclosure is typically achieved by preparative chromatography, using a chiral column to achieve the purpose of separating chiral compounds.

[0109] "Deuterated" as used herein refers to a derivative of a compound of the present disclosure in which one or more hydrogen atoms have been replaced with deuterium atoms.

[0110] The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents may be any on a chemically feasible basis; for example, the term "optionally substituted with one or more R" means that it may be substituted or unsubstituted with one or more R. When any variable appears more than once in a compound composition or structure, its definition is independent in each occurrence. For example, a group may be substituted with 0 to 2 R a When substituted by, the group may optionally be substituted by up to two R a and in each case R a have independent choices.

[0111] In the structure of the substituent [ka] appears, it means that the atom in question is the bonding atom, for example, [ka] means that the C atom on the pyrimidine ring is the linking atom. The appearance of a dash "-" in a substituent structure indicates the attachment point of the substituent, for example, -CH3 is linked via a C atom.

[0112] [ka] is the absolute configuration of the stereocenter, i.e., R or S configuration.

[0113] [ka] indicates a cis or trans configuration, a double solid line or a double dashed line indicates a cis configuration, and a combination of a solid line and a dashed line indicates a trans configuration.

[0114] In the present disclosure, L is -(B 1 )n1-(B 2 )n2-(B 3 )n3-, and when n1, n2, or n3 is 0, the corresponding group does not exist, and the groups on the left and right sides are directly connected via a chemical bond. Specifically, for example, when only n1 is 0, L is -(B 2 )n2-(B 3 )n3-, and if only n2 is 0, L is -(B 1 )n1-(B 3 )n3-, and if only n3 is 0, L is -(B 1 )n1-(B 2 )n2-.

[0115] If the bond of a substituent can cross-link two atoms on the ring, then the substituent can be attached to any atom on the ring. For example, the structural unit [ka] means that the substituent R can be substituted at any position on the benzene ring.

[0116] When a given substituent does not indicate through which atom it is linked to a given group or to a given structural formula, the substituent may be linked through any of its available atoms.

[0117] As used herein, "alkyl" refers to a group derived by removing one hydrogen atom from a branched or straight-chain saturated aliphatic alkane having the specified number of carbon atoms. For example, "C 1-10 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 Contains alkyl, "C 1-6 Alkyl," "C 1-4 Alkyl," "C 1-3 Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, and the like.

[0118] The term "haloalkyl" as used herein refers to a group in which one or more halogen atoms have been substituted for the hydrogen atoms of an alkyl group. For example, "fluoromethyl" includes monofluoromethyl, difluoromethyl, and trifluoromethyl. Preferably, the term "haloalkyl" as used herein refers to a group in which one or more halogen atoms have been substituted for the hydrogen atoms of an alkyl group. 1-6 Alkyl, HaloC 1-4 Alkyl is as defined above.

[0119] "Oxo" as used herein refers to the group being substituted with an "=O" structure, meaning that "-CH2-" is oxidized to form "-C(O)-", and "S" is oxidized to form "S(O)" or "S(O)2".

[0120] The term "alkylene" as used herein refers to a group derived by removing two hydrogen atoms from a branched or straight-chain alkane, alkene, or alkyne having a specified number of carbon atoms, and includes "alkylene," "alkenylene," and "alkynylene," which may be further substituted with other groups. Here, "alkenylene" and "alkynylene" refer to unsaturated hydrocarbon chains containing at least one double bond or triple bond, respectively, in the hydrocarbon chain. The term "alkylene" as used herein refers to "C 1-15 alkylene”, preferably “C 2-10 alkylene," "C 4-6 alkylene," "C 2-10 alkylene," "C 5-7 alkynylene," "C 7-10 alkylene," "C 5-7 alkenylene," "C 1-6 alkylene," "C 1-3 alkylene," "C 2-6Preferably, the "alkylene" described in the present disclosure is preferably a "straight chain alkylene", and specific examples of said alkylene chain include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH2)CH2-, -CH2CH2CH2CH2-, -CH(CH2)CH2CH2-, -CH(CH2)CH2CH2-, -CH(CH2CH2)CH2-, -C(CH2)(CH2)CH2-, -CH2CH2CH2CH2CH2-, etc., and preferably, the "methylene unit" described in the present disclosure refers to -CH2-. Specific examples of "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-, and specific examples of "alkynylene" described in the present disclosure include, but are not limited to, -C≡C-CH2-, -C≡C-CH2-, -C≡C-CH2CH2CH2-, -CH2-C≡C-CH2CH2CH2-, -C≡C-CH2C≡C-, -C≡C-CH2CH=CH-, and the like. Furthermore, the phrase "any methylene unit is optionally substituted" as used herein means that, for example, when any methylene unit in "-CHCHCH-" is substituted with -C(O)-, structures such as -C(O)CHCH-, -CHC(O)CH-, -CHCHC(O)-, and -C(O)CHC(O)- may be formed, but is not limited to these.

[0121] The term "ring" as used herein includes, but is not limited to, "cycloalkane," "spirocycloalkane," "bridged cycloalkane," "heterocycle," "heterocycloolefin," "spiroheterocycle," "bridged heterocycle," "fused heterocycle," "heteroaromatic ring," "fused heteroaromatic ring," and the like. Monovalent rings derived therefrom are, respectively, "cycloalkyl," "spirocycloalkyl," "bridged cycloalkyl," "heterocycle," "heterocyclic alkenyl," "spiroheterocycle," "bridged heterocycle," "heteroaryl," and "fused heteroaryl." A derived "divalent ring" refers to a group derived by removing two hydrogen atoms from a ring structure, and the bonding sites may be bonded to different groups or to different positions on the same group. The derived divalent rings are, respectively, "cycloalkylene," "bridged cycloalkylene," "spirocycloalkylene," "heterocyclylene," "heterocyclylene," "spiroheterocyclylene," "bridged heterocyclylene," "fused heterocyclylene," "heteroarylene," and the like.

[0122] "Cycloalkane" as used herein refers to a monocyclic, saturated cyclic alkane structure, in which the carbon atoms may be oxylated, i.e., 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, cyclooctane, and the like.

[0123] The term "spirocycloalkane" as used herein refers to a cyclic structure formed by two or more adjacent cycloalkanes sharing one ring atom, wherein a carbon atom of the cycloalkane may be substituted with oxo, i.e., a carbon atom may be substituted with -C(O)-. 7-11 Spirocycloalkanes, C 7-9 Spirocycloalkanes, etc., and specific examples include [ka] Including, but not limited to, the following:

[0124] The term "bridged cycloalkane" as used herein refers to a cyclic structure formed by two or more adjacent cycloalkanes sharing two non-adjacent ring atoms, and a carbon atom in the cycloalkane may be oxylated, i.e., the carbon atom is replaced by -C(O)-. 6-10 Bridged cycloalkanes, C 6-8 Specific examples include "bridged cycloalkanes" and [ka] Including, but not limited to, the following:

[0125] The term "heterocycle" as used herein refers to a cyclic structure derived by replacing at least one carbon atom of a "cycloalkane" with a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from O, NR, N(O), S, S(O), and S(O), where R is H or an optional substituent, and the "cycloalkane" is as defined above. The heterocycle preferably contains 1 to 2 heteroatoms selected from NR and / or O, more preferably one NR and zero to one heteroatom of NR or O. 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- to 8-membered heterocycle, a 3- to 6-membered heterocycle, a 4- to 6-membered heterocycle, a 5- to 6-membered heterocycle, a 4- to 6-membered nitrogen-containing heterocycle, and a 5- to 6-membered nitrogen-containing heterocycle. Specific examples include tetrahydrofuran, tetrahydropyrrole, piperidine, morpholine, piperazine, [ka] Including, but not limited to, the following:

[0126] The "heterocyclic olefin" described in the present disclosure refers to a heterocyclic group that contains at least one ring-forming double bond in the "heterocycle" and does not have aromaticity. The heterocyclic olefin preferably contains 1 to 2 heteroatoms selected from NR and / or O, and more preferably contains one NR and 0 to 1 heteroatom of NR or O. The "heterocyclic olefin" includes "5- to 8-membered heterocyclic olefin" and "6- to 8-membered heterocyclic olefin". Specific examples include: [ka] Including, but not limited to, the following:

[0127] The term "spiroheterocycle" used herein refers to a ring structure derived from a "spirocycloalkane" by replacing at least one carbon atom with a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from O, NR, N(O), S, S(O), and S(O), where R is H or an optional substituent, and the "spirocycloalkane" is as defined above. This term includes, but is not limited to, heterocyclic spiroheterocycles and ring structures formed by heterocyclic spirocycloalkanes. The spiroheterocycle preferably contains 1 to 2 heteroatoms selected from NR and / or O, more preferably 1 NR and 0 to 1 heteroatom(s) of NR or O. The spiroheterocycle is preferably a "nitrogen-containing spiroheterocycle," which refers to a spiroheterocycle in which at least one ring atom is NR. The spiro heterocycle includes a 7- to 11-membered spiro heterocycle, a 7- to 9-membered spiro heterocycle, a 7- to 11-membered nitrogen-containing spiro heterocycle, and a 7- to 9-membered nitrogen-containing spiro heterocycle. [ka] Including, but not limited to, the following:

[0128] The term "bridged heterocycle" as used herein refers to a cyclic structure derived by replacing at least one carbon atom of a "bridged cycloalkane" with a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from O, NR, N(O), S, S(O), and S(O)2, R is H or an optional substituent, 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. Examples of the bridged heterocycle include a "6- to 10-membered bridged heterocycle," a "6- to 8-membered bridged heterocycle," and the like. Specific examples include: [ka] Including, but not limited to, the following:

[0129] The term "fused heterocycle" as used herein refers to a saturated ring structure formed by two or more rings sharing two adjacent ring atoms, wherein at least one ring is a heterocycle, and the "heterocycle" is as defined above. This includes, but is not limited to, a structure formed by a heterocycle and a heterocycle, and a heterocycle and a cycloalkane. The fused heterocycle preferably contains 1 to 2 heteroatoms selected from NR and / or O, more preferably one NR and zero to one heteroatom selected from NR or O. 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 a 6- to 10-membered fused heterocycle and an 8- to 10-membered fused heterocycle. Specific examples thereof include: [ka] Including, but not limited to:

[0130] The term "heteroaromatic ring" used herein refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one ring atom is a heteroatom, the heteroatom being selected from N, O, and S. When the heteroaromatic ring contains a N atom, its nitrogen oxide is also included. The polycyclic heteroaromatic ring, i.e., the fused heteroaromatic ring, includes, but is not limited to, a 5- to 6-membered benzo heteroaromatic ring, a 5- to 6-membered heteroaromatic ring, and a 5- to 6-membered heteroaromatic ring. The heteroaromatic ring includes a 5- to 6-membered heteroaromatic ring, a 7- to 10-membered bicyclic fused heteroaromatic ring, and an 8- to 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 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, [ka] Including, but not limited to, the following:

[0131] Combinations of substituents and / or variables described in this disclosure are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure refers to a compound that is sufficiently stable to survive chemical reactions, be isolated to a useful degree of purity, and be manufactured into an effective therapeutic agent.

[0132] As used herein, the term "degrader" refers to a bifunctional compound that binds between IRAK4 kinase and an 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.

[0133] Beneficial Effects of Compounds of the Present Disclosure: (1) The compounds of the present disclosure have good degradation activity against the IRAK4 target and can effectively inhibit the secretion of inflammatory factors. (2) The compounds of the present disclosure have good pharmacokinetic properties and have excellent properties such as high exposure and adequate clearance. (3) The compounds of the present disclosure have excellent safety, such as lower cardiac toxicity.

[0134] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the concentration levels of inflammatory factors in mouse plasma and peritoneal lavage fluid after oral administration of KT-474 and the compound of Example 22 of the present disclosure at three different dose levels of 15 mg / kg, 50 mg / kg, and 150 mg / kg in Test Example 6. FIG. 2 shows the biodegradation levels of IRAK4 in the spleen of mice after oral administration of KT-474 and the compound of Example 22 of the present disclosure at three different dose levels of 15 mg / kg, 50 mg / kg, and 150 mg / kg in Test Example 6.

[0135] [Mode for Carrying Out the Invention] The preparation methods of some compounds in the present disclosure refer to the preparation methods of similar compounds described above. Those skilled in the art should understand that when using or referring to the cited preparation methods, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to different reactants.

[0136] The compounds of the present disclosure can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0137] Unless otherwise specified, all reactions in this disclosure are carried out under continuous magnetic stirring in a dry nitrogen or argon gas atmosphere, and dry solvents are used, where (i) temperatures are expressed in degrees Celsius (°C), and operations are carried out at room temperature, which is generally 15-35°C, preferably 20-30°C, and more preferably 20-25°C, (ii) solvents are removed using reduced pressure evaporation using a rotary evaporator, (iii) reaction progress is monitored by LC-MS or thin-layer chromatography (TLC), and (iv) the final product has satisfactory proton nuclear magnetic resonance spectrum (H-NMR) and / or mass spectrometry (MS) data. Purification methods for the products disclosed herein include, but are not limited to, preparative high-performance liquid chromatography, thin-layer chromatography, or column chromatography. Purification reagents used are solvents commonly used in the art, such as dichloromethane, methanol, ethyl acetate, petroleum ether, acetonitrile, and water, and the specific types and proportions can be determined by methods commonly used in the art.

[0138] Test equipment: The structure of the compounds of the present disclosure can be identified by nuclear magnetic resonance (NMR) or / and liquid chromatography mass spectrometry (LC-MS). NMR chemical shifts (δ) are expressed in parts per million (ppm). NMR measurements were performed using a Bruker Neo 400M or Bruker Ascend 400 nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d), deuterated methanol (CD3OD), and / or deuterated chloroform (CDCl3) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0139] For liquid chromatography-mass spectrometry (LC-MS), a Shimadzu 2030Plus-LCMS2020 mass spectrometer, an Agilent 1260-6125B single quadrupole mass spectrometer, or a Shimadzu LCMS-2020 mass spectrometer was used, and for HPLC, a Shimadzu LCMS-2020 or an Agilent 1260 high-performance liquid chromatograph was used.

[0140] For preparative high-efficiency liquid chromatography, a Shimadzu FRC-40 equipped with LC-20AP and PDA-20A (chromatographic column: Synergi Max-RP, 150 × 30 mm, 4 m) or a GILSON Trilution LC (chromatographic column: SunFire Prep C18, 10 μm, 19 × 250 mm; XBridge Prep C18, 10 μm, 19 × 250 mm) was used.

[0141] The raw materials or intermediate compounds used in this disclosure are commercially available or are synthesized in-house, and the structures of the in-house synthesized intermediates and their preparation methods are described in this disclosure. The chirality of the chiral intermediates or chiral products in this disclosure can be determined from the chiral raw materials used, and when the reaction site is a non-chiral site, the chirality of the raw materials is usually the same as the chirality of the product.

[0142] Chemical abbreviations used in this disclosure and the chemical names they refer to are as follows: [Table 1]

[0143] Synthesis of IRAK4 Warhead A: [ka] Step 1: At room temperature under argon gas protection, 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 solution was then stirred at 60 °C overnight. LC-MS analysis indicated that the starting material was completely consumed and only the product Ab was produced. After cooling, water (100 mL) was added to the reaction solution, followed by extraction 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 under reduced pressure, and the resulting residue was separated by silica gel column chromatography to give Ab (10.1 g). 1 H NMR (400 MHz, CDCl3) δ 8.32 - 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).

[0144] Step 2: Ab (10.1 g, 35.03 mmol) was dissolved in anhydrous methanol / water (100 mL / 25 mL) at room temperature, and lithium hydroxide monohydrate (8.82 g, 210.19 mmol) was added with stirring. The reaction solution was then stirred at 60 °C overnight. LC-MS showed that a small amount of starting material remained, and the main product was Ac. After cooling, the 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 phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give Ac (8.7 g). 1H NMR (400 MHz, CDCl3) δ 8.36 - 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).

[0145] Step 3: 1H-Pyrazole-5-carbaldehyde (58.7 g, 610.89 mmol) and TsOH·HO were dissolved in DCM (580 mL) and cooled to 0 °C. 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 solution, which was then rotary evaporated and concentrated. The residue was purified using a silica gel column to give Ad (88 g). 1 H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.68 (dd, J = 2.6, 0.6 Hz, 1H), 6.83 (d, J = 2.8 Hz, 1H), 5.49 - 5.45 (m, 1H), 4.09 - 4.05 m, 1H), 3.77 - 3.70 (m, 1H), 2.16 - 2.03 (m, 3H), 1.77 - 1.63 (m, 3H).

[0146] 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 proceed overnight at room temperature. TLC (PE / EtOAc = 10 / 1) monitoring indicated that the reaction was not complete. The reaction solution was slowly quenched with NaHCO (3 L), the organic phase was separated, and the aqueous phase was extracted with DCM (3 × 1 L). The organic phases were combined, dried over NaSO, filtered, rotary evaporated, and concentrated. The residue was purified by silica gel column to give Ae (69.65 g). 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 2.4 Hz, 1H), 6.70 (t, J = 55.0 Hz, 1H), 6.51 (d, J = 2.4 Hz, 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).

[0147] Step 5: Ae (25.7 g, 127.10 mmol) was dissolved in MeOH (254 mL), and HCl (4 M in 1,4-dioxane) (254 mL, 1.016 mol) was added at 0 °C. The ice bath was removed, and the reaction was allowed to proceed overnight at room temperature. The completion of the reaction was monitored by TLC. After concentrating the reaction solution, saturated NaHSO (420 mL) and EtOAc (420 mL) were added, and the mixture was stirred at room temperature for 1 h. The mixture was extracted with EtOAc (3 × 200 mL). The combined organic phases were dried over NaSO, and rotary evaporated and concentrated to give Af (16.8 g). 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.63 (m, 1H), 6.80 (t, J = 55.6 Hz, 1H), 6.56 - 6.54 (m, 1H).

[0148] 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 mixture was slowly warmed to room temperature, then gradually heated to 60 °C, and reacted at 115 °C overnight. The reaction solution 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, rotary evaporated, concentrated, and purified to give Ag (7.79 g). 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H),7.35 (t, J = 53.6 Hz, 1H).

[0149] Step 7: 2-Oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (9.57 g, 39.99 mmol) was dissolved in anhydrous methanol (100 mL) at room temperature, and sodium borohydride (1.82 g, 47.99 mmol) was slowly added to the solution while stirring in an ice-water bath. The reaction solution was slowly warmed to room temperature and stirred for 1 hour. Thin-layer chromatography showed that the reaction of the raw material was complete. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 100 mL). The combined organic phase was 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 give Ah (9.14 g). 1 H NMR (400 MHz, CDCl3) δ 4.37 - 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).

[0150] 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 in an ice-water bath with stirring. The reaction solution was slowly warmed to room temperature and stirred for 1 hour, then heated to 60 °C and stirred for 1 hour. LC-MS showed that the reaction of the raw materials was complete. Water (200 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 200 mL). The combined organic phase was 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 give Ai (7.98 g). 1H NMR (400 MHz, CDCl3) δ 4.54 - 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).

[0151] Step 9: Ai (5 g, 14.24 mmol) and Ag (2.11 g, 12.94 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature, and potassium carbonate (3.58 g, 25.88 mmol) was added with stirring. The reaction solution was then stirred at 100 °C overnight. LC-MS showed that the reaction of the raw materials was complete. The reaction solution was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography to give Aj (3.8 g, yield: 76%). 1 H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 7.32 (t, J = 53.0 Hz, 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).

[0152] 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 gas balloon for 3 hours. LC-MS showed that the reaction of the raw materials was complete. The reaction solution was filtered, and the 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+ ].

[0153] Step 11: At room temperature and under argon gas protection, Ak (2.00 g, 5.61 mmol) and Ac (1.50 g, 5.76 mmol) were dissolved in acetonitrile (40 mL). 1-Methylimidazole (1.60 mL, 20.07 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 2.40 g, 8.55 mmol) were added to the solution while stirring in an ice-water bath. The mixture was purged with argon gas three times, and the reaction solution was then stirred overnight at 50 °C under argon gas protection. LC-MS showed that the reaction of the raw materials was complete. Saturated aqueous sodium bicarbonate solution (40 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 40 mL). The combined organic phase was 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 + ].

[0154] Step 12: Al (3.40 g, 5.68 mmol) was dissolved in dichloromethane (40 mL) at room temperature, and hydrochloric acid / 1,4-dioxane solution (4 M, 14 mL, 56 mmol) was added while stirring in an ice-water bath. The reaction solution was then stirred at room temperature for 2 hours. LC-MS showed that the reaction of the raw materials was complete. The reaction solution was concentrated to give the desired crude product A (3.87 g, hydrochloride salt). MS (ESI) M / Z: 499.6 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (d, J = 5.2 Hz, 1H), 8.89 (s, 2H), 8.79 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.14 (t, J = 53.6 Hz, 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).

[0155] Synthesis of intermediate B: [ka] Step 1: Glutarimide (100 g, 884.0 mmol) was placed in a 500 mL sealed vessel at room temperature, chloroform (200 mL) was added, and liquid bromine (141 g, 884.0 mmol) was slowly added while stirring. After sealing, the reaction solution was stirred at 105 °C overnight. LC-MS showed that the starting materials had reacted almost completely, and the major product was Bb. The reaction solution was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate (1 L), washed with saturated aqueous sodium bicarbonate (500 mL), washed with saturated brine (500 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 the desired product Bb (78 g). MS (ESI) M / Z: 192.0 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 4.88 (t, J = 4.8 Hz, 1H), 2.56 - 2.52 (m, 2H), 2.49 - 2.43 (m, 1H), 2.19 - 2.10 (m, 1H).

[0156] Step 2: p-Methoxybenzyl alcohol (20.6 g, 148.9 mmol) was dissolved in dry tetrahydrofuran (500 mL) at room temperature. Triphenylphosphine (39.1 g, 148.9 mmol) and Bb (26 g, 135.4 mmol) were added with stirring. The reaction solution was then cooled to 0 °C, and diethyl azodicarboxylate (25.9 g, 148.9 mmol) was added dropwise slowly under argon gas protection. After the addition was complete, the reaction solution was allowed to warm to room temperature and stirred overnight. LC-MS showed the reaction of the raw materials was complete. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the desired product, Bc (29.7 g). 1 H NMR (400 MHz, CDCl3) δ 7.34 - 7.27 (m, 2H), 6.87 - 6.78 (m, 2H), 4.90 (dd, J = 37.9, 13.8 Hz, 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).

[0157] Step 3: Bd (19.8 g, 87.4 mmol) was dispersed in dry tetrahydrofuran (400 mL) at room temperature and cooled to 0°C with stirring. Under argon gas protection, potassium tert-butoxide (16.7 g, 148.5 mmol) was added and the reaction solution was stirred at that temperature for 1 hour. The temperature was then raised to 45°C, and a solution of Bc (30.0 g, 96.1 mmol) in dry tetrahydrofuran (300 mL) was slowly added dropwise over 6 hours. After the dropwise addition was completed, the reaction solution was stirred at 45°C for 3 hours. LC-MS showed that the starting materials had reacted almost completely. The reaction solution was cooled to 0°C and quenched by slowly adding saturated brine (300 mL). The organic phase was washed once with saturated brine (300 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 Be (18.3 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.29 - 7.15 (m, 3H), 7.13 - 7.04 (m, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.89 - 6.81 (m, 2H), 5.57 (dd, J = 13.0, 5.4 Hz, 1H), 4.79 (q, J = 14.3 Hz, 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).

[0158] Step 4: Be (18.3 g, 19.9 mmol) was dissolved in toluene (140 mL) and methanesulfonic acid (70 mL) at room temperature, heated to 120 °C, and stirred for 5 h. LC-MS showed the reaction of the raw materials was complete. The reaction solution was cooled to room temperature and concentrated. The resulting residue was slowly added dropwise to ice water (1 L), filtered, and dried to obtain the desired product B (10.5 g). 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.98 (t, J = 8.2 Hz, 1H), 5.41 (dd, J = 12.4, 5.2 Hz, 1H), 3.64 (s, 3H), 2.96 - 2.82 (m, 1H), 2.77 - 2.59 (m, 2H), 2.10 - 1.98 (m, 1H).

[0159] Example 1 [ka] Step 1: B (300 mg, 0.89 mmol) and dry N,N-dimethylformamide (5 mL) were placed in a dry 100 mL single-neck flask at room temperature. Under argon gas protection, hydroxyethyl propargyl ether (179 mg, 1.78 mmol), bis(triphenylphosphine)palladium(II) dichloride (62 mg, 0.089 mmol), cuprous iodide (17 mg, 0.089 mmol), and cesium carbonate (870 mg, 2.67 mmol) were added. The mixture was purged with argon gas three times and heated to 80 °C under argon gas protection and stirred for 2 h. LC-MS showed the reaction was complete. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride (20 mL) was added with stirring, and 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 obtain the desired compound 1a (103 mg).

[0160] 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 methanesulfonyl chloride (120 mg, 1.05 mmol) was added to the solution in an ice-water bath with stirring. The reaction solution was then heated to 30°C and stirred for 1 hour under argon gas protection. LC-MS showed that the starting material had disappeared. Water (30 mL) was added to the cooled reaction solution, followed by extraction 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 preparative thin-layer chromatography to give 1b (80 mg). MS (ESI) M / Z: 436.1 [M+H + ]; 434.1 [MH - ]. 1 H NMR (400 MHz, CDCl3) δ 11.23 (s, 1H), 7.20 - 7.12 (m, 2H), 7.06 - 7.01 (m, 1H), 5.40 (dd, J = 12.2, 5.4 Hz, 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).

[0161] Step 3: At room temperature under argon gas protection, 1b (30 mg, 68.89 μmol) and A (crude hydrochloride, 51 mg, 103.34 μmol) were dissolved in acetonitrile (2 mL), 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 overnight at 85°C under argon gas protection. LC-MS showed that a small amount of starting material remained and the major product was 1. After the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (30 mL) was added, followed by extraction 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 preparative thin-layer chromatography to give 1 (7.93 mg). MS (ESI) M / Z: 838.5 [M+H + ]; 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.50 (d, J = 5.2 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.41 - 8.39 (m, 1H), 8.25 (d, J = 5.2 Hz, 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).

[0162] Example 2 [ka] Step 1: B (6.0 g, 17.7 mmol) and 3-(prop-2-yn-1-yloxy)propan-1-ol (4.0 g, 35.5 mmol) were dissolved in dry N,N-dimethylformamide (60 mL) at room temperature. Under argon gas protection, 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) were added sequentially with stirring. The reaction solution was then stirred at 80° C. under argon gas protection for 5 hours.

[0163] LC-MS showed that the reaction of the raw materials was complete. The reaction solution was cooled to room temperature and filtered. The filtrate was concentrated, and the resulting residue was separated by adding ethyl acetate (200 mL) and saturated brine (100 mL). The organic phase was further 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 (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 7.3 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 5.40 (dd, J = 12.6, 5.3 Hz, 1H), 4.54 - 4.31 (m, 3H), 3.64 (s, 3H), 3.60 (t, J = 6.5 Hz, 2H), 3.47 (t, J = 6.3 Hz, 2H), 2.97 - 2.82 (m, 1H), 2.78 - 2.57 (m, 2H), 2.10 - 1.98 (m, 1H), 1.77 - 1.61 (m, 2H).

[0164] 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 Dess-Martin oxidant (162.7 mg, 383.7 μmol) was added with stirring. The reaction solution was stirred at room temperature overnight. LC-MS showed the disappearance of the starting material. The reaction solution was filtered, and the filtrate was partitioned with water (20 mL) and dichloromethane (20 mL). The aqueous phase was further extracted with dichloromethane (10 mL × 2). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative thin-layer chromatography to give 2b (46 mg). MS (ESI) M / Z: 370.1 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.67 (t, J = 1.9 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.15 - 7.10 (m, 1H), 7.03 (t, J = 7.8 Hz, 1H), 5.40 (dd, J = 12.6, 5.4 Hz, 1H), 4.45 (s, 2H), 3.87 (t, J = 6.0 Hz, 2H), 3.64 (s, 3H), 2.96 - 2.82 (m, 1H), 2.81 - 2.56 (m, 4H), 2.10 - 1.95 (m, 1H).

[0165] Step 3: 2b (35 mg, 0.09 mmol) and A (crude hydrochloride, 47 mg, 0.09 mmol) were dissolved in tetrahydrofuran (2 mL) at room temperature, and sodium triacetoxyborohydride (100 mg, 0.47 mmol) was added in an ice-water bath with stirring. The reaction solution was then stirred at room temperature for 2 hours. LC-MS showed that the reaction of the raw material was complete. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (2 × 30 mL). The combined organic phase was washed with saturated brine (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude residue obtained was purified by preparative thin-layer chromatography to give the desired product 2 (10.79 mg). MS (ESI) M / Z: 852 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.50 (d, J = 5.6 Hz, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.27 - 7.00 (m, 4H), 6.86 - 6.44 (m, 1H), 5.43 - 5.35 (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).

[0166] Example 3 [ka] Step 1: 3a (2.0 g, 12.72 mmol) was dissolved in acetonitrile (63 mL) at room temperature, and potassium carbonate (4.4 g, 31.8 mmol) was added with stirring. The mixture was cooled to 0 °C in an ice-water bath, and 3-bromopropyne (1.72 g, 13.99 mmol) was added with stirring. The reaction solution was then stirred at room temperature for 1 h. Thin layer chromatography showed that the starting material was completely consumed, and a new spot was formed. The reaction solution was slowly added dropwise to water, and the mixture was further extracted with ethyl acetate (3 × 40 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 purified by silica gel column chromatography to give 3b (2.75 g, 81% yield) as a colorless liquid. 1 H NMR (400 MHz, CDCl3) δ 4.14 (q, J = 7.1 Hz, 2H), 3.30 (d, J = 2.4 Hz, 2H), 2.89 - 2.85 (m, 2H), 2.35 - 2.21 (m, 4H), 2.09 - 1.62 (m, 4H), 1.25 (t, J = 7.1 Hz, 3H).

[0167] Step 2: 3b (2.03 g, 10.40 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature. A solution of lithium aluminum hydride in tetrahydrofuran (2.5 M, 12.48 mL, 31.2 mmol) was slowly added dropwise to the reaction solution while stirring at 0 °C. The reaction solution was then stirred at 0 °C for 1 h. Thin layer chromatography showed that the starting material was completely consumed and the product was formed. The reaction solution was quenched by slowly adding ice water dropwise, and the resulting mixture was further extracted with ethyl acetate (3 × 50 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 silica gel column chromatography to give 3c (1.18 g). 1H NMR (400 MHz, CDCl3) δ 3.50 (d, J = 6.5 Hz, 2H), 3.30 (d, J = 2.4 Hz, 2H), 2.92 (d, J = 11.5 Hz, 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).

[0168] Step 3: 3c (159 mg, 1.04 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature. Under argon gas protection, 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 solution was purged with argon gas three times, and then bis(triphenylphosphine)palladium(II) dichloride (146 mg, 0.21 mmol) was added. The reaction solution was stirred at 80 °C for 2 h under argon gas protection. LC-MS indicated complete consumption of the starting material and the formation of the product. The cooled reaction solution was diluted with water, and the resulting mixture was extracted with ethyl acetate (3 × 50 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 purified by silica gel column chromatography to give 3d (178 mg). MS (ESI) M / Z: 411.2 [M+H + ].

[0169] 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 Dess-Martin oxidant (165 mg, 0.389 mmol) was added with stirring. The reaction solution was then stirred at room temperature for 4 h. LC-MS analysis indicated that the starting material had been completely consumed and the product had been formed. The reaction solution was slowly added dropwise to 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 preparative thin-layer chromatography to give 3e (48 mg). MS (ESI) M / Z: 409.2 [M+H + ]. 1 H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 8.06 (s, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 5.19 (dd, J = 12.6, 5.3 Hz, 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).

[0170] 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 and stirred in an ice-water bath for 20 minutes. Sodium triacetoxyborohydride (50 mg, 0.235 mmol) was added. The reaction solution was then stirred overnight at room temperature. LC-MS analysis showed that the starting material had been completely consumed and the product had been formed. The reaction solution was quenched by slowly adding water, and the resulting mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by preparative thin-layer chromatography to give 3 (13.8 mg, yield: 26%). MS (ESI) M / Z: 891.4 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.50 (d, J = 5.1 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H), 8.25 (d, J = 5.6 Hz, 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).

[0171] Example 4 [ka] Step 1: 1,4-Butanediol (11.36 g, 126.09 mmol) was dissolved in tetrahydrofuran (30 mL) at room temperature, cooled to 0 °C, and sodium hydride (60%, 2.02 g, 50.44 mmol) was added with stirring. The reaction solution was then stirred at room temperature for 1 hour. The solution was cooled to 0 °C, and a solution of 3-bromopropyne (3.0 g, 25.22 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise with stirring. After the addition was complete, the reaction solution was stirred at room temperature overnight. Thin layer chromatography showed that the starting material was completely consumed and a new spot was formed. The reaction solution was diluted with water and extracted with ethyl acetate (3 × 40 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 silica gel column chromatography to give 4a (2.75 g). 1 H NMR (400 MHz, CDCl3) δ 4.15 (d, J = 2.4 Hz, 2H), 3.67 (t, J = 5.8 Hz, 2H), 3.57 (t, J = 5.9 Hz, 2H), 2.43 (t, J = 2.4 Hz, 1H), 1.78 - 1.65 (m, 5H).

[0172] The subsequent reaction steps were performed in accordance with Example 2. 4 (22.06 mg, yield: 42%) was obtained. MS (ESI) M / Z: 866.5 [M+H + ]. 11H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.50 (d, J = 4.8 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 3.6 Hz, 1H), 8.26 (d, J = 5.6 Hz, 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).

[0173] Example 5

Chemical formula

[0174] Step 2: 5a (1.0 g, 5.43 mmol) was dissolved in methanol / water (10 mL / 5 mL) at room temperature, and sodium hydroxide (2.17 g, 54.3 mmol) was added. The reaction solution was stirred at 100 °C for 2 h. Thin layer chromatography showed that the reaction was complete. The pH of the cooled reaction solution was adjusted to 5 with concentrated hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give crude product 5b (772 mg). 1 H NMR (400 MHz, CDCl3) δ 4.18 (d, J = 2.4 Hz, 2H), 3.55 (s, 2H), 2.43 (t, J = 2.2 Hz, 1H), 1.24 (s, 6H).

[0175] 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) in an ice-water bath, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 72 mg, 0.56 mmol) was added. After 5 minutes, N,N-diisopropylethylamine (0.1 mL, 0.42 mmol) was added. The reaction solution was then stirred at room temperature for 5 hours. LC-MS showed the reaction was complete. Water (approximately 5 mL) was added to the reaction solution, followed by extraction with ethyl acetate (3 × 10 mL). The combined organic phase was washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude product residue was separated by silica gel column chromatography to give the crude product (106 mg). The crude product was further purified by preparative thin layer chromatography to give 5c (58 mg). MS (ESI) M / Z: 637.4 [M+H + ].

[0176] Step 4: Under argon gas protection, B (15 mg, 0.044 mmol) and 5c (58 mg, 0.091 mmol) were dissolved in N,N-dimethylformamide (2 mL). Cesium carbonate (29 mg, 0.090 mmol), cuprous iodide (2 mg, 0.0089 mmol), and bis(triphenylphosphine)palladium(II) dichloride (3 mg, 0.0046 mmol) were added sequentially. The reaction solution was then stirred at 80 °C under argon gas protection for 6 h. LC-MS showed the reaction was complete. After cooling, the reaction solution was filtered through diatomaceous earth. The cake was washed with ethyl acetate (approximately 10 mL). Water was added to the filtrate, which was then 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 preparative thin-layer chromatography to give 5 (8.81 mg). MS (ESI) M / Z: 894.3 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.51 (d, J = 5.6 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.39 (d, J = 4.0 Hz, 1H), 8.27 (d, J = 5.6 Hz, 1H), 7.28 - 7.01 (m, 5H), 6.88 - 6.44 (m, 1H), 5.42 - 5.37 (m, 1H), 5.28 - 5.07 (m, 1H), 4.94 - 4.85 (m, 2H), 4.77 (d, J = 16.0 Hz, 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 = 9.6 Hz, 3H), 2.06 - 1.90 (m, 5H), 1.60 - 1.44 (m, 6H).

[0177] Example 6

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[0178] Example 7

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[0179] Example 8

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[0180] Step 2: To a solution of dried B (200 mg, 0.59 mmol) and 8a (220 mg, 1.18 mmol) in dry N,N-dimethylformamide (8 mL) at room temperature, N,N-diisopropylethylamine (459 mg, 3.56 mmol) was added in one portion. Under argon gas, bis(triphenylphosphine)palladium(II) dichloride (28 mg, 0.04 mmol) and cuprous iodide (24 mg, 0.12 mmol) were added. The reaction solution was heated to 80 °C under argon gas protection and stirred for 5 h. LC-MS indicated complete reaction of the starting material, with the major product being 8b (40%, 254 nm; [M+H]). += 442, RT = 1.57 min). The cooled reaction solution was diluted with ethyl acetate (30 mL) and then filtered through diatomaceous earth. The cake was washed with ethyl acetate (30 mL). Water (50 mL) was added to the filtrate, which was then extracted with ethyl acetate (3 x 50 mL). The combined organic phase was 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 give pure 8b (146 mg). MS (ESI) M / Z: 464.1 [M+Na + ].

[0181] Step 3: Trifluoroacetic acid (2 mL) was added dropwise to a stirred solution of 8b (146 mg, 0.33 mmol) in dichloromethane (2 mL) in an ice-water bath. The reaction solution was then slowly warmed to room temperature and stirred for 2 hours. LC-MS analysis indicated that the main product was 8c and that 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 resulting crude residue, which was then freeze-dried overnight to give crude product 8c (58 mg). MS (ESI) M / Z: 386.1 [M+H + ].

[0182] Step 4: To a stirred solution of A (50 mg, 0.1 mmol) in N,N-dimethylformamide (3 mL) at room temperature under argon gas protection, 8c (57.9 mg, 0.15 mmol), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol), and N,N-diisopropylethylamine (64.5 mg, 0.5 mmol) were added sequentially. The reaction solution was slowly warmed to room temperature and stirred under argon gas protection for 1 h. LC-MS showed that the reaction of the raw material was complete, and the major product was 8 (34%). Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, which was then extracted with ethyl acetate (3 × 30 mL). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by preparative thin-layer chromatography to give pure 8 (2.07 mg + 16.31 mg, yield: 22%). MS (ESI) M / Z: 866.55 [M+H + ]; 864.30 [MH - ]. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.51 (d, J = 5.2 Hz, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.6 Hz, 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).

[0183] Example 9

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[0184] Example 10

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[0185] The subsequent steps were performed in accordance with Example 5 to obtain the desired product 10 (4.6 mg). MS (ESI) M / Z: 880.5 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.50 (d, J = 4.8 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.6 Hz, 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 = 17.2 Hz, 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).

[0186] Example 11

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[0187] Example 12

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[0188] Example 13

Chemical Structure

[0189] Step 2: In an ice-water bath, 13a (300 mg, 604.15 μmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1.17 g, 12.08 mmol) was added with stirring. The reaction solution was slowly warmed to room temperature and stirred for 2 h. LC-MS showed that the starting material was completely consumed and 13b was the major product. The reaction solution was concentrated under reduced pressure to give 13b (236 mg, trifluoroacetate salt). 1H NMR (400 MHz, DMSO-d6) δ 7.25 - 7.00 (m, 3H), 5.40 (dd, J = 12.6, 5.4 Hz, 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).

[0190] 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 solution was stirred at room temperature under argon gas protection for 1 h. LC-MS showed the disappearance of the raw material. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, followed by extraction 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 purified by preparative thin-layer chromatography to give 13c (77 mg). 1 H NMR (400 MHz, CDCl3) δ 8.28 - 8.23 ​​(m, 2H), 8.20 - 8.13 (m, 1H), 7.32 - 7.28 (m, 2H), 7.18 (d, J = 8.8 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 7.2 Hz, 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).

[0191] Step 4: At room temperature under argon gas protection, 13c (57 mg, 101.50 μmol) and A (61 mg, 121.81 μmol) were dissolved in N,N-dimethylformamide (2 mL), and potassium carbonate (42 mg, 304.51 μmol) was added with stirring. The reaction solution was then reacted overnight at 80 °C under argon gas protection. LC-MS analysis indicated that a small amount of starting material remained and that the major 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 preparative thin-layer chromatography to give 13 (26.78 mg). MS (ESI) M / Z: 921.4 [M+H + ]; 1 H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.50 (d, J = 5.2 Hz, 1H), 8.78 (d, J = 7.6 Hz, 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).

[0192] Example 14 [ka] 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) in an ice-water bath. After stirring for 0.5 h in the ice-water bath, the reaction solution was allowed to warm to room temperature and stirred for 0.5 h. 3-Bromopropyne (8.32 g, 69.97 mmol, 6.03 mL) was added to the reaction solution. The reaction solution was then stirred overnight at 60 °C under argon gas protection. LC-MS showed the reaction was complete. After cooling, the reaction solution was quenched by adding saturated aqueous ammonium chloride (approximately 100 mL) in an ice-water bath with stirring. The resulting mixture was diluted with water (approximately 100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic phase was 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 give the desired product 14a (11.60 g). 1 H NMR (400 MHz, DMSO-d6) δ 4.39 - 4.32 (m, 1H), 4.14 (d, J = 2.4 Hz, 2H), 4.04 - 3.99 (m, 2H), 3.71 - 3.67 (m, 2H), 3.46 (t, J = 2.4 Hz, 1H), 1.37 (s, 9H).

[0193] The subsequent reaction was carried out in accordance with Example 13 to obtain the desired product 14 (25.4 mg). MS (ESI) M / Z: 893.2 [M+H + ]; 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.83 (br, 1H), 8.49 (d, J = 10.0 Hz, 2H), 8.32 (d, J = 7.6 Hz, 1H), 7.17 (dd, J = 8.0, 0.8 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.92 - 6.64 (m, 2H), 6.12 (d, J = 7.6 Hz, 1H), 5.45 (s, 1H), 5.22 (dd, J = 12.8, 5.2 Hz, 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 = 9.2 Hz, 1H), 3.49 (d, J = 9.2 Hz, 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).

[0194] Example 15

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[0195] Example 16

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[0196] Example 17

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[0197] Example 18

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[0198] Step 4: A (100 mg, 200.59 μmol) and p-nitrophenyl chloroformate (61 mg, 300.88 μmol) were dissolved in dichloromethane (3 mL) with stirring in an ice-water bath. Triethylamine (61 mg, 601.76 μmol) was added to the solution with stirring in an ice-water bath. The reaction solution was then warmed to room temperature and stirred under argon gas for 1 h. LC-MS showed the disappearance of the starting material. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was 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 preparative thin-layer chromatography to give 18d (85 mg). 1 H NMR (400 MHz, CDCl3) δ 9.62 (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 = 54.0 Hz, 1H), 6.13 (d, J = 8.0 Hz, 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).

[0199] Step 5: At room temperature under argon gas protection, 18d (70 mg, 105.48 μmol) and 18c (61 mg, 158.22 μmol) were dissolved in dimethyl sulfoxide (1 mL), and N,N-diisopropylethylamine (136 mg, 1.05 mmol) was added with stirring. The reaction solution was then stirred overnight at 100°C under argon gas protection. LC-MS indicated that the major product was 18. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, followed by extraction 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 preparative thin-layer chromatography to give 18 (5.11 mg). MS (ESI) M / Z: 907.4 [M+H + ]; 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.50 (d, J = 4.8 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.41 - 8.40 (m, 1H), 8.26 (d, J = 5.6 Hz, 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).

[0200] Example 19 [ka] The desired product 19 (12.02 mg) was obtained by following the procedure of Example 18. MS (ESI) M / Z: 907.5 [M+H + ]. 1 H NMR (400 MHz, CDCl3) δ 9.73 - 9.20 (m, 2H), 8.64 - 8.52 (m, 2H), 8.32 (d, J = 6.8 Hz, 1H), 7.19 - 7.16 (m, 1H), 7.01 - 6.96 (m, 1H), 6.91 - 6.63 (m, 2H), 6.12 (d, J = 7.6 Hz, 1H), 5.45 (s, 1H), 5.32 - 5.22 (m, 1H), 4.79 (s, 1H), 4.69 (t, J = 8.0 Hz, 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 = 1.2 Hz, 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).

[0201] Example 20 [ka] Referring to Example 12, the desired product 20 (1.96 mg) was obtained. MS (ESI) M / Z: 892.6 [M+H + ]. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.51 (d, J = 8.8 Hz, 1H), 8.75 (d, J = 15.2 Hz, 1H), 8.41 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 5.2 Hz, 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 = 13.6 Hz, 2H), 4.38 (s, 2H), 4.10 (d, J = 8.4 Hz, 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).

[0202] Example 21

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[0203] 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) while stirring in an ice-water bath. The reaction solution was allowed to warm to room temperature after 10 minutes and stirred under argon gas for 2 hours. LC-MS showed the reaction was complete. Saturated aqueous sodium bicarbonate solution (15 mL) was added to the reaction solution, which was then 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 then by preparative thin-layer chromatography to give 21b (38 mg). MS (ESI) M / Z: 479.1 [M+H + ]. 1 H NMR (400 MHz, CDCl3) δ 8.32 - 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).

[0204] Step 3: In an ice-water bath, A (300 mg, 601.76 μmol) and 1-Boc-3-azetidinone (515 mg, 3.01 mmol) were dissolved in tetrahydrofuran (5 mL), and sodium triacetoxyborohydride (510 mg, 2.41 mmol) was added while stirring in an ice-water bath. 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 produced. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was 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 preparative thin-layer chromatography to give 21c (240 mg). MS (ESI) M / Z: 654.5 [M+H + ].

[0205] Step 4: In an ice-water bath, 21c (240 mg, 367.12 μmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (418 mg, 3.67 mmol) was added with stirring. The reaction solution was slowly warmed to room temperature and stirred for 1 h. LC-MS showed that the starting material was completely consumed and 21d was the major product. The reaction solution was concentrated under reduced pressure to give 21d (80 mg, crude trifluoroacetate salt). 1 H NMR (400 MHz, DMSO-d6) δ 9.51 (d, J = 5.2 Hz, 1H), 9.30 - 9.08 (m, 3H), 8.79 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 5.2 Hz, 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 - 4.08 (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).

[0206] Step 5: 21d (60 mg, 108.69 μmol), 21b (40 mg, 83.61 μmol), and potassium carbonate (35 mg, 250.83 μmol) were dispersed 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 analysis indicated that a small amount of starting material remained and the product was formed. The reaction solution was cooled to room temperature, and saturated aqueous sodium bicarbonate solution (10 mL) was added, followed by extraction 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 preparative thin-layer chromatography to give 21 (17.52 mg). MS (ESI) M / Z: 893.4 [M+H + ]. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.49 (d, J = 5.2 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.39 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 5.6 Hz, 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).

[0207] Example 22 [ka] Step 1: 3-Butyn-1-ol (0.5 g, 7.13 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Then, p-toluenesulfonyl chloride (1.63 g, 8.56 mmol) and pyridine (850 mg, 10.70 mmol) were added sequentially in an ice-water bath with stirring. The reaction solution was then stirred at room temperature for 16 hours. Thin layer chromatography showed that the reaction of the raw materials was complete. A saturated aqueous solution of ammonium chloride (20 mL) was added to the reaction solution, followed by extraction with ethyl acetate (2 × 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 crude residue was separated by silica gel column chromatography to obtain the desired product 22a (860 mg). 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 4.10 (t, J = 7.0 Hz, 2H), 2.57 - 2.52 (m, 2H), 2.45 (s, 3H), 1.99 (t, J = 2.8 Hz, 1H).

[0208] Step 2: 22a (201.8 mg, 0.90 mmL) 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 reaction of the raw materials was complete. Water (30 mL) was added to the cooled reaction solution, followed by extraction with ethyl acetate (3 × 30 mL). The combined organic phase was washed with saturated aqueous sodium bicarbonate (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 give the desired product 22b (123 mg). MS (ESI) M / Z: 551.4 [M+H + ]; 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.43 (t, J = 8.4 Hz, 2H), 8.32 (d, J = 7.6 Hz, 1H), 6.78 (t, J = 54.0 Hz, 1H), 6.13 (d, J = 7.6 Hz, 1H), 5.46 (s, 1H), 4.81 (d, J = 10.4 Hz, 1H), 4.75 - 4.67 (m, 1H), 4.02 - 3.94 (m, 2H), 3.62 - 3.44 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.55 - 2.35 (m, 8H), 2.33 - 2.24 (m, 2H), 2.14 - 2.09 (m, 1H), 1.99 (t, J = 2.6 Hz, 2H), 1.78 - 1.70 (m, 5H).

[0209] Step 3: At room temperature and under argon gas protection, 22b (123 mg, 0.22 mmol) and B (50 mg, 0.15 mmol) were dissolved in dry N,N-dimethylformamide (2 mL). Cesium carbonate (122.2 mg, 0.38 mmol), bis(triphenylphosphine)palladium(II) dichloride (16 mg, 0.022 mmol), and cuprous iodide (9.0 mg, 0.045 mmol) were added sequentially. The reaction mixture was then stirred at 80 °C under argon gas protection for 5 h. LC-MS analysis indicated the formation of product 22. After cooling, the reaction mixture was filtered, and the cake was washed with ethyl acetate (20 mL). The filtrate was added with saturated aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phase was 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 give the desired product 22 (6.9 mg). MS (ESI) M / Z: 808.6 [M+H + ]; 1H NMR (400 MHz, CDCl3) δ 9.61 (s, 1H), 8.43 (t, J = 10.8 Hz, 2H), 8.32 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.78 (t, J = 54.6 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 6.13 (t, J = 7.6 Hz. 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).

[0210] Example 23

change

[0211] Example 24 [ka] Step 1: 4-Pentynoic acid (2 g, 19.04 mmol) and tert-butanol (21.16 g, 285.46 mmol) were dissolved in dichloromethane (40 mL) at room temperature. Dicyclohexylcarbodiimide (DCC, 6.31 g, 30.59 mmol) and 4-dimethylaminopyridine (DMAP, 0.5 g, 4.08 mmol) were added to the solution while stirring in an ice-water bath. The reaction solution was then stirred overnight at room temperature. Thin-layer chromatography (TLC) showed that the reaction of the raw materials was complete. Dilute hydrochloric acid (0.5 M, 50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (2 × 100 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 crude residue was separated by silica gel column chromatography to give the desired product 24a (1.27 g). 1H NMR (400 MHz, CDCl3) δ 2.45 (s, 4H), 1.97 (s, 1H), 1.46 (s, 9H). The subsequent steps were performed in accordance with Example 8 to obtain the desired product 24 (17.05 mg). MS (ESI) M / Z: 836.6 [M+H + ]. 1 H NMR (400 MHz, CDCl3) δ 11.11 (s, 1H), 9.50 (d, J = 5.2 Hz, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.41 (d, J = 3.6 Hz, 1H), 8.26 (t, J = 5.6 Hz, 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), 5.03 - 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).

[0212] Example 25 [ka] The desired product 25 (2.25 mg) was obtained by following the procedure of Example 24. MS (ESI) M / Z: 850.6 [M+H + ]; 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.51 (d, J = 5.2 Hz, 1H), 8.80 (d, J = 7.2 Hz, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 4.8 Hz, 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).

[0213] Example 26 [ka] Step 1: To a stirred solution of 3-(2-hydroxyethyl)azetidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.97 mmol) in dichloromethane (20 mL) was added Dess-Martin oxidant (4.22 g, 9.94 mmol) in an ice-water bath. The reaction mixture was allowed to warm to room temperature after 10 min and continued stirring under argon gas for 1 h. Thin-layer chromatography showed the reaction was complete. The reaction mixture was filtered through diatomaceous earth. The cake was washed with ethyl acetate (30 mL). 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 purified by silica gel column chromatography to give 26a (567 mg). 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 4.13 (t, J = 8.6 Hz, 2H), 3.59 - 3.55 (m, 2H), 2.99 - 2.82 (m, 3H), 1.43 (s, 9H).

[0214] Step 2: To a 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) while stirring at room temperature. The reaction solution was stirred overnight at room temperature under argon gas protection. Thin layer chromatography showed that the reaction of the raw material was complete. Water (30 mL) was added to the reaction solution, which was then 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 to give 26b (600 mg). 1 H NMR (400 MHz, DMSO-d6) δ 3.89 (brs, 2H), 3.55 (brs, 2H), 2.85 (t, J = 2.6 Hz, 1H), 2.70 - 2.62 (m, 1H), 2.43 - 2.40 (m, 2H), 1.37 (s, 9H).

[0215] The subsequent steps were performed in accordance with Example 18 to obtain the desired product 26 (14.70 mg). MS (ESI) M / Z: 877.3 [M+H + ]; 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.50 (d, J = 5.6 Hz, 1H), 8.79 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.26 (d, J = 5.6 Hz, 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).

[0216] Example 27

change

[0217] Example 28

Chemical formula

[0218] 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 mixture was purged with nitrogen gas and stirred at 25 °C for 3 h. After TLC showed the disappearance of the starting material, dichloromethane (30 mL) was added to the reaction solution to dilute it. The reaction solution was washed three times with water (30 mL × 3). The organic phase was extracted, washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 28b (70 mg). MS (ESI) M / Z: 314.1 [M+H + ]. 1 H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 7.15 (d, J = 7.7 Hz, 1H), 7.10 - 7.06 (m, 1H), 7.02 (t, J = 7.8 Hz, 1H), 5.40 (dd, J = 12.7, 5.3 Hz, 1H), 4.36 (s, 2H), 2.96 - 2.83 (m, 1H), 2.65 (s, 2H), 1.99 (s, 1H), 1.17 (s, 1H).

[0219] Step 3: 28b (70 mg, 0.22 mmol) was dissolved in ethyl acetate (5 mL). The reaction system was purged with nitrogen gas. Manganese dioxide (350 mg, 2.2 mmol) was slowly added to the reaction solution and stirred overnight at room temperature. After TLC detection showed the disappearance of the raw materials, ethyl acetate (20 mL) was added to the reaction solution to dilute it. The filtrate was then filtered to obtain the filtrate. The organic phase was washed with saturated brine (20 mL), 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 + ].

[0220] Step 4: At room temperature, (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). The reaction system was evacuated and purged with nitrogen gas several times. The reaction solution was stirred in an oil bath at 25 °C for 12 h. After LC-MS detection showed the disappearance of the starting material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was 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 28d (1.8 g).

[0221] Step 5: At room temperature, 28d (300 mg, 1.5 mmol) and triethylamine (450 mg, 4.5 mmol) were dissolved in dichloromethane (5 mL). The reaction mixture was cooled to 0 °C, and methanesulfonyl chloride (258 mg, 2.25 mmol) was slowly added dropwise. The mixture was then evacuated and purged with nitrogen several times. The reaction mixture was stirred in an oil bath at 25 °C for 12 h. After LC-MS showed the disappearance of the starting material, the reaction mixture was quenched by adding water (30 mL). The mixture 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).

[0222] Step 6: At room temperature, 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) were dissolved in N,N-dimethylformamide (10 mL). The reaction system was evacuated and purged with nitrogen gas several times. The reaction solution was stirred in an oil bath at 90 °C for 12 h. After LC-MS detection showed the disappearance of the starting material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was 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 28f (270 mg). MS (ESI) M / Z: 583.1 [M+H+].

[0223] Step 7: 28f (270 mg, 0.39 mmol) was dissolved in dioxane (3 mL) at room temperature, and then hydrochloric acid in dioxane (3 mL) was added dropwise at 0 °C. The reaction solution was stirred in an oil bath at 25 °C for 2 h. After LCMS detection showed the disappearance of the raw materials, the mixture was concentrated under reduced pressure, the pH value was adjusted to 7-8, and then 28g (170 mg) was obtained by reverse-phase fractionation. MS (ESI) M / Z: 583.1 [M+H+].

[0224] Step 8: At room temperature, 28g (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). The reaction system was evacuated and purged with nitrogen gas several times. The reaction solution was stirred in an oil bath at 85 °C for 3 h. After LC-MS detection showed the disappearance of the starting material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was 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 28 (140 mg). MS (ESI) M / Z: 398.1 [M+H+]. 1 H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.18 (d, J = 7.5 Hz, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.19 (dd, J = 12.4, 5.2 Hz, 1H), 4.89 (t, J = 3.4 Hz, 1H), 4.53 (d, J = 3.6 Hz, 2H), 3.93 - 3.84 (m, 1H), 3.79 (d, J = 4.4 Hz, 3H), 3.60 - 3.53 (m, 1H), 1.85 - 1.73 (m, 2H), 1.67 - 1.50 (m, 9H).

[0225] Example 29 [ka] Step 1: (1R,3R)-methyl 3-hydroxycyclobutane-1-carboxylate (5.0 g, 38.4 mmol) was dissolved in dry tetrahydrofuran (32 mL) and placed in an ice-water bath. The reaction mixture was cooled to 0 °C. Under a nitrogen atmosphere, lithium aluminum hydride (2.5 M, 30.7 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 3 h. After TLC showed the disappearance of the starting material, the reaction mixture was first diluted with tetrahydrofuran (300 mL). Then, NaSO·10H2O was slowly added to quench the excess lithium aluminum hydride. A large amount of white solid formed in the reaction mixture. The solid was filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 29a (2.7 g). 1 H NMR (400 MHz, DMSO) δ 4.86 (d, J = 6.3 Hz, 1H), 4.46 (t, J = 5.4 Hz, 1H), 4.16 - 4.09 (m, 1H), 3.35 (dd, J = 7.0, 5.5 Hz, 2H), 2.18 - 2.05 (m, 1H), 2.01 - 1.92 (m, 2H), 1.88 - 1.78 (m, 2H).

[0226] Step 2: 29a (2.5 g, 24.5 mmol) and imidazole (5.0 g, 73.5 mmol) were dissolved in dichloromethane (30 mL). The reaction mixture was purged with nitrogen gas and placed in an ice-water bath. The reaction mixture was cooled to 0 °C. Under a nitrogen atmosphere, tert-butyldiphenylsilyl chloride (8.1 g, 29.4 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 25 °C for 3 h. After TLC showed the disappearance of the starting materials, dichloromethane (30 mL) was added to the reaction mixture to dilute the reaction mixture. The reaction mixture was washed three times with water (30 mL × 3). The organic phase was extracted, washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 29b (2.7 g). 1H NMR (400 MHz, DMSO) δ 7.65 - 7.54 (m, 5H), 7.54 - 7.36 (m, 5H), 4.92 (d, J = 6.3 Hz, 1H), 4.15 (dd, J = 13.7, 6.8 Hz, 1H), 3.61 (d, J = 6.5 Hz, 2H), 2.33 - 2.21 (m, 1H), 2.09 - 2.00 (m, 2H), 1.95 - 1.85 (m, 2H), 1.00 (s, 9H).

[0227] Step 3: 29b (220 mg, 0.65 mmol) was dissolved in dry tetrahydrofuran (3.5 mL). The reaction mixture was purged with nitrogen and placed in an ice-water bath. The reaction mixture was cooled to 0 °C, and under a nitrogen atmosphere, sodium hydride (52 mg, 1.30 mmol) was slowly added to the reaction mixture. After stirring at 0 °C for 1 h, propargyl bromide (153.4 mg, 1.29 mmol) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred overnight. After TLC showed the disappearance of the starting material, the reaction mixture was quenched by adding saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was 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 29c (190 mg). 1 H NMR (400 MHz, DMSO) δ 7.74 - 7.52 (m, 4H), 7.52 - 7.37 (m, 6H), 4.27 - 4.13 (m, 1H), 4.00 (d, J = 2.4 Hz, 2H), 3.63 (d, J = 6.1 Hz,2H), 3.36 (t, J = 2.4 Hz, 1H), 2.41 - 2.29 (m, 1H), 2.12 - 2.04 (m, 2H), 2.04 - 1.93 (m, 2H), 1.01 (s, 9H).

[0228] Step 4: 29c (190 mg, 0.50 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature, and then tetrabutylammonium fluoride (1.0 M, 1.0 mL) was slowly added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. After LC-MS detection showed the disappearance of the starting material, the reaction solution was quenched by adding saturated aqueous ammonium chloride (15 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed first 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 29d (70 mg). 1 H NMR (400 MHz, DMSO) δ 4.56 (t, J = 5.3 Hz, 1H), 4.15 - 4.10 (m, 1H), 4.00 (d, J = 2.4 Hz, 2H), 3.42 - 3.34 (m, 3H), 2.28 - 2.14 (m, 1H), 2.04 - 1.88 (m, 4H).

[0229] Step 5: 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) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature. The reaction system was evacuated and flushed with nitrogen several times. The reaction solution was sealed in an oil bath at 85 °C and stirred for 3 h. After LC-MS detection showed the disappearance of the starting material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were 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). 1H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.14 - 7.09 (m, 1H), 7.03 (t, J = 7.9 Hz, 1H), 5.40 (dd, J = 12.7, 5.3 Hz, 1H), 4.58 (t, J = 5.3 Hz, 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, 5.5 Hz, 2H), 2.96 - 2.82 (m, 1H), 2.77 - 2.59 (m, 2H), 2.28 - 2.18 (m, 1H), 2.08 - 1.97 (m, 5H).

[0230] Step 6: At room temperature, 29e (110 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL). At 0 °C, triethylamine (85 mg, 0.84 mmol) and p-methylsulfonyl chloride (47.8 mg, 0.42 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. After LC-MS detection showed the disappearance of the raw material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with dichloromethane (30 mL × 3), and the organic phases were combined. The organic phase was 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 + ].

[0231] 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 purged with nitrogen gas several times. The reaction solution was stirred at 50 °C for 18 h. After LC-MS detection showed the disappearance of the starting material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was 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 (400 MHz, DMSO) δ 11.12 (s, 1H), 9.49 (d, J = 5.4 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.39 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.31 - 6.97 (m, 4H), 6.87 (d, J = 7.8 Hz, 0.5H), 6.45 (d, J = 7.8 Hz, 0.5H), 5.4 (dd, J = 12.7, 5.4 Hz, 1H), 5.27 (s, 0.5H), 5.07 (s, 0.5H), 4.98 - 4.87 (m, 1H), 4.77 (d, J = 16.2 Hz, 1H), 4.34 (s, 2H), 4.31 - 4.21 (m, 1H), 3.82 (d, J = 9.9 Hz, 2H), 3.74 (d, J = 7.5 Hz, 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, 1H), 2.35 - 2.27 (m, 6H), 2.23 - 2.11 (m, 3H), 2.07 - 1.93 (m, 7H), 1.58 (dd, J = 16.5, 12.2 Hz, 4H).

[0232] Example 30

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[0233] Example 31 [Chemical formula] 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. The reaction mixture was cooled to 0 °C. Under a nitrogen atmosphere, lithium aluminum hydride (2.5 M, 25.2 mL) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 3 h. After TLC showed the disappearance of the starting material, tetrahydrofuran (300 mL) was added to dilute the reaction mixture. Then, Na2SO4·10H2O was slowly added to quench the excess lithium aluminum hydride. A large amount of white solid formed in the reaction mixture. The solid was filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 31a (2.6 g). 1 H NMR (400 MHz, DMSO) δ 4.44 (d, J = 4.4 Hz, 1H), 4.34 (t, J = 5.3 Hz, 1H), 3.32 - 3.24 (m, 1H), 3.18 (t, J = 5.8 Hz, 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).

[0234] Step 2: 31a (2.3 g, 17.7 mmol) and imidazole (3.6 g, 53.1 mmol) were dissolved in dichloromethane (40 mL). The reaction mixture was purged with nitrogen gas and placed in an ice-water bath. The reaction mixture was cooled to 0 °C. Under a nitrogen atmosphere, tert-butyldiphenylsilyl chloride (5.8 g, 21.2 mmol) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at 25 °C for 3 h. After TLC showed the disappearance of the starting material, dichloromethane (50 mL) was added to the reaction mixture to dilute it. The reaction mixture was washed three times with water (50 mL × 3). The organic phase was extracted, washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give 31b (3.8 g).1 H NMR (400 MHz, MeOD) δ 7.72 - 7.58 (m, 4H), 7.47 - 7.32 (m, 6H), 3.52 - 3.38 (m, 3H), 1.98 - 1.91 (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).

[0235] Step 3: 31b (3.5 g, 9.5 mmol) was dissolved in dry tetrahydrofuran (3.5 mL). The reaction mixture was purged with nitrogen and placed in an ice-water bath. The reaction mixture was cooled to 0 °C and, under a nitrogen atmosphere, sodium hydride (1.1 g, 28.4 mmol) was slowly added to the reaction mixture. After stirring at 0 °C for 1 hour, propargyl bromide (3.4 g, 28.4 mmol) was slowly added dropwise to the reaction mixture. The reaction mixture was allowed to warm to room temperature and stirred overnight. After TLC showed the disappearance of the starting material, the reaction mixture was quenched by adding saturated aqueous ammonium chloride (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was 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 give 31c (2.0 g).

[0236] Step 4: At room temperature, 31c (1.8 g, 4.4 mmol) was dissolved in tetrahydrofuran (20 mL), and then tetrabutylammonium fluoride (1.0 M, 8.8 mL) was slowly added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. After LC-MS detection showed the disappearance of the starting material, the reaction solution was quenched by adding saturated aqueous ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed first 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 31d (670 mg).1 H NMR (400 MHz, DMSO) δ 4.38 (t, J = 5.3 Hz, 1H), 4.13 (d, J = 2.4 Hz, 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).

[0237] Step 5: At room temperature, 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) were dissolved in N,N-dimethylformamide (10 mL). The reaction system was evacuated and purged with nitrogen gas several times. The reaction solution was sealed in an oil bath at 85 °C and stirred for 3 h. After LC-MS detection 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 × 3), and the organic phases were combined. The organic phase was 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 31e (300 mg). 1H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 7.0 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 5.40 (dd, J = 12.7, 5.3 Hz, 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 = 11.6 Hz, 2H), 1.37 - 1.25 (m, 1H), 1.16 - 1.06 (m, 1H), 0.99 - 0.77 (m, 2H).

[0238] Step 6: At room temperature, 31e (270 mg, 0.63 mmol) was dissolved in dichloromethane (8 mL). At 0 °C, triethylamine (318.8 mg, 3.1 mmol) and p-methylsulfonyl chloride (291.9 mg, 2.5 mmol) were added, and the reaction solution was stirred at room temperature for 2 hours. After LC-MS detection showed the disappearance of the raw material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with dichloromethane (30 mL × 3), and the organic phases were combined. The organic phase was 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 + ].

[0239] 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 purged with nitrogen gas several times. The reaction solution was stirred at 50 °C for 18 h. After LC-MS detection showed the disappearance of the raw material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was 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 (400 MHz, DMSO) δ 11.12 (s, 1H), 9.49 (d, J = 5.2 Hz, 1H), 8.78 (d, J = 7.7 Hz, 1H), 8.39 (d, J = 3.9 Hz, 1H), 8.25 (d, J = 5.7 Hz, 1H), 7.41 - 6.92 (m, 4H), 6.87 (d, J = 7.9 Hz, 0.5H), 6.45 (d, J = 7.7 Hz, 0.5H), 5.40 (dd, J = 12.7, 5.3 Hz, 1H), 5.28 (s, 0.5H), 5.08 (s, 0.5H), 5.00 - 4.86 (m, 1H), 4.77 (d, J = 16.4 Hz, 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 = 11.9 Hz, 2H), 1.61 (d, J = 22.8 Hz, 4H), 1.52 - 1.38 (m, 1H), 1.21 - 1.07 (m, 2H), 0.95 - 0.76 (m, 2H).

[0240] Example 32

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[0241] Example 33

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[0242] Example 34

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[0243] Example 35

Chem.

[0244] 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 mixture was stirred at room temperature under a hydrogen gas atmosphere for 3 hours. After TLC showed the disappearance of the starting material, ethanol (100 mL) was added to the reaction mixture to dilute it. The black solid was filtered through a Buchner funnel, the 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 + ].

[0245] Step 3: 35b (2.2 g, 9.6 mmol) was dissolved in dry tetrahydrofuran (30 mL) and placed in an ice-water bath. The reaction mixture was cooled to 0 °C. Under a nitrogen atmosphere, lithium aluminum hydride (2.5 M, 7.7 mL) was slowly added dropwise to the reaction mixture, and the mixture was stirred at 0 °C for 3 h. After TLC showed the disappearance of the starting material, tetrahydrofuran (300 mL) was added to dilute the reaction mixture. Then, NaSO·10H2O was slowly added to quench the excess lithium aluminum hydride. A large amount of white solid was formed 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, distilled under reduced pressure, and dried in suspension to give 35c (1.45 g). 1 H NMR (400 MHz, DMSO) δ 4.31 (t, J = 5.1 Hz, 1H), 3.83 (s, 4H), 3.47 - 3.37 (m, 2H), 1.63 (d, J = 10.1 Hz, 4H), 1.47 - 1.28 (m, 5H), 1.18 - 1.04 (m, 2H).

[0246] Step 4: Oxalyl chloride (0.2 mL, 2.42 mmol) was dissolved in dry dichloromethane (3 mL), the reaction mixture was flushed with nitrogen, and then placed in a dry ice acetone bath. The reaction mixture was cooled to -78 °C, and dimethyl sulfoxide (0.35 mL, 4.84 mmol, dissolved in 3 mL of dichloromethane) was slowly added to the reaction mixture under a nitrogen atmosphere. After stirring at -78 °C for 0.5 h, 35c (300 mg, 1.61 mmol, dissolved in 3 mL of dichloromethane) was slowly added dropwise to the reaction mixture, and the reaction mixture was continued to stir at -78 °C for 1 h. After TLC showed the disappearance of the starting material, triethylamine (12 mL) was added to the reaction solution and stirred at room temperature for 0.5 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was 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 (400 MHz, DMSO) δ 9.65 (t, J = 2.0 Hz, 1H), 3.83 (s, 4H), 2.33 (dd, J = 6.8, 2.0 Hz, 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).

[0247] 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. Next, (1-diazo-2-oxo-propanol)-phosphonic acid dimethyl ester (313.0 mg, 4.08 mmol) was added, and the reaction solution was stirred at room temperature for 18 h. After LC-MS detection showed the disappearance of the starting material, the reaction solution was concentrated under reduced pressure, and the residue was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was 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 35e (220 mg, yield: 89.8%). 1 H NMR (400 MHz, DMSO) δ 3.83 (s, 4H), 2.77 (t, J = 2.7 Hz, 1H), 2.09 (dd, J = 6.5, 2.7 Hz, 2H), 1.73 - 1.61 (m, 4H), 1.50 - 1.38 (m, 3H), 1.30 - 1.20 (m, 2H).

[0248] Step 6: At room temperature, 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). The reaction system was evacuated and purged with nitrogen gas several times. The reaction solution was sealed in an oil bath at 85 °C and stirred for 3 h. After LC-MS detection 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 × 3), and the organic phases were combined. The organic phase was 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 35f (100 mg). MS (ESI) M / Z: 438.3 [M+H + ].

[0249] Step 7: At room temperature, 35f (100 mg, 0.23 mmol) was dissolved in dichloromethane / acetone (4 mL / 1 mL), and then iron(III) chloride hexahydrate (216.5 mg, 0.8 mmol) was slowly added to the reaction solution. The reaction solution was stirred overnight at room temperature. After LC-MS detection showed the disappearance of the raw material, the reaction solution was quenched by adding aqueous sodium bicarbonate (20 mL). The mixture was extracted with dichloromethane (20 mL x 3). The combined organic phases were washed first 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 + ].

[0250] Step 8: At room temperature, 35g (60 mg, 0.15 mmol) was dissolved in a tetrahydrofuran / N,N-dimethylformamide mixture (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 solution. The reaction system was evacuated and purged with nitrogen gas several times. The reaction solution was stirred at 25°C for 2 hours. Sodium cyanoborohydride (18.9 mg, 0.30 mmol) was then slowly added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. After LC-MS detection showed the disappearance of the starting material, the reaction solution 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 high performance liquid chromatography to give the final product 35 (12.0 mg). MS (ESI) M / Z: 876.5 [M+H + ]. 1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.50 (d, J = 5.1 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.39 (d, J = 4.1 Hz, 1H), 8.26 (d, J = 5.7 Hz, 1H), 7.20 - 6.92 (m, 4H), 6.87 (d, J = 7.9 Hz, 0.5H), 6.46 (d, J = 7.8 Hz, 0.5H), 5.38 (dd, J = 12.7, 5.4 Hz, 1H), 5.28 (s, 0.5H), 5.08 (s, 0.5H), 5.00 - 4.85 (m, 1H), 4.77 (d, J = 16.4 Hz, 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).

[0251] Example 36

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[0252] Example 37

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[0253] Example 38

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[0254] Example 39

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[0255] Example 40

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[0256] Example 41

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[0257] Example 42

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[0258] Example 43

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[0259] Example 44

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[0260] Example 45

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[0261] Example 46

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[0262] Example 47

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[0263] Example 48

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[0264] Example 49

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[0265] Example 50

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[0266] Example 51 [ka] 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 and stirred. 1 M sodium hydroxide solution (5.8 mL, 5.8 mmol) was added dropwise at room temperature to form a clear solution. 4 M aqueous silver nitrate solution (1.5 mL, 6.0 mmol) was added and stirred at room temperature for 2 hours. After filtration, the residue was washed with water, methyl tert-butyl ether, and acetone. The solvent was evaporated to dryness to give 51a (1.82 g).

[0267] Step 2: 51a (1.82 g, 5.75 mmol) was added to a reaction flask, the atmosphere was purged with N, n-hexane (12 mL) was added, and liquid bromine (920 mg, 5.75 mmol) was added dropwise and stirred for 4 hours. The filtrate was collected by filtration, and the residue was washed with methyl tert-butyl ether (15 mL × 3) and saturated sodium bicarbonate solution (20 mL × 3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and spin-dried to give 51b (909 mg). 1 H NMR (400 MHz, Chloroform-d) δ 3.63 (s, 3H), 2.29 - 2.19 (m, 6H), 2.00 - 1.93 (m, 6H).

[0268] Step 3: A reaction flask was charged with 51b (13.3 g, 53.8 mmol), sodium hydroxide (12.9 g, 323 mmol), and water (300 mL). The reaction was carried out at 110 °C for 24 h. After completion of the reaction, 4 M hydrochloric acid solution was added to adjust the pH to 3-4, and EA (50 mL × 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 give 51c (4.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 4.21 (s, 1H), 1.79 - 1.72 (m, 6H), 1.55 - 1.44 (m, 6H).

[0269] Step 4: 51c (4.5 g, 26.5 mmol) was added to a reaction flask, and the mixture was purged with nitrogen gas. Anhydrous dichloromethane (10 mL) and anhydrous methanol (10 mL) were added to clear the solution. Under a nitrogen atmosphere, (trimethylsilyl)diazomethane (2 M, 53 mmol, 26.5 mL) was added dropwise and the mixture was allowed to react at room temperature overnight. After completion of the reaction, the product was separated by column chromatography to give 51d (2.0 g). 1 H NMR (400 MHz, Chloroform-d) δ 3.63 (s, 3H), 1.94 - 1.88 (m, 6H), 1.70 - 1.62 (m, 6H).

[0270] Step 5: 51d (2.0 g, 10.9 mmol) was added to a reaction flask, which was then purged with nitrogen gas. Anhydrous DMF (10 mL) and sodium hydride (60% wt, 872 mg, 21.8 mmol) were added, and the mixture was allowed to react at room temperature for 30 minutes. Next, propargyl bromide (2.59 g, 21.8 mmol) was added, and the mixture was allowed to react at room temperature overnight. After completion of the reaction, the mixture was quenched by adding water (30 mL), extracted with EA (30 mL × 4), and the organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and purified by column chromatography to give 51e (720 mg). 1 H NMR (400 MHz, Chloroform-d) δ 4.00 (d, J = 2.4 Hz, 2H), 3.57 (s, 3H), 2.31 (t, J = 2.4 Hz, 1H), 1.91 - 1.81 (m, 6H), 1.71 - 1.62 (m, 6H).

[0271] 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 overnight at room temperature. After completion of the reaction, 1 M dilute aqueous hydrochloric acid was added to adjust the pH to 3-4, and EA (10 mL × 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 (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 4.01 (d, J = 2.4 Hz, 2H), 3.27 (t, J = 2.4 Hz, 1H), 1.83 - 1.74 (m, 6H), 1.66 - 1.57 (m, 6H).

[0272] Step 7: 51f (20 mg, 0.096 mmol) was added to a reaction flask, which was then flushed with nitrogen. Anhydrous DMF (2 mL) and HATU (40 mg, 0.106 mmol) were added, and the mixture was allowed to react at room temperature for 30 minutes. A (48 mg, 0.096 mmol) was added, and the mixture was allowed to react at room temperature overnight. After the reaction was complete, water (10 mL) was added, and the aqueous phase was extracted with EA (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 5), dried over anhydrous sodium sulfate, and spin-dried to give 51g (38 mg). [M+H] + = 689.5

[0273] Step 8: B (110 mg, 0.32 mmol), 51g (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) were dissolved in ultra-dry DMF (3 mL) at room temperature. After thoroughly purging with N2, the mixture was stirred at 90 °C for 12 h. LC-MS monitoring was performed. The mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3 mL). The combined organic phases were dried over anhydrous sodium sulfate, and the product was separated and purified by preparative TLC to give the desired product 51 (4.5 mg). MS (ESI) M / Z: 946.7 [M+H + ]; 1H NMR (400 MHz, DMSO-d6) δ 11.1 (s, 1H), 9.50 (d, J = 5.2 Hz, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 4.0 Hz, 1H), 8.25 (d, J = 5.2 Hz, 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).

[0274] Example 52 [ka] Step 1: 51e (260 mg, 1.17 mmol) was dissolved in ultra-dry THF (4 mL) at room temperature, and lithium aluminum hydride (1.75 mL, 1.75 mmol) was slowly added at 0 °C. The mixture was warmed to room temperature and stirred for 3 h. After completion of the reaction, the mixture was quenched with water and extracted with EA (5 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate to give 52a (170 mg, 74.9%).

[0275] Step 2: 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) were dissolved in ultra-dry DMF (5 mL) at room temperature, thoroughly purged with N2, and stirred at 90 °C for 4 h. LC-MS monitoring was performed. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, and purified by preparative TLC to give 52b (120 mg). MS (ESI) M / Z: 452.3 [M+H + ].

[0276] Step 3: 52b (120 mg, 0.26 mmol) was dissolved in DCM (3 mL) at room temperature, and Dess-Martin oxidant (Dess-Martin reagent, 124 mg, 0.29 mmol) was added. The mixture was stirred 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 give 52c (90 mg, 75.6%). MS (ESI) M / Z: 450.1 [M+H] + .

[0277] 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) and extracted with DCM (5 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and purified by preparative TLC to give the crude product (30 mg), which was then further purified by high-pressure preparative liquid-phase separation to give the desired product 52 (13.8 mg). MS (ESI) M / Z: 932.8 [M+H + ]; 1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.55 (d, J = 5.2 Hz, 1H), 8.82 (d, J = 7.6 Hz, 1H), 8.43 (d, J = 4.0 Hz, 1H), 8.31 (d, J = 5.6 Hz, 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).

[0278] Example 53

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[0279] Example 54

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[0280] Example 55

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[0281] Example 56 [ka] Step 1: Methyl 4-piperidinecarboxylate (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. The mixture was then stirred for 10 minutes. CuI (66 mg, 0.349 mmol) was added to the reaction mixture, and the mixture was stirred for 0.5 hours. The mixture was then extracted three times with 40 mL of water and 80 mL of ethyl acetate. The organic phase was then collected and dried over anhydrous sodium sulfate. After spin-drying, product 56a (470 mg) was obtained. 1 H NMR (400 MHz, Chloroform-d) δ 3.61 (s, 3H), 2.99 (dt, J = 11.7, 3.6 Hz, 2H), 2.28 - 2.07 (m, 4H), 1.68 (qd, J = 11.6, 3.7 Hz, 2H), 1.33 (s, 6H).

[0282] 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 h. After completion of the reaction, the crude product was obtained by filtration through diatomaceous earth and purified by preparative TLC to give product 56b (90 mg). MS (ESI) M / Z: 467.2 [M+H + ].

[0283] Step 3: 56b (47 mg, 0.1 mmol) was dissolved in a 1:1 mixture of THF and MeOH (6 mL) at room temperature, LiOH (36 mg, 1.5 mmol) was added, and the reaction mixture was stirred at 40 °C for 1 h. 40 mL of dichloromethane was added, and the excess salt was filtered off. The resulting mixture was purified by preparative TLC to give 56c (25 mg). MS (ESI) M / Z: 453.3 [M+H + ].

[0284] Step 4: 56c (20 mg, 0.044 mmol) and HATU (18.5 mg, 0.048 mmol) were added to 0.5 mL of dichloromethane at room temperature and stirred for 5 minutes. 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 mixture. The mixture was stirred at 40 °C for 2 hours. After completion of the reaction, the product was purified by preparative TLC to give the desired product 56 (13.3 mg). MS (ESI) M / Z: 933.6 [M+H + ]; 1H NMR (400 MHz, Chloroform-d) δ 9.53 (s, 1H), 8.50 (s, 1H), 8.35 (d, J = 10.0 Hz, 1H), 8.24 (s, 1H), 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 = 21.9 Hz, 2H), 3.90 (s, 2H), 3.71 (s, 3H), 3.47 (d, J = 38.1 Hz, 4H), 3.27 (s, 1H), 3.19 (s, 2H), 2.76 (d, J = 69.2 Hz, 4H), 2.34 (d, J = 37.0 Hz, 8H), 1.83 (d, J = 80.8 Hz, 10H), 1.43 (s, 6H).

[0285] Example 57

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[0286] Example 58

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[0287] Example 59

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[0288] Example 60

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[0289] Example 61

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[0290] Example 62

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[0291] Example 63

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[0292] Example 64

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[0293] Example 65

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[0294] Example 66

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[0295] Example 67

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[0296] Example 68

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[0297] Example 69

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[0298] Example 70

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[0299] Example 71

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[0300] P1 1 H NMR (400 MHz, CDCl3) δ 4.15 (t, J = 5.0 Hz, 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). P2 1 H NMR (400 MHz, CDCl3) δ 4.19 (d, J = 2.4 Hz, 2H), 3.67 (s, 3H), 3.47 (tt, J = 10.5, 4.1 Hz, 1H), 2.41 (t, J = 2.4 Hz, 1H), 2.28 (tt, J = 11.7, 3.7 Hz, 1H), 2.15 - 2.02 (m, 4H), 1.55 - 1.44 (m, 2H), 1.33 - 1.26 (m, 2H).

[0301] Step 2: At room temperature, 71a (200 mg, 1.1 mmol) was dissolved in tetrahydrofuran / water (4 mL / 0.8 mL), lithium hydroxide (230 mg, 5.49 mmol) was added, and the reaction mixture was stirred at 50 °C overnight. After LCMS detection showed the disappearance of the starting material, the reaction mixture was extracted with ethyl acetate (30 mL × 2). The pH of the aqueous phase was adjusted to 3-4 with 1 M hydrochloric acid, and then extracted with ethyl acetate (30 mL × 2) to give intermediate 71b (160 mg, pale yellow solid). 1 H NMR (400 MHz, DMSO) δ 12.04 (s, 1H), 4.13 (t, J = 3.9 Hz, 2H), 3.35 (m, J = 2.4 Hz, 2H), 2.15 (tt, J = 11.5, 3.6 Hz, 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).

[0302] Step 3: 71b (101 mg, 0.554 mmol), Intermediate A (230 mg, 0.462 mmol), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (263 mg, 0.693 mmol) were dissolved in N,N-dimethylformamide (4 mL), N,N-diisopropylethylamine (150 mg, 1.155 mmol) was added, and the reaction was stirred at room temperature for 1 h.

[0303] After TLC showed that the raw materials had disappeared, ethyl acetate (30 mL) was added to the reaction solution, and the mixture was extracted with water (30 mL x 3). The organic phases were combined, washed with saturated brine, 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 71c (150 mg). MS (ESI) M / Z: 663.3 [M+H + ].

[0304] Step 4: At room temperature, 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) were dissolved in N,N-dimethylformamide (4 mL). The reaction system was evacuated and purged with nitrogen gas several times. The reaction solution was stirred in an oil bath at 85 °C for 3 h. After LCMS detection showed the disappearance of the starting material, the reaction solution was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was 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 collect the product, yielding the final product 71 (5.6 mg). MS (ESI) M / Z: 920.1 [M+H + ]; 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.50 (d, J = 5.2 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.42 (d, J = 4.1 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.31 - 7.09 (m, 3H), 7.03 (dd, J = 9.8, 5.9 Hz, 1H), 6.87 (d, J = 7.9 Hz, 0.5H), 6.46 (d, J = 7.8 Hz, 0.5H), 5.40 (dd, J = 12.7, 5.4 Hz, 1H), 5.28 (s, 0.5H), 5.08 (s, 0.5H), 4.99 (d, J = 7.0 Hz, 1H), 4.77 (d, J = 16.0 Hz, 1H), 4.47 (s, 2H), 3.80 (t, J = 16.7 Hz, 2H), 3.65 (s, 3H), 3.61 (d, J = 10.7 Hz, 1.5H), 3.45 (d, J = 9.3 Hz, 3.5H), 3.37 (s, 2H), 2.93 - 2.84 (m, 1H), 2.77 - 2.68 (m, 1H), 2.65 (t, J = 5.4 Hz, 1H), 2.40 (s, 2H), 2.23 (t, J = 9.3 Hz, 2H), 2.12 - 2.02 (m, 4H), 2.01 - 1.91 (m, 2H), 1.67 (s, 3H), 1.59 (s, 2H), 1.51 (s, 1H), 1.40 (dd, J = 25.0, 11.6 Hz, 2H), 1.27 (d, J = 10.9 Hz, 2H).

[0305] Example 72

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[0306] Example of biological activity test The control molecule used in this test example was KT-474, which was produced by referring to the production method of compound I-417 in patent WO2020113233A1, and its structure is as follows:

[0307] [ka] Test Example 1: Degradation of IRAK4 by Compounds in SU-DHL-2 and OCI-LY3 Cells (1) Experimental Purpose Flow cytometry was used to detect the degradation level of IRAK4 protein by compounds in the SU-DHL-2 cell line.

[0308] (2) Experimental materials Fix Buffer I, BD Phosflow TM , 557870 Perm III buffer, BD Phosflow TM , 558050 LIVE / DEAD TM Fixable Violet Dead Cell Stain Kit, Thermo Fisher, L34966 Alexa Fluor 647 mouse anti-human IRAK4 clone L29-525 (RUO), BD Phosflow TM , 560315

[0309] (3) Experimental equipment Flow cytometer, BD, Model: BD LSRFortessa

[0310] (4) Experimental method Step 1: SU-DHL-2 cell line was cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% double antibody.

[0311] Step 2: On day 1, plate cells at 2 x 10 in a 96-well plate. 5 100 μL of each compound was seeded at a density of 100 μM per well. Compounds were dissolved in DMSO to a final concentration of 10 mM and diluted 1:5 with medium to achieve a final concentration of 10 μM. A positive control well contained 0.1% DMSO. The cells were cultured at 37°C in a 5% CO2 incubator for 24 hours.

[0312] Step 3: After centrifugation, cells were washed with FACS buffer. LIVE / DEAD TMLive / dead staining of cells was performed using Fixable Blue Dead Cell Stain Kit, and surface staining marking of monocytes was performed using PE mouse anti-human CD14 and incubated at 4°C for 30 min.

[0313] Step 4: After centrifugation, the cells were washed with FACS buffer. An equal volume of Fix buffer I was added to the cells, and the cells were fixed at 37°C for 10 minutes.

[0314] Step 5: After centrifugation, the cells were washed with FACS buffer. 150 μL of Perm III reagent was added and incubated at 4°C for 30 minutes to disrupt the cell membrane. After centrifugation, the cells were washed with FACS buffer.

[0315] Step 6: Cells were stained using Alexa Fluor 647 mouse anti-human IRAK4 antibody and incubated for 1 hour at 4°C. Flow cytometry analysis was performed using a flow cytometer.

[0316] (5) Data processing Flow cytometry data were analyzed using Flowjo software. Data presentation and DC 50 Prism 8.0.2 (GraphPad) was used to calculate the half-maximum degradation concentration.

[0317] (6) Experimental results See Table 1 for the results of IRAK4 degradation activity of the compounds of the examples of the present disclosure.

[0318] The compounds of the examples of the present disclosure generally had a Dmax of 50% or more against SU-DHL-2 and OCI-LY3 cells, and reached a maximum of about 90%.

[0319] The results confirmed that the compounds of the examples of the present disclosure exhibited excellent degradation activity against the IRAK4 target in SU-DHL-2 and OCI-LY3 cells. [Table 2] JPEG2026508341000155.jpg197169

[0320] Test Example 2: Degradation of IRAK4 by compounds in human PBMCs (1) Experimental Purpose Flow cytometry was used to measure the effect of compounds on the level of IRAK4 degradation in monocytes in human peripheral blood mononuclear cells (hPBMC).

[0321] (2) Experimental materials Fix Buffer I, BD Phosflow TM , 557870 Perm III buffer, BD Phosflow TM , 558050 LIVE / DEAD TM Fixable Blue Dead Cell Stain Kit for UV Excitation, Thermo Fisher, L34962 PE mouse anti-human CD14, BD Pharmingen TM , 555398 Alexa Fluor 647 mouse anti-human IRAK4 clone L29-525 (RUO), BD Phosflow TM , 560315

[0322] (3) Experimental equipment Flow cytometer, BD, Model: BD LSRFortessa

[0323] (4) Experimental method Cryopreserved hPBMCs were thawed and then cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% Pen+Strep, and allowed to recover at 37°C for 1 hour.

[0324] On day 1, cells were plated at 2 x 10 in a 96-well plate. 5 100 μL of each was seeded at a density of 10 cells / well.

[0325] Compounds were dissolved in DMSO to a final concentration of 10 mM, diluted 1:5 with medium to 10 concentrations, and added to cells to a maximum final concentration of 2 μM. Cell wells containing 0.1% DMSO served as a positive control.

[0326] The cells were cultured for 24 hours in an incubator at 37°C and 5% CO2.

[0327] After centrifugation, the cells were washed with FACS buffer.

[0328] LIVE / DEAD TM Live / dead staining of cells was performed using Fixable Blue Dead Cell Stain Kit, and surface staining marking of monocytes was performed using PE mouse anti-human CD14 and incubated at 4°C for 30 min.

[0329] After centrifugation, the cells were washed with FACS buffer.

[0330] Fix buffer I was added in an amount equal to the amount of cells, and the cells were fixed at 37°C for 10 minutes.

[0331] After centrifugation, the cells were washed with FACS buffer.

[0332] 150 μl of Perm III reagent was added, and the mixture was incubated at 4° C. for 30 minutes to disrupt the cell membrane.

[0333] After centrifugation, the cells were washed with FACS buffer.

[0334] Cells were stained using Alexa Fluor 647 mouse anti-human IRAK4 antibody and incubated at 4°C for 1 hour.

[0335] Flow cytometric analysis was performed using a flow cytometer.

[0336] 5. How we process your data Flow cytometry data were analyzed using Flowjo software. Data presentation and DC 50Prism 8.0.2 (GraphPad) was used for the calculation.

[0337] (6) Experimental results See Table 2 for the results of IRAK4 degradation activity of the compounds of the examples of the present disclosure.

[0338] The results confirmed that the compounds of the examples of the present disclosure exhibited excellent degradation activity against the IRAK4 target in human PBMC cells. [Table 3]

[0339] Test Example 3: Inhibition of compounds on the secretion of inflammatory factors induced by human PBMCs (1) Experimental Purpose Based on the CBA method (microsample multi-indicator flow cytometry protein quantification technique), the purpose of this study is to detect the effects of PROTAC small molecules on TLR and IL-1-induced IRAK4 downstream PBMC cell inflammatory factors.

[0340] (2) Experimental materials [Table 4]

[0341] (3) Experimental equipment Flow cytometer, BD, Model: BD LSRFortessa

[0342] (4) Experimental method Step 1: Resuscitation of human PBMCs

[0343] Step 2: The PBMC cell density was adjusted to 1 E6 / mL, and the PBMCs were seeded into a 96-well plate in 150 μL of 1640 complete medium and incubated at 37°C for 1 hour.

[0344] Step 3: 50 μL of serially diluted small molecule (working concentration: 10000 nM, diluted 1:3) drugs were inoculated onto the plates in a 37°C incubator for 8 hours.

[0345] Step 4: Add 10 μL of each stimulant to achieve a final concentration of 100 ng / mL for LPS, 1 μg / mL for R848, and 100 ng / mL for IL-1β.

[0346] Step 5: CBA detection. Hu IL-6 CBA Flex Set A7 and Hu TNF-α CBA Flex Set D9 were used to measure IL-6 and TNF-α concentrations in cell culture supernatants.

[0347] Step 6: Standards were set up: 2500 pg / mL, 1250 pg / mL, … 0.10 diluted in a 1:2 gradient.

[0348] Step 7: The mixed capture beads were resuspended in capture bead diluent (1:50), and cell culture supernatant (50 μL) was added and incubated at room temperature for 10 minutes.

[0349] Step 8: Add the detection reagent prepared with the detection diluent and incubate for 3 hours at room temperature, away from light. At the end of incubation, wash once with washing buffer, resuspend and detect.

[0350] (5) Data processing The concentrations of IL-6 and TNFα were calculated using the standard curve method. Data presentation and IC 50 Prism 8.0.2 was used for the calculations.

[0351] (6) Experimental results See Tables 3 and 4 for the results of inhibition of the secretion of inflammatory factors induced by human PBMCs by compounds according to the examples of the present disclosure.

[0352] The compounds of the examples of the present disclosure have been shown to effectively inhibit the secretion of inflammatory factors and have potential value in the treatment of inflammatory diseases. [Table 5] [Table 6] [Table 7] [Table 8]

[0353] Test Example 4: Compound Inhibition of the hERG Potassium Channel (1) Experimental Purpose The effects of compounds on hERG potassium channel (human Ether-a-go-go Relatedgene potassium channel) currents were measured using the electrophysiological whole-cell manual voltage clamp technique.

[0354] (2) Experimental materials Sodium chloride (NaCl) Sigma S7653, Potassium chloride (KCl) Sigma P9333, Magnesium chloride (MgCl2) Sigma M1028 Calcium chloride (CaCl2) Sigma 21115, glucose (Glucose) Sigmag7528, HEPES Sigma H3375, EGTA Sigma E3889, sodium hydroxide (NaOH) Sinopharm 10019718, potassium hydroxide (KOH) Sinopharm 10017018, CHO-hERG cell line (Chinese Hamster Ovary): Chinese hamster ovary cells stably expressing hERG channels Preparation of extracellular solution (mM): 140 NaCl, 5 KCl, 1 CaCl2, 1.25 MgCl2, 10 HEPES and 10 Glucose, pH adjusted to 7.4 with NaOH.

[0355] Preparation of intracellular solution (mM): 140 KCl, 1 MgCl2, 1 CaCl2, 10 EGTA and 10 HEPES, pH adjusted to 7.2 with KOH.

[0356] (3) Experimental equipment Patch clamp amplifier (Multiclamp 700B, Axon, USA) Digital-to-analog converter (DigiData 1440A, Axon, USA) Inverted microscope (IX71, Olympus, Japan) Rapid administration system (RSC-200, Bio-Logic, France) Micromanipulator (MX7600R, Syskiyou, USA) Electrode tensioning machine (P-97, Sutter, USA) Glass electrode (BF150-86-10, Sutter, USA) Vibration isolation table and shielding net (63-534, TMC, USA) Data collection and analysis software (pClamp, Axon, USA) Carbon dioxide incubator (HERAcell 150i, Thermo, USA) Biocabinet (MODEL 1384, Thermo, USA) Water purifier (Milli Q, Millipore, USA)

[0357] (4) Experimental method (4.1) Cell culture and treatment CHO cells stably expressing hERG were cultured in 35 mm cell dishes and placed in a 37°C, 5% CO2 incubator. They were subcultured at a 1:5 ratio every 48 hours in a medium formulation 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 medium was aspirated, washed once with extracellular solution, and then 0.25% Trypsin-EDTA (Invitrogen) solution was added and digested for 3–5 minutes at room temperature. The digestion solution was aspirated, resuspended in extracellular solution, and the cells were transferred to a dish for electrophysiological recording.

[0358] (4.2) Preparation of compounds On the day of the test, the compounds were prepared in DMSO to a 10 mM stock solution, then further diluted to 1 mM with DMSO, and then diluted 1000-fold with extracellular solution to obtain the final test concentration. Preparation of the positive control compound, cisapride: 10 μL of the 150 μM cisapride DMSO stock solution was taken and added to 4990 L of extracellular solution, followed by a 500-fold dilution to obtain a final test concentration of 300 nM. The DMSO content of the final test concentration did not exceed 0.2%, and DMSO at this concentration did not affect the hERG potassium channel.

[0359] (4.3) Electrophysiological recording process hERG potassium channel currents were recorded from CHO cells stably expressing the hERG potassium channel using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were prepared by stretching glass electrode blanks (BF150-86-10, Sutter) in a stretching machine. After filling the electrode with the internal solution, the tip resistance was approximately 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe and connected to a patch clamp amplifier. The clamp voltage and data recording were controlled and recorded by a computer using pClamp software, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After whole-cell recordings were obtained, the cells were clamped at -100 mV. A step voltage was applied to induce the hERG potassium current (I hERG) by applying a depolarizing voltage from -100 mV to +20 mV for 2 s, followed by a repolarization to -50 mV and a 1 s return to -100 mV. The voltage stimulation was applied every 5 s, and the hERG potassium current was confirmed to be stable (1 min) before the administration process began. Compounds were administered for at least 1 minute or up to 3 minutes at each test concentration until steady state effects were reached, and at least two cells (n≧2) were tested at each concentration.

[0360] (5) Data processing Data analysis and processing were performed using pClamp, GraphPad Prism 8 and Excel software. The inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) at different compound concentrations was calculated using the following formula:

[0361] Inhibition%=[1-(I / Io)]×100% Here, Inhibition% represents the rate of inhibition of the hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after and before drug administration, respectively.

[0362] (6) Experimental results Test Example 5: hERG potassium channel inhibition results [Table 9] Note: @1 uM indicates the concentration of the test compound.

[0363] The experimental results showed that the compounds of the examples of the present disclosure did not exhibit any obvious inhibitory activity against hERG, and that the compounds of the present disclosure have good safety.

[0364] Test Example 5: Measurement of Pharmacokinetics of Compounds in the Body Test 1: C57BL / 6 mice were used as test animals to study the pharmacokinetic behavior of plasma in mice when the compounds of the present disclosure were orally administered at a dose of 100 mg / kg.

[0365] 1. Test Protocol 1.1 Test Medications: Examples 13, 22, and 31 of the present disclosure.

[0366] 1.2 Test animals C57BL / 6, male, transferred from the laboratory animal stockpile (999M-018).

[0367] 1.3 Administration: Three male C57BL / 6 mice were fasted overnight (10-14 hours) before administration and allowed free access to water. Food was provided 4 hours after administration. The PO dose was 100 mg / kg, and the administration volume was 20 mL / kg.

[0368] 1.4 Experimental equipment The centrifuge (5810R) was purchased from Eppendorf, the pipettes were purchased from Eppendorf, and the vortexer was purchased from Scientific Industries.

[0369] 1.5 Sample Collection After administration, 0.03 mL of blood was collected from the mice via vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in an EDTA-K2 test tube, centrifuged at 2-8°C and 6800 rpm for 5 minutes, and the plasma was separated and stored at -80°C.

[0370] 1.6 Sample processing 1) 10 μL of plasma sample was precipitated by adding 200 μL of methanol, mixed, and then centrifuged at 18,000 g for 10 minutes. 2) After treatment, the supernatant solution was collected and analyzed for the concentration of the test compound by LC / MS / MS.

[0371] 1.7 Liquid phase analysis Liquid phase conditions: Shimadzu LC-30AD pump Mass spectrometry conditions: AB Sciex API 550 mass spectrometer Column: Phenomenex Kinetex 2.6 μm C18 50 3.0 mm Mobile phase: Solution A is 0.1% formic acid in water, and solution B is 0.1% formic acid in acetonitrile.

[0372] Flow rate: 0.6mL / min Elution time: gradient elution 0-1.6 min.

[0373] 2. Experimental results and analysis The main pharmacokinetic parameters were calculated using WinNonlin 8.0.

[0374] Experimental results show that the compounds of the examples of the present disclosure have excellent pharmacokinetic properties. [Table 10]

[0375] Test 2: 1.1 Test Medications: Example 52 of the present disclosure.

[0376] 1.2 Test animals C57BL / 6J, male, purchased from JH Laboratory Animal Co. Ltd. Qualification number: SCXK (SH) 2022-0009 20220009007223

[0377] 1.3 Administration: Two male C57BL / 6 mice were given food and water ad libitum. The PO dose was 100 mg / kg, and the administration volume was 10 mL / kg.

[0378] 1.4 Experimental equipment The centrifuge (5810R) was purchased from Eppendorf, the pipettes were purchased from Eppendorf, and the vortexer was purchased from Scientific Industries.

[0379] 1.5 Sample Collection After administration, 0.025 mL of blood was collected from the mice via vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, placed in EDTA-K2 test tubes, centrifuged at 2000 g for 5 minutes at 4°C, and the plasma was separated and stored at -70°C.

[0380] 1.6 Sample processing 1) 5 μL of plasma sample was precipitated by adding 100 μL of acetonitrile, mixed, and then centrifuged at 5800 rpm for 10 minutes. 2) After treatment, the supernatant solution was collected and analyzed for the concentration of the test compound by LCMS / MS.

[0381] 1.7 Liquid phase analysis LC-MS / MS instrument: LCMS / MS-45 (Triple Quad 6500+) Chromatography column: Waters BEH C18 (2.1 x 50 mm, 1.7 μm) Mobile phase: Solution A is H2O-0.025% FA-1mM NH4OAc, Solution B is MeOH-0.025% FA-1mM NH4OAc Flow rate: 0.6mL / min Elution time: Gradient elution 0-2.5 min.

[0382] 2. Experimental results and analysis The main pharmacokinetic parameters were calculated using WinNonlin 8.2, and the pharmacokinetic parameters of the drug orally administered to mice are shown in Table 7 below. The experimental results show that compound 52 of the present disclosure has good pharmacokinetic properties. [Table 11]

[0383] Test 3: 1.1 Test Medications: Examples 13, 22, 31 and 52 of the present disclosure.

[0384] 1.2 Test animals Healthy male beagles, weighing approximately 8-10 kg, 3 per group.

[0385] 1.3 Experimental Protocol: Beagles (3 animals / group) were intragastrically administered 2.5 mg / kg of the compound in a 5 mL / kg volume containing 10% DMSO, 50% PEG400, and 40% water (w / v). The animals were not fasted and had free access to water.

[0386] 0.5–0.8 mL of blood was collected from the vein at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after intragastric administration, placed in a K2EDTA test tube, and centrifuged at 4°C to separate the plasma. The compound concentration in the plasma was measured by liquid chromatography-tandem mass spectrometry.

[0387] 1.4 Experimental results: The main pharmacokinetic parameters were calculated using WinNonlin, and the pharmacokinetic parameters of the drug administered orally to 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. [Table 12]

[0388] Test Example 6: Evaluation of the effect of compounds on IL-33-induced acute inflammation in mice (1) Experimental Purpose IL-33 is a member of the IL-1 cytokine family and a ligand for IL-1 receptor-like 1 (ST2). IL-33 transgenic mice specifically express IL-33 in keratinocytes and spontaneously develop AD (atopic dermatitis)-like eczema, suggesting that the IL-33 pathway plays an important role in AD. IL-33 was intraperitoneally administered to induce an acute inflammation model in mice, and the effects of compounds on inflammation via the IL-1R signaling pathway were examined.

[0389] (2) Experimental materials and methods Experimental animals: SPF-grade male C57BL / 6J mice, 6-8 weeks old.

[0390] Preparation of compound: 10% DMSO + 50% PEG400 + 40% sterile water for injection. The compound was dissolved in DMSO, then PEG400 and sterile water for injection were added, and the solution was adjusted with 6N hydrochloric acid until it became transparent.

[0391] Preparation of IL-33 inducer: Mouse recombinant IL-33 powder was prepared as a 1 μg / μL mother solution. At the time of use, 3960 μL of PBS was added to 40 μL of the 1 μg / μL IL-33 solution, and the mixture was mixed by inversion to obtain 4 mL of IL-33 solution with a concentration of 1 μg / 100 μL. This solution was used immediately after preparation.

[0392] Compound administration and IL-33 inflammation induction: Mice were randomly divided into groups based on body weight and orally administered the compound twice daily at final doses of 15 mg / kg, 50 mg / kg, or 150 mg / kg. Four hours after the final compound administration, the mice were intraperitoneally injected with IL-33 1 μg / 100 μl PBS to induce inflammation.

[0393] End, sample collection and data: Plasma, peritoneal lavage fluid and spleen were collected and subsequent sample indicator detection was performed.

[0394] The experiment was terminated 8 hours after the final administration, and the mice were anesthetized and blood was collected from the heart. The blood samples were anticoagulated with EDTA-K2, then centrifuged at 3500 rpm for 15 minutes, and the upper layer of plasma was collected. The euthanized mice were disinfected by immersion in 75% ethanol for 3 minutes in a sterile clean bench. 2.5 mL of PBS pre-cooled at 4°C was injected intraperitoneally. The abdomen of the mice was massaged for 5 minutes, and the abdominal skin was incised with sterile scissors and sterile tweezers to expose the peritoneum. The sternum at the xiphoid process was lifted with sterile tweezers, and a 1 mm needle was inserted into the peritoneum at the xiphoid process. 2 An incision was made, a pipette was inserted into the abdominal cavity, and 2 mL of lavage fluid was aspirated and dispensed into 1.5 mL centrifuge tubes for storage at -80°C. ELISA detection was used to measure the expression levels of inflammatory factors in the mouse plasma and peritoneal lavage fluid, and LC-MS detection was used to detect the expression level of IRAK4 protein in the mouse spleen.

[0395] (3) Experimental results and analysis [Table 13]

[0396] The results in Table 9 show that at a dose of 50 mpk, Example 22 achieved plasma and spleen concentrations equivalent to those of KT-474 at 150 mpk, indicating that the dose of Example 22 was lower.

[0397] Figure 1 shows that the concentrations of inflammatory factors in the plasma and peritoneal lavage fluid of mice were dose-dependently reduced after three PO doses of Example 22. At comparable plasma drug concentrations, the anti-inflammatory effect of Example 22 was superior to that of KT474.

[0398] Figure 2 shows the biodegradation of IRAK4 in the spleen of mice after three PO doses of Example 22. At comparable drug concentrations in the spleen, Example 22 at 50 mpk showed 2-3 times greater degradation effect than KT-474 at 150 mpk.

[0399] The above description is only a preferred embodiment of the present invention, and does not limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall all be included in the scope of protection of the present application. [Brief explanation of the drawings]

[0400] [Figure 1] Test Example 6 shows the concentration levels of inflammatory factors in mouse plasma and peritoneal lavage fluid after oral administration of KT-474 and the compound of Example 22 of the present disclosure to mice at three different dose levels of 15 mg / kg, 50 mg / kg, and 150 mg / kg. [Figure 2] Test Example 6 shows the biodegradation levels of IRAK4 in the spleen of mice after oral administration of KT-474 and the compound of Example 22 of the present disclosure at three different dose levels of 15 mg / kg, 50 mg / kg, and 150 mg / kg to mice.

Claims

1. A bifunctional compound represented by general formula (I), an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (wherein Ring C is phenyl, 5- to 6-membered heteroaryl, or 9- to 10-membered fused heteroaryl; R １ is -CN, -NR １ａ R １ｂ , —OH, halogen, C １－６ Alkyl, haloC １－６ Alkyl, hydroxy C １－６ Alkyl, C １－６ Alkoxy, HaloC １－６ is selected from alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 7- to 9-membered bridged heterocyclyl, 6- to 10-membered fused heterocyclyl, 3- to 6-membered cycloalkyl-NH-, phenyl, 5- to 6-membered heteroaryl, 9- to 10-membered fused heteroaryl, wherein said heterocyclyl, bridged heterocyclyl, fused heterocyclyl, cycloalkyl, heteroaryl, fused heteroaryl is optionally substituted by one or more Rx, and said Rx is selected from -NH ２ , -NR １ａ R １ｂ , -CN, -OH, halogen, C １－６ Alkyl, haloC １－６ alkyl, R １ａ , R １ｂ are each independently H, C １－６ Alkyl, haloC １－６ Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C １－６ Alkyl-, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-C １－６ alkyl-, m is selected from 0, 1, 2, 3, and 4; Ring B is selected from 5- to 6-membered heteroaryl, 9- to 10-membered fused heteroaryl; R ２ is H, halogen, C １－６ Alkyl, haloC １－６ Alkyl, hydroxy C １－６ Alkyl, C １－６ Alkoxy, HaloC １－６ alkoxy; q is selected from 0, 1, 2, 3, and 4; Lx is —C(O)—NR Ｌａ - and R Ｌａ is H, C １－６ Alkyl, haloC １－６ alkyl, 3- to 6-membered cycloalkyl; Ring A is a divalent group optionally substituted by one or more Rz selected from the group consisting of 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridged cycloalkylene, and 7- to 9-membered bridged heterocyclylene, wherein Rz is selected from halogen, —OH, —NH ２ , C １－６ Alkyl, haloC １－６ Alkyl, C １－６ Alkoxy, HaloC １－６ selected from alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl; L is -(B １ ) n １ - (B ２ ) n ２ - (B ３ ) n ３ - and B １ is C １－６ an alkylene chain, any methylene unit of which is optionally —O—, —C(O)—, —C(R ａ ) (R ｂ ) -, -N(R ｃ ) -, -S-, n １ is selected from 0 and 1, B ２ is a divalent ring optionally substituted by one or more Ry: ３－６ Cycloalkylene, C ５－８ R is selected from the group consisting of bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene, and 6- to 8-membered heterocycloalkenylene, and R is selected from the group consisting of oxo, halogen, C １－６ Alkyl, haloC １－６ alkyl, n ２ is selected from 0 and 1, B ３ is saturated or unsaturated C １－６ alkylene chains, any methylene unit of which is optionally selected from —O—, —C(O)—, —C(R ａ ) (R ｂ ) -, -N(R ｃ ) -, -S-, n ３ is selected from 0 and 1, R ａ , R ｂ are each independently H, deuterium, halogen, or C １－６ Alkyl, haloC １－６ alkyl, and R ａ , R ｂ At the same time, it is not H, Alternatively, R on the same carbon atom ａ , R ｂ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl, a 3- to 6-membered heterocyclyl, R ｃ is H, C １－６ alkyl, A degradant is a ligand that binds to the E3 enzyme.

2. The bifunctional compound according to claim 1, its isomer, its deuterated derivative or its pharmaceutically acceptable salt, characterized in that the bifunctional compound is represented by the following formula (IA): 【Chemistry 2】 (However, R １ is -CN, halogen, C １－４ Alkyl, haloC １－４ Alkyl, C １－４ alkoxy, 5- to 6-membered heterocyclyl, 7- to 9-membered bridged heterocyclyl, 6- to 10-membered fused heterocyclyl, 3- to 6-membered cycloalkyl-NH-, wherein said heterocyclyl, bridged heterocyclyl, fused heterocyclyl, cycloalkyl is optionally substituted by one or more Rx, and said Rx is -NH ２ , —OH, halogen, C １－４ Alkyl, haloC １－４ alkyl, m is selected from 0, 1, 2, 3, and 4; R ２ is C １－４ Alkyl, haloC １－４ alkyl, Ring A is selected from the following divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridged cycloalkylene, 7- to 9-membered bridged heterocyclylene; L is -(B １ ) n １ - (B ２ ) n ２ - (B ３ ) n ３ - is selected from, B １ is C １－３ alkylene chains, any methylene unit of which may optionally be —O—, —C(O)—, —C(R ａ ) (R ｂ ) -, -N(R ｃ ) -, -S-, n １ is selected from 0 and 1, B ２ is a divalent ring optionally substituted by one or more Ry: ３－６ Cycloalkylene, C ５－８ R is selected from the group consisting of bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene, and 6- to 8-membered heterocycloalkenylene, and R is selected from the group consisting of oxo, halogen, C １－４ Alkyl, haloC １－４ alkyl, n ２ is selected from 0 and 1, B ３ is saturated or unsaturated C １－６ alkylene chains, wherein any methylene unit thereof is optionally —O—, —C(O)—, —C(R ａ ) (R ｂ ) -, -N(R ｃ ) -, -S-, n ３ is selected from 0 and 1, R ａ , R ｂ are each independently H, deuterium, halogen, or C １－４ Alkyl, haloC １－４ alkyl, and R ａ , R ｂ At the same time, it is not H, Alternatively, R on the same carbon atom ａ , R ｂ together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl; R ｃ is H, C １－４ alkyl.)

3. (1) The heteroatoms in the heterocyclyl, bridged heterocyclyl, fused heterocyclyl, heteroaryl, fused heteroaryl, and spiroheterocyclyl 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 is -CN, halogen, C １－６ Alkyl, haloC １－６ Alkyl, C １－６ the condition selected from alkoxy, 3- to 6-membered heterocyclyl, 7- to 9-membered bridged heterocyclyl, 6- to 10-membered fused heterocyclyl, 3- to 6-membered cycloalkyl-NH—; (3) Rx is —NH ２ or C １－６ alkyl, (4) m is selected from 1 or 2, preferably 1; (5) Ring B is a 5- to 6-membered heteroaryl; (6) R ２ is C １－６ Alkyl or haloC １－６ alkyl, preferably haloC １－６ The condition that it is alkyl, (7) q is 1; (8) Lx is —C(O)—NR Ｌａ -*, where the * end is connected to ring B; (9) In L, -(B ３ ) n ３ - the condition that the terminus is linked to a decomposer, (10) The provision that ring A is selected from the following unsubstituted divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridged cycloalkylene, and 7- to 9-membered bridged heterocyclylene; 3. The bifunctional compound according to claim 1, its isomer, its deuterated derivative or its pharmaceutically acceptable salt, characterized in that it satisfies one or more of the following conditions:

4. R １ The bifunctional compound, its isomer, its deuterated derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein is selected from 7- to 9-membered bridged heterocyclyl.

5. R １ は、-F、-CH ３ 、-CN、-CHF ２ 、-CF ３ ,-OCH ３ 、 【Transformation 3】 is selected from, preferably 【Chemistry 4】 and The bifunctional compound, its isomer, its deuterated derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 3, wherein m is selected from 1 or 2.

6. R ２ is -CH ３ , -CH ２ F, -CHF ２ , -CF ３ is selected from, preferably —CHF ２ 6. The bifunctional compound according to claim 1, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, wherein:

7. The bifunctional compound, its isomer, its deuterated derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 6, wherein ring A is selected from 7- to 9-membered nitrogen-containing spiroheterocyclylenes.

8. Ring A is 【Transformation 5】 wherein the "a" end represents the end that connects to L in general formula (IA); Preferably, ring A is 【Transformation 6】 The bifunctional compound according to any one of claims 1 to 6, an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following:

9. L is -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 - the end is linked to a decomposer, Alternatively, L is -B ３ The bifunctional compound according to any one of claims 1 to 8, its isomer, its deuterated derivative or its pharmaceutically acceptable salt, characterized in that it is selected from the following:

10. (1) B １ is C １－３ alkylene chains, one to two of which methylene units are optionally selected from -O-, -C(O)-, -C(R ａ ) (R ｂ ) -, -N(R ｃ )-, preferably one methylene unit is optionally replaced by -C(O)-, (2) B ３ is unsaturated C ２－６ alkylene chains, wherein one to two methylene units are optionally —O—, —C(O)—, —C(R ａ ) (R ｂ )-, said alkylene chain being connected to a decomposer via an alkynyl terminus, preferably one methylene unit being optionally replaced by -O-, (3) R ａ , R ｂ are each independently H, deuterium, or —CH ３ and R ａ , R ｂ is not H at the same time, or R on the same carbon atom ａ , R ｂ conditions under which cyclopropyl and cyclobutyl groups form together with the carbon atom to which they are attached, (4) R ｃ is H, -CH ３ and preferably H, (5) B ２ is the following group: 【Transformation 7】 is selected from, preferably 【Transformation 8】 and preferably B ２ is the following group: 【Chemistry 9】 wherein the B terminus is selected from -(B ３ ) n ３ -, preferably linked to 【Chemistry 10】 the condition that The bifunctional compound, its isomer, its deuterated derivative, or its pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that it satisfies one or more of the following conditions:

11. B １ is C １－３ alkylene chains, one to two of which methylene units are optionally selected from -O-, -C(O)-, -C(R ａ ) (R ｂ ) -, -N(R ｃ )-substituted by B ３ is unsaturated C ２－６ alkylene chains, wherein one to two methylene units are optionally —O—, —C(O)—, —C(R ａ ) (R ｂ )-, and the alkylene chain is connected to a decomposer via an alkynyl terminus, R ａ , R ｂ are each independently H, deuterium, or —CH ３ and R ａ , R ｂ is not H at the same time, or R on the same carbon atom ａ , R ｂ together with the carbon atom to which they are attached form cyclopropyl, cyclobutyl, R ｃ is H, -CH ３ is selected from B ２ is the following group: 【Chemistry 11】 The bifunctional compound according to any one of claims 1 to 10, an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following:

12. B ３ is C ２－６ An alkynylene chain, wherein one to two methylene units are optionally replaced by -O-, -C(O)-, and the alkynylene chain is connected to a decomposer via the alkynyl terminus, preferably B ３ is a C having one triple bond only at the terminal ２－６ Alkynylene chains, more preferably B ３ is a C having one triple bond only at the terminal ２－４ The bifunctional compound according to any one of claims 1 to 11, an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, characterized in that the alkynylene chain is selected from the group consisting of alkynylene chains.

13. B １ is -CH ２ -, -CD ２ -, -C(O)-, B ２ is the following bivalent ring: C ５－６ Cycloalkylene, C ６－８ selected from bridged cycloalkylene, 6-membered heterocyclylene, and 6- to 8-membered bridged heterocyclylene; B ３ teeth, 【Chemistry 12】 The bifunctional compound according to any one of claims 1 to 12, an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following:

14. L is, 【Chemistry 13】 【change】 is selected from Preferably, L is 【Chemistry 14】 is selected from More preferably, the alkynyl terminus of L is linked to a decomposer, a bifunctional compound, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13.

15. (1) Each 9- to 10-membered fused heteroaryl is pyrazolopyrimidinyl, for example: 【Chemistry 15】 the condition that (2) each halogen is fluorine, chlorine, bromine, or iodine, e.g., fluorine; (3) Each C １－６ Alkyl is C １－４ alkyl, e.g., methyl; (4) Each C １－６ Alkoxy is C １－４ the condition that it is alkoxy, for example, methoxy; (5) The heteroatoms in each 3- to 6-membered heterocyclyl are each independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is each independently 1 or 2, for example: 【Chemistry 16】 the condition that (6) The heteroatoms in each 7- to 9-membered bridged heterocyclyl are each independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is each independently 1 or 2, for example: 【Chemistry 17】 the condition that (7) The heteroatoms in each 6- to 10-membered fused heterocyclyl are each independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is each independently 1 or 2, for example: [Chemistry 18] the condition that (8) each 3- to 6-membered cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, for example, cyclohexyl; (9) Each 5- to 6-membered heteroaryl is pyrazolyl, for example: 【Chemistry 19】 the condition that (10) Each 7- to 11-membered spirocycloalkylene is 【Chemistry 20】 the condition that (11) Each 7- to 11-membered spiroheterocyclylene is 【Chemistry 21】 the condition that (12) Each 7- to 9-membered bridged cycloalkylene is 【Chemistry 22】 the condition that (13) Each 7- to 9-membered bridged heterocyclylene is 【Chemistry 23】 the condition that (14) Each C １－６ The alkylene chain is C １－４ the condition that it is an alkylene chain, for example, methylene or ethylene; (15) Each C ３－６ Cycloalkylene is 【Chemistry 24】 the condition that (16) Each C ５－８ The bridged cycloalkylene is 【Chemistry 25】 the condition that (17) Each 4- to 6-membered heterocyclylene is 【Chemistry 26】 the condition that (18) Each 6- to 8-membered bridged heterocyclylene is 【Chemistry 27】 the condition that (19) Each 6- to 8-membered heterocycloalkenylene is 【Chemistry 28】 the condition that (20) Each saturated or unsaturated C １－６ The alkylene chain is an unsaturated C ３－６ an alkynylene chain, preferably 【Chemistry 29】 the condition that The bifunctional compound, its isomer, its deuterated product, or its pharmaceutically acceptable salt according to any one of claims 1 to 14, characterized in that it satisfies one or more of the following conditions:

16. The bifunctional compound according to any one of claims 1 to 15, characterized in that the bifunctional compound has a structure represented by the following general formula: 【Transformation 30】 (Rings A and L are as defined in any one of claims 1 to 15.)

17. The bifunctional compound, its isomer, its deuterated derivative, or its pharmaceutically acceptable salt. 【Chemistry 31】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

18. A bifunctional compound represented by the following formula (IB), an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 32】 (wherein rings A and L are as defined in any one of claims 1 to 15, Ring B is selected from 8-10 membered fused heteroaryls; L １ is -N(R ｄ )-C(O)- or -C(O)-N(R ｄ ) - is selected from R ｄ is H, C １－４ alkyl, R ３ is C １－４ Alkyl, C １－４ Alkoxy, HaloC １－４ alkyl, p is selected from 0, 1, 2, and 3; R ４ is C １－４ Alkyl, haloC １－４ alkyl, 7- to 9-membered bridged heterocyclyl; q is selected from 0, 1, 2, 3, and 4; LBM is, 【Transformation 33】 is selected from

19. Ring B is 【Transformation 34】 19. The bifunctional compound according to claim 18, its isomer, its deuterated derivative or its pharmaceutically acceptable salt, characterized in that it is selected from:

20. R ３ is -CH ３ , -CH ２ CH ３ , -OCH ３ , -OCH ２ CH ３ and p is selected from 0, 1, and 2. The bifunctional compound, its isomer, its deuterated derivative, or its pharmaceutically acceptable salt according to claim 18 or 19,

21. The bifunctional compound according to any one of claims 18 to 20, characterized in that it has the structure represented by the following formula: 【Chemistry 35】 (wherein rings A and L are as defined in any one of claims 1 to 15.)

22. The bifunctional compound according to any one of claims 18 to 21, characterized in that it has the structure represented by the following formula: 【Transformation 36】

23. A pharmaceutical composition comprising the bifunctional compound of any one of claims 1 to 22, its isomer, its deuterated derivative or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, Preferably, the content of the compound, its isomer, its deuterated derivative, or its pharmaceutically acceptable salt in the pharmaceutical composition is 1% to 95%; Preferably, in said pharmaceutical composition, said pharmaceutically acceptable excipients comprise one or more of a filler, a disintegrant, an adhesive, a glidant, a lubricant.

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

25. A compound represented by formula (Z), an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof: 【Chemistry 37】 (wherein ring A is as defined in any one of claims 1 to 15).

26. A compound represented by formula (X), an isomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof: 【Transformation 38】 (However, L is B １－１ -B ２ -B ３－１ - and B １－１ is a C substituted with hydroxy, amino, carboxyl, or hydroxy １－３ is alkyl, B ３－１ is C １－３ an alkylene chain, any methylene unit of which is optionally —O—, —C(O)—, —C(R ａ ) (R ｂ ) -, -N(R ｃ ) -, -S-, R ａ , R ｂ are each independently H, deuterium, halogen, or C １－６ Alkyl, haloC １－６ alkyl, and R ａ , R ｂ But at the same time, it's not H, B ２ is as defined in any one of claims 1 to 15.

27. A compound represented by the following formula, an isomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 39】 【change】

28. Use of a compound described in claim 25 or claim 26, its isomer, its deuterated derivative or a pharmaceutically acceptable salt thereof in the manufacture of an IRAK4 decomposing agent, wherein preferably the IRAK4 decomposing agent is a bifunctional compound described in claim 1, its isomer, its deuterated derivative or a pharmaceutically acceptable salt thereof.

29. Use of the compound according to claim 27, its isomer, its deuterated derivative or its pharmaceutically acceptable salt in the manufacture of an IRAK4 decomposing agent.

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