IRAK4 DEGRADER AND ITS USE

Description

1 / 161 IRAK4 DEGRADER AND ITS USE

[0001] This application claims priority to Chinese patent application 2023102043068 filed on March 3, 2023, Chinese patent application 2023105328859 filed on May 11, 2023, Chinese patent application 2023107154349 filed on June 15, 2023, Chinese patent application 2023110041666 filed on August 9, 2023, and Chinese patent application 2024101967699 filed on February 22, 2024. The contents of the above Chinese patent applications are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] This disclosure pertains to the field of medicine and relates specifically to a compound that binds to interleukin-1 receptor-associated kinase 4 (IRAK4), an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, a method of preparation thereof and a medical use thereof. BACKGROUND

[0003] Proteolysis-targeted chimeric technology (abbreviated as PROTACs) is an emerging drug development technology in recent years. Unlike the principle of traditional small molecules that inhibit protein function, PROTACs work by delivering these proteins to the proteasome for complete degradation, which breaks the definition of traditional drugs. Compared to traditional small molecule inhibitor drugs, it offers multiple advantages, such as transforming undrugable targets into drugable ones, not depending on a targeting mechanism for occupancy, and addressing drug resistance issues.

[0004] PROTAC is a bifunctional conjugated molecule comprising three parts: one end is a linker structure directed to the target protein (TBM, a small molecule inhibitor or common functional group capable of recognizing the target protein); the other end is a linker structure capable of recruiting a protein degradation system, such as an E3 ligase; and the middle is a linker that connects these two linkers. The molecule Petition 870250078555, dated 03 / 09 / 2025, page 14 / 1278 2 / 161 PROTAC recruits the target protein (TBM) to the E3 ligase by binding to the target protein, allowing the E3 ligase to ubiquitinate the target protein (the E2 enzyme bound to the E3 ligase places the TBM close enough for polyubiquitination). The ubiquitinated target protein can be degraded via the proteasomal pathway. There are over 600 types of E3 ligases in the human body, but so far only about 10 types have been developed for use in protein degraders (CRBN, BVS, IAP, MDM2, DCAF15, DCAF16, RNF114, etc.), with CRBN and BVS being the most widely used. These two E3 ligases exhibit the highest functional domains and allow for flexible and efficient degradation of a wide range of target proteins, with relatively broad expression ranges to achieve high levels of systemic degradation.

[0005] Interleukin-1 receptor-associated kinase 4 (IRAK-4), as a member of the intracellular serine-threonine kinase IRAK family, mediates inflammatory signaling pathways mediated by the activation of Toll-like receptors (TLRs) and IL-1 receptors (IL-1Rs) and plays a key bridging role in innate immune signaling pathways. IRAK4 can be activated by being recruited by MyD88 to form the Myddosome, thus activating downstream IRAK1 / 2, leading to its subsequent hyperphosphorylation, dissociation from the complex, and binding to TRAF6. The activated TRAF6 complex triggers downstream signaling pathways to generate pro-inflammatory factors (NF-κB, CREB, AP-1, IRF, etc.). Inhibition of IRAK4 may play an important role in the initiation and progression of inflammatory diseases. Currently, no inhibitor targeting IRAK4 has been approved. Therefore, eliminating IRAK4 using PROTAC technology may be another strategy for treating IRAK4-related diseases.

[0006] The KT-474 developed by Kymera is a potent, highly selective, and orally bioavailable IRAK4 degrader that functions primarily as a heterobifunctional molecule targeting IRAK4 binding to IRAK4 and recruiting E3 ubiquitin ligase to label IRAK4, thus utilizing the proteasome degradation system to degrade IRAK4. KT-474 is primarily used for the treatment of IL1R / TLR-driven diseases, including atopic dermatitis (HS) and hidradenitis suppurativa (AD), as well as rheumatoid arthritis (RA) and other inflammatory diseases. In preclinical studies, KT-474 exhibits potent anti-inflammatory activity. Results from healthy patients in the clinical trial of Petition 870250078555, dated 03 / 09 / 2025, page 15 / 1278 3 / 161 Phase I studies demonstrated that a single dose of KT-474 reduced IRAK4 levels and several pro-inflammatory cytokines in a dose-dependent manner, with good safety and tolerability.

[0007] Although there are IRAK4 degraders under development for the treatment of inflammatory diseases, there is still great uncertainty before the products reach the market. Clinically, there is still a lack of drugs with structural diversity, therapeutic differentiation, and good safety. Therefore, the continued development of new IRAK4 degraders to expand the range of clinical samples and improve patient accessibility remains of significant clinical importance.

[0008] SUMMARY

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

[0010] The bifunctional IRAK4-targeted compound described in this disclosure, i.e., an IRAK4 degrader, is a tripartite compound comprising a target structure, a ligand and a degron, as shown in formula (X), Binder Target structure Degron

[0011] wherein the target structure can specifically bind to a target protein, such as an IRAK protein, and is linked to the ligand in the tripartite compound via a covalent bond; the ligand is a linking group between the target structure and the degron, with one end covalently linked to the target structure and the other end covalently linked to the degron; the degron can bind to a ubiquitin ligase, such as an E3 ubiquitin ligase, and is covalently linked to the ligand.

[0012] Specifically, in a first aspect, the present disclosure provides a bifunctional compound represented by the following general formula (I), an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof, Petition 870250078555, dated 03 / 09 / 2025, p. 16 / 1278 4 / 161 Target structure Formula (I)

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

[0014] R1 is selected from the group consisting of -CN, -NRlaRlb, -OH, halogen, C1-6 alkyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 7- to 9-membered bridging 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 heterocyclyl, bridging heterocyclyl, fused heterocyclyl, cycloalkyl, heteroaryl and fused heteroaryl are optionally replaced by one or more Rx, and Rx is selected from the group consisting of -NH2, -NRlaRlb, -CN, -OH, halogen, C1-6 alkyl and halo-Ci-6 alkyl;

[0015] RlaeRlbsão, each independently selected from the group consisting of H, C1-6 alkyl, halo-C1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C1-6 alkyl-, 3- to 6-membered heterocyclyl and 3- to 6-membered heterocyclyl-C1-6 alkyl-;

[0016] m is selected from the group consisting of 0, 1, 2, 3 and 4;

[0017] ring B is selected from the group consisting of 5- to 6-membered heteroaryl and 9- to 10-membered fused heteroaryl;

[0018] R2 is selected from the group consisting of H, halogen, C1-6 alkyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy and halo-C1-6 alkoxy;

[0019] q is selected from the group consisting of 0, 1, 2, 3 and 4;

[0020] Lx is-C(O)-NRLa-;

[0021] RLa is selected from the group consisting of H, C1-6 alkyl, halo-C1-6 alkyl and cycloalkyl of 3 to 6 members;

[0022] ring A is selected from the group consisting of divalent groups optionally substituted by one or more Rz: 7- to 11-membered spirocycloalkylene, spiroheterocyclylene Petition 870250078555, dated 03 / 09 / 2025, p. 17 / 1278 5 / 161 of 7 to 11 members, 7 to 9 member bridged cycloalkylene and 7 to 9 member bridged heterocyclylene, wherein Rz is selected from the group consisting of halogen, -OH, -NH2, C1-6 alkyl, halo-C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, 3 to 6 member cycloalkyl and 3 to 6 member heterocyclylene.

[0023] L is -(B1)ni-(B2)n2-(B3)n3-;

[0024] B1 is a C1-6 alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, -N(Rc)- or -S-; ni is selected from the group consisting of 0 and 1;

[0025] B2 is selected from the group consisting of the following divalent rings optionally substituted by one or more Ry: C3-6 cycloalkylene, C5-8 bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene and 6- to 8-membered heterocycloalkenylene, wherein Ry is selected from the group consisting of oxo, halogen, C1-6 alkyl and halo-C1-6 alkyl; n2 is selected from the group consisting of O and I;

[0026] B3 is a saturated or unsaturated C1-6 hydrocarbylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, -N(Rc)- or -S-; n3 is selected from the group consisting of 0 and 1;

[0027] Rae Rbsão, each independently selected from the group consisting of H, deuterium, halogen, C1-6 alkyl and halo-C1-6 alkyl, and Rae Rbnão are not simultaneously H;

[0028] Alternatively, Rae Rbno, the same carbon atom, together with the carbon atom to which they are attached, form a 3- to 6-membered cycloalkyl ring or a 3- to 6-membered heterocyclyl ring;

[0029] Rcé selected from the group consisting of H and C1-6 alkyl;

[0030] degron is a ligand that binds to an E3 enzyme.

[0031] In another preferred embodiment, the bifunctional compound, an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof has a structure represented by the following formula (IA), Petition 870250078555, dated 03 / 09 / 2025, p. 18 / 1278 6 / 161 Target structure Formula (IA)

[0032] wherein R1 is selected from the group consisting of -CN, halogen, C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, 5- to 6-membered heterocyclyl, 7- to 9-membered bridging heterocyclyl, 6- to 10-membered fused heterocyclyl and 3- to 6-membered cycloalkyl-NH-, wherein the heterocyclyl, bridging heterocyclyl, fused heterocyclyl and cycloalkyl are optionally replaced by one or more Rx, and Rx is selected from the group consisting of -NEh, -OH, halogen, C1-4 alkyl and halo-C1-4 alkyl;

[0033] m is selected from the group consisting of 0, 1, 2, 3 and 4;

[0034] R2 is selected from the group consisting of C1-4 alkyl and halo-C1-4 alkyl;

[0035] ring A is selected from the group consisting of the following divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridging cycloalkylene and 7- to 9-membered bridging heterocyclylene;

[0036] L is -(B1)ni-(B2)n2-(B3)n3-;

[0037] B1 is a C1-3 alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, -N(RC)- or -S-; m is selected from the group consisting of 0 and 1;

[0038] B2 is selected from the group consisting of the following divalent rings optionally substituted by one or more Ry: C3-6 cycloalkylene, C5-8 bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene and 6- to 8-membered heterocycloalkenylene, wherein Ry is selected from the group consisting of oxo, halogen, C1-4 alkyl and halo-C1-4 alkyl; n2 is selected from the group consisting of O and I;

[0039] B3 is a saturated or unsaturated C1-6 hydrocarbylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, -N(RC)- or -S-; n3 is selected from the group consisting of 0 and 1; Petition 870250078555, dated 03 / 09 / 2025, p. 19 / 1278 7 / 161

[0040] Rae Rbsion, each independently selected from the group consisting of H, deuterium, halogen, C1-4 alkyl and halo-C1-4 alkyl, and Rae Rb are not simultaneously H;

[0041] Alternatively, Rae Rbno, the same carbon atom, together with the carbon atom to which they are attached, form a 3- to 6-membered cycloalkyl ring;

[0042] Rcé selected from the group consisting of H and C1-4 alkyl.

[0043] In another preferred embodiment, the bifunctional compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, Degron target structure Formula (IA)

[0044] wherein R1 is selected from the group consisting of -CN, halogen, C1-4 alkyl, haloC1-4 alkyl, C1-4 alkoxy, 5- to 6-membered heterocyclyl, 7- to 9-membered bridging heterocyclyl, 6- to 10-membered fused heterocyclyl and 3- to 6-membered cycloalkyl-NH-, wherein the heterocyclyl, bridging heterocyclyl, fused heterocyclyl and cycloalkyl are optionally replaced by one or more Rx, and Rx is selected from the group consisting of -NEh, -OH, halogen, C1-4 alkyl and halo-C1-4 alkyl;

[0045] m is selected from the group consisting of 0, 1, 2, 3 and 4;

[0046] R2 is selected from the group consisting of C1-4 alkyl and halo-C1-4 alkyl;

[0047] ring A is selected from the group consisting of the following divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridging cycloalkylene and 7- to 9-membered bridging heterocyclylene;

[0048] L is -(B1)ni-(B2)n2-(B3)n3-;

[0049] B1 is a C1-3 alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, -N(RC)- or -S-; m is selected from the group consisting of 0 and 1;

[0050] B2 is selected from the group consisting of the following optionally divalent rings Petition 870250078555, dated 03 / 09 / 2025, p. 20 / 1278 8 / 161 replaced by one or more Ry: C3-6 cycloalkylene, C1-8 bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene and 6- to 8-membered heterocycloalkenylene, wherein Ry is selected from the group consisting of oxo, halogen, C1-4 alkyl and halo-C1-4 alkyl; n2 is selected from the group consisting of O and I;

[0051] B3 is a saturated or unsaturated C1-6 hydrocarbylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, -N(RC)- or -S-; n3 is selected from the group consisting of 0 and 1;

[0052] Rae Rbsão, each independently selected from the group consisting of H, deuterium, halogen, C1-4 alkyl and halo-C1-4 alkyl, and Rae Rbnão are not simultaneously H;

[0053] Alternatively, Rae Rbno, the same carbon atom, together with the carbon atom to which they are attached, form a 3- to 6-membered cycloalkyl ring;

[0054] Rcé selected from the group consisting of H and C1-4 alkyl.

[0055] In another preferred embodiment, the bifunctional compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, Deeron target structure Formula (IA)

[0056] wherein R1 is selected from the group consisting of -CN, halogen, C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, 5- to 6-membered heterocyclyl, 7- to 9-membered bridging heterocyclyl, 6- to 10-membered fused heterocyclyl and 3- to 6-membered cycloalkyl-NH-, wherein the heterocyclyl, bridging heterocyclyl, fused heterocyclyl and cycloalkyl are optionally replaced by one or more Rx, and Rx is selected from the group consisting of -NH2, -OH, halogen, C1-4 alkyl and halo-C1-4 alkyl;

[0057] m is selected from the group consisting of 0, 1, 2, 3 and 4;

[0058] R2 is selected from the group consisting of C1-4 alkyl and halo-C1-4 alkyl; Petition 870250078555, dated 03 / 09 / 2025, p. 21 / 1278 9 / 161

[0059] ring A is selected from the group consisting of the following divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridging cycloalkylene and 7- to 9-membered bridging heterocyclylene;

[0060] L is -(B1)ni-(B2)n2-(B3)n3-;

[0061] B1 is a C1-3 alkylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, -N(Rc)- or -S-; ni is selected from the group consisting of 0 and 1;

[0062] B2 is selected from the group consisting of the following divalent rings optionally substituted by one or more Ry: C3-6 cycloalkylene, C6-8 bridged cycloalkylene, 4- to 6-membered heterocyclylene and 6- to 8-membered bridged heterocyclylene, wherein Ry is selected from the group consisting of oxo, halogen, C1-4 alkyl and halo-C1-4 alkyl; n2 is selected from the group consisting of O and I;

[0063] B3 is a saturated or unsaturated C1-6 hydrocarbylene chain, any methylene unit of which is optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, -N(Rc)- or -S-; n3 is selected from the group consisting of 0 and 1;

[0064] Rae Rbsão, each one , independently selected from the group consisting of H, halogen, C1-4 alkyl and halo-C1-4 alkyl, and Rae Rbnão are not simultaneously H;

[0065] Alternatively, Rae Rbno, the same carbon atom, together with the carbon atom to which they are attached, form a 3- to 6-membered cycloalkyl ring;

[0066] Rcé selected from the group consisting of H and C1-4 alkyl.

[0067] In another preferred embodiment, the heteroatom in the heterocyclyl, bridging heterocyclyl, fused heterocyclyl, heteroaryl, fused heteroaryl or spiro-heterocyclyl is independently selected from the group consisting of one, two or three types of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0068] In another preferred embodiment, R1 is selected from the group consisting of -CN, halogen, C1-6 alkyl, halo-C1-6 alkyl, C1-6 alkoxy, 3- to 6-membered heterocyclyl, 7- to 9-membered bridging heterocyclyl, 6- to 10-membered fused heterocyclyl and 3- to 6-membered cycloalkyl-NH-.

[0069] In another preferred embodiment, R1 is a 7- to 9-membered heterocyclic bridge.

[0070] In another preferred modality, R1 is selected from the group consisting of -F, Petition 870250078555, dated 03 / 09 / 2025, page 22 / 1278 10 / 161 CH3, -CN, -CHF2, -CF3, -OCH3, nh2. ;

[0071] m is selected from the group consisting of 1 and 2.

[0072] In another preferred embodiment, R1 is selected from the group consisting of -<2° and / .

[0073] In another preferred embodiment, Rx is selected from the group consisting of -NH2 and C1-6 alkyl.

[0074] In another preferred embodiment, m is selected from the group consisting of 1 and 2, preferably 1.

[0075] In another preferred embodiment, ring B is heteroaryl with 5 to 6 members.

[0076] In another preferred embodiment, R2 is C1-6 alkyl or halo-C1-6 alkyl, preferably halo-C1-6 alkyl.

[0077] In another preferred embodiment, R2 is selected from the group consisting of -CH3, CH2F, -CHF2 and -CF3.

[0078] In another preferred form, R2 is -CHF2.

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

[0080] In another preferred embodiment, Lx is -C(O) -NRLa-*, wherein the terminal * is connected to ring B.

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

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

[0083] In another preferred embodiment, ring A is selected from the group consisting of Petition 870250078555, dated 03 / 09 / 2025, p. 23 / 1278 11 / 161 where terminal a denotes the end connected to L in the general formula (IA).

[0084] In another preferred embodiment, the ring A isX— / .

[0085] In another preferred embodiment, in L, the terminal -(B3) n3- is connected to the degron.

[0086] In another preferred embodiment, L is selected from the group consisting of -B1-B2B3-,-B1-B3- and -B2-B3-; preferably, the terminal -B3- is connected to the degron.

[0087] In another preferred embodiment, L is-B1-B2-B3-; preferably, terminal-B3 is connected to the degron.

[0088] In another preferred embodiment, L is -B3-.

[0089] In another preferred embodiment, B1 is a C1-3 alkylene chain, in which 1 to 2 methylene units are optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, or -N(Rc)-; preferably, 1 methylene unit is optionally replaced by -C(O)-.

[0090] In another preferred embodiment, B3 is an unsaturated C2-6 hydrocarbylene chain, in which 1 to 2 methylene units are optionally replaced by -O-, -C(O)- or C(Ra)(Rb)-; the hydrocarbylene chain is connected to the degron via the alkyne terminal; preferably, 1 methylene unit is optionally replaced by -O-.

[0091] In another preferred embodiment, Rae Rbsão, each independently selected from the group consisting of H, deuterium and -CH3; and Rae Rbnão are not simultaneously H;

[0092] Alternatively, Rae Rbno same carbon atom, together with the atom of Petition 870250078555, dated 03 / 09 / 2025, p. 24 / 1278 12 / 161 carbon to which they are attached, form a cyclopropyl ring or a cyclobutyl ring.

[0093] In another preferred embodiment, R is selected from the group consisting of H and CH3; preferably H.

[0094] In another preferred embodiment, B2 is selected from the group consisting of the following groups: preferably and

[0095] In another preferred embodiment, B2 is selected from the group consisting of following groups: S1)- > ; Ç> í e νθν , ,epreferencialmente hO-i », ^^^, ou , onde o terminal b está conecta a -(B3)n3-;

[0096] In another preferred embodiment, B1 is a C1-3 alkylene chain, in which 1 to 2 methylene units are optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, or -N(Rc);

[0097] B3 is an unsaturated C2-6 hydrocarbylene chain in which 1 to 2 methylene units are optionally replaced by -O-, -C(O)- or -C(Ra)(Rb)-; the hydrocarbylene chain is Petition 870250078555, dated 03 / 09 / 2025, p. 25 / 1278 13 / 161 connected to the degron through the alkyne terminal;

[0098] RaeRbsion, each independently selected from the group consisting of H, deuterium and -CH3; and Rae Rb are not simultaneously H;

[0099] Alternatively, Rae Rbno the same carbon atom together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclobutyl ring;

[0100] Rcé selected from the group consisting of H and -CH3;

[0101] B2 is selected from the group consisting of the following groups:

[0102] In another preferred embodiment, B1 is a C1-3 alkylene chain, in which 1 to 2 methylene units are optionally replaced by -O-, -C(O)-, -C(Ra)(Rb)-, or -N(Rc);

[0103] B3 is an unsaturated C2-6 hydrocarbylene chain in which 1 to 2 methylene units are optionally replaced by -O-, -C(O)- or -C(Ra)(Rb)-; the hydrocarbylene chain is connected to the degron via the alkyne terminal;

[0104] Rae Rbsion, each independently selected from the group consisting of H and -CH3; and Rae Rb are not simultaneously H;

[0105] Alternatively, Rae Rbno the same carbon atom together with the carbon atom to which they are attached form a cyclopropyl ring or a cyclobutyl ring;

[0106] Rcé selected from the group consisting of H and -CH3;

[0107] B2 is selected from the group consisting of the following groups: Petition 870250078555, dated 03 / 09 / 2025, p. 26 / 1278 14 / 161 tClH ,,,,, where the description of group B2 does not limit the connection sequence with adjacent groups on both sides.

[0108] In another preferred embodiment, B2 is selected from the group consisting of the following O Γΐλ / =\ pV hQ-i groups: * ey.

[0109] In another preferred embodiment, B2 is selected from the group consisting of the following groups: and .

[0110] In another preferred embodiment, Rae Rbsão, each independently deuterium.

[0111] In another preferred embodiment, B3 is a C2-6 alkynylene chain, in which 1 to 2 methylene units are optionally replaced by -O- or -C(O)-; the alkynylene chain is connected to the degron via the alkyne terminal.

[0112] In another preferred embodiment, B3 is a C2-6 alkynylene chain containing only one triple bond at the terminal, wherein 1 to 2 methylene units are optionally replaced by -O- or -C(O)-; the alkynylene chain is connected to the degron via the alkyne terminal.

[0113] In another preferred embodiment, B3 is a C2-4 alkynylene chain containing only one triple bond at the terminal, wherein 1 to 2 methylene units are optionally replaced by -O- or -C(O)-; the alkynylene chain is connected to the degron via the alkyne terminal.

[0114] In another preferred embodiment, B1 is selected from the group consisting of -CH2-, -CD2- and -C(O)-;

[0115] B2 is selected from the group consisting of the following divalent rings: cycloalkylene Petition 870250078555, dated 03 / 09 / 2025, p. 27 / 1278 15 / 161 C5-6, bridged cycloalkylene; C-8, 6-membered heterocyclylene and 8-membered bridged heterocyclylene; B3 is selected from the group consisting of

[0116]

[0117] In another preferred embodiment, L is selected from the group consisting of Petition 870250078555, dated 03 / 09 / 2025, page 28 / 1278 16 / 161 Petition 870250078555, dated 03 / 09 / 2025, page 29 / 1278 17 / 161 and, preferably, the alkyne terminal of L is connected to the degron.

[0118] In another preferred embodiment, L is selected from the group consisting of Petition 870250078555, dated 03 / 09 / 2025, page 30 / 1278 18 / 161 connected to Degron. Preferably, the alkyne terminal of L is preferred, L is selected from the group consisting of

[0119] In another modality Petition 870250078555, dated 03 / 09 / 2025, p. 31 / 1278 19 / 161 O DD, and; Preferably, the alkyne terminus of L is connected to the degron. In another preferred form, L is selected from the group consisting of

[0120] , and ; preferably, the alkyne terminal L is connected to degron.

[0121] In another preferred embodiment, L is selected from the group consisting of Petition 870250078555, dated 03 / 09 / 2025, p. 32 / 1278 20 / 161 preferably, the alkyne terminal of L is connected to the degron.

[0122] In another preferred embodiment, L is selected from the group consisting of degron.

[0123] In another preferred embodiment, the bifunctional compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof has a structure represented by the following general formula: Formula (IA- 1b) or

[0124] rings A and L are as defined in any of the previous embodiments.

[0125] In another preferred embodiment, each fused heteroaryl of 9 to 10 members is pyrazolopyrimidinyl, for example,

[0126] In another preferred embodiment, each halogen is fluorine, chlorine, bromine, or iodine, for example, fluorine. Petition 870250078555, dated 03 / 09 / 2025, page 33 / 1278 21 / 161

[0127] In another preferred embodiment, each C1-6 alkyl is C1-4 alkyl, for example, methyl.

[0128] In another preferred embodiment, each C1-6 alkoxy is a C1-4 alkoxy, for example, methoxy.

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

[0130] In another preferred embodiment, the heteroatom in each 7- to 9-membered bridging heterocycle is independently selected from the group consisting of one, two, or three types of N, O, and S, and the number of heteroatoms is independently 1 or 2, for example, or

[0131] In another preferred embodiment, the heteroatom in each fused heterocyclyl of 6 to 10 members is independently selected from the group consisting of one, two, or three types of N, O, and S, and the number of heteroatoms is independently 1 or 2, for example,

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

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

[0134] In another preferred embodiment, each 7- to 11-membered spirocycloalkylene is or In another preferred embodiment, each 7- to 11-membered spiroheterocycline is , , ,

[0135] Petition 870250078555, dated 03 / 09 / 2025, p. 34 / 1278 22 / 161

[0136] In another preferred embodiment, each 7- to 9-membered bridged cycloalkylene is or

[0137] In another preferred embodiment, each 7- to 9-membered bridge heterocycline is

[0138] In another preferred embodiment, each C1-6 alkylene chain is a C1-4 alkylene chain, for example, methylene or ethylene. In another preferred embodiment, each C3-6 cycloalkylene is:

[0139] or In another preferred embodiment, each C5-8 bridged cycloalkylene is

[0140]

[0141] In another preferred embodiment, each 4- to 6-membered heterocycline is or

[0142] In another preferred embodiment, each 6- to 8-membered bridge heterocycline is either nD* or KD-1.

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

[0144] In another preferred embodiment, each saturated or unsaturated C1-6 hydrocarbylene chain is an unsaturated C3-6 alkynylene chain, for example,

[0145] Any substitute and any optional group thereof in the technical solutions described in this disclosure may be combined to form a new complete technical solution. The newly formed technical solution has the same or similar technical effects as those described in this application, and all are included within the scope of this Petition 870250078555, dated 03 / 09 / 2025, p. 35 / 1278 23 / 161 disclosure.

[0146] The technical solutions above this disclosure may be combined with each other for limitation and all newly formed solutions are included within the scope of this disclosure.

[0147] In another preferred embodiment, the bifunctional compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds: Petition 870250078555, dated 03 / 09 / 2025, p. 36 / 1278 24 / 161 Petition 870250078555, dated 03 / 09 / 2025, p. 37 / 1278 25 / 161 Petition 870250078555, dated 03 / 09 / 2025, p. 38 / 1278 26 / 161 Petition 870250078555, dated 03 / 09 / 2025, p. 39 / 1278 27 / 161 Petition 870250078555, dated 03 / 09 / 2025, p. 40 / 1278 28 / 161 Petition 870250078555, dated 03 / 09 / 2025, p. 41 / 1278 29 / 161 Petition 870250078555, dated 03 / 09 / 2025, p. 42 / 1278 30 / 161

[0148] In another preferred embodiment, the bifunctional compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following compounds:

[0149] A second aspect of the present disclosure further provides a compound represented by the following formula (IB), an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof: Petition 870250078555, dated 03 / 09 / 2025, p. 43 / 1278 31 / 161

[0150] wherein ring B is an 8- to 10-membered fused heteroaryl;

[0151] Li is selected from the group consisting of -N(Rd)-C(O)- and -C(O)-N(Rd)-;

[0152] Rdé selected from the group consisting of H and C1-4 alkyl;

[0153] R3 is selected from the group consisting of C1-4 alkyl, C1-4 alkoxy and halo-C1-4 alkyl;

[0154] p is selected from the group consisting of 0, 1, 2 and 3;

[0155] R4 is selected from the group consisting of C1-4 alkyl, halo-C1-4 alkyl and 7- to 9-membered bridged heterocyclyls;

[0156] q is selected from the group consisting of 0, 1, 2, 3 and 4; THE Λ' NH ° rt 1

[0157] LBM is selected from the group consisting of \ and THE Vnh O o

[0158] Rings A and L are as defined in any of the embodiments of the first aspect of this disclosure.

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

[0160] In another embodiment of this disclosure, R3 is selected from the group consisting of -CH3, -CH2CH3, -OCEE and -OCEECEE; p is selected from the group consisting of 0, e2.

[0161] In another embodiment of the present disclosure, the bifunctional compound, the isomer of Petition 870250078555, dated 03 / 09 / 2025, p. 44 / 1278 32 / 161, the deuterated compound thereof or the pharmaceutically acceptable salt thereof has a structure as shown below: Formula (IB-1)

[0162] where rings A and L are as defined in any of the embodiments above.

[0163] In another embodiment of the present disclosure, the compound represented by formula (IB), an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0164] A third aspect of this disclosure further provides a pharmaceutical composition comprising the compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, according to any of the embodiments in the first and second aspects of this disclosure, and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition may be in any pharmaceutically acceptable dosage form. According to this disclosure, a pharmaceutically acceptable excipient is a non-toxic substance that is compatible with the active ingredient and otherwise biologically suitable for use in an organism. Petition 870250078555, dated 03 / 09 / 2025, p. 45 / 1278 33 / 161 The selection of a particular excipient will depend on the route of administration for the treatment of a particular patient or the type and state of the disease. Examples of pharmaceutically acceptable excipients include, but are not limited to: conventional solvents, diluents, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, binders, lubricants, stabilizers, moisturizing agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavoring agents, antioxidants and the like in the pharmaceutical field. If necessary, fragrance agents, preservatives, sweeteners and the like may also be added to the pharmaceutical composition.

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

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

[0167] A fourth aspect of this disclosure further provides for the use of the compound, its isomer, its deuterated compound or its pharmaceutically acceptable salt according to any of the embodiments in the first and second aspects of this disclosure in the manufacture of a medicament to prevent and / or treat an IRAK4-mediated related disease.

[0168] In another preferred embodiment, the IRAK4-mediated related disease is selected from the group consisting of immune inflammatory diseases.

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

[0170] A fifth aspect of the present disclosure further provides a method for treating a related IRAK4-mediated disease, comprising administering a therapeutically effective amount of the compound, its isomer, its deuterated compound or its pharmaceutically acceptable salt according to any of the embodiments in Petition 870250078555, dated 03 / 09 / 2025, page 46 / 1278 34 / 161 first aspect of the present disclosure to a subject. The subject refers primarily to a human.

[0171] In another preferred embodiment, the IRAK4-mediated related disease is selected from the group consisting of immune inflammatory diseases.

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

[0173] Aspect six of the present disclosure provides a compound as shown below, an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof: Formula Z

[0174] wherein ring A is as defined in any of the preceding embodiments.

[0175] In another preferred embodiment, a compound represented by formula (Z), an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of the following structures: Petition 870250078555, dated 03 / 09 / 2025, page 47 / 1278 35 / 161

[0176] In another preferred embodiment, a compound represented by formula (Z), an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof has the following structure:

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

[0178] where L is B1-1-B2-B3-1-;

[0179] B1-1 is hydroxyl, amino, carboxyl or C1-3 alkyl substituted by hydroxy;

[0180] B3-1 is a C1-3 alkylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(Ra)(Rb)-, -N(Rc)- or -S-; Ra and Rb are each independently selected from the group consisting of H, deuterium, halogen, C1-6 alkyl and halo-C1-6 alkyl, and Ra and Rb are not simultaneously H;

[0181] B2 is as defined in the first aspect of this disclosure.

[0182] In another preferred embodiment, a compound represented by formula (X), an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt. Petition 870250078555, dated 03 / 09 / 2025, p. 48 / 1278 36 / 161 of the same is selected from the group consisting of the following structures: Petition 870250078555, dated 03 / 09 / 2025, p. 49 / 1278 37 / 161

[0183] An eighth aspect of the present disclosure provides a compound as shown below, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0184] A ninth aspect of this disclosure further comprises a use of the compound, an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof involved in the sixth or seventh aspect in the manufacture of an IRAK4 degrader; preferably, the IRAK4 degrader is as described in the first aspect of this disclosure.

[0185] A tenth aspect of the present disclosure further comprises a use of the compound, an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof involved in the eighth aspect in the manufacture of an IRAK4 degrader.

[0186] Description and definition

[0187] In this disclosure, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. However, for a better understanding of this disclosure, definitions of some terms are provided below. Where the definitions of terms provided in this disclosure are inconsistent with the meanings commonly understood by those skilled in the art, the definitions and explanations of the terms provided in Petition 870250078555, dated 03 / 09 / 2025, page 50 / 1278 38 / 161 present disclosure shall prevail.

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

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

[0190] The term pharmaceutically acceptable salt refers to a derivative prepared from the compound of the present disclosure with a relatively non-toxic acid or base. These salts may be prepared during the synthesis, separation, and purification of the compound, or the free form of the purified compound may be used alone to react with a suitable acid or base. When the compound contains a relatively acidic functional group, the compound reacts with an alkali metal, alkaline earth metal hydroxide, or organic amine to obtain an alkaline addition salt, including alkali metal and alkaline earth metal-based cations and non-toxic ammonium, quaternary ammonium, and amine cations. Amino acid salts are also covered. When the compound contains a relatively basic functional group, the compound reacts with an organic acid or an inorganic acid to obtain an acid addition salt.

[0191] The term prophylactic or therapeutically effective amount refers to a sufficient amount of the compound or pharmaceutically acceptable salt thereof of this disclosure that is sufficient to treat a disorder at a reasonable effect / risk ratio appropriate for any medical treatment and / or prophylaxis. It should be recognized that the total daily dose of the compound, or pharmaceutically acceptable salt thereof, and the composition thereof in this disclosure, should be determined by the attending physician within the scope of reliable medical judgment. For any specific patient, the specific therapeutically effective dose level depends on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of a specific compound used; Petition 870250078555, dated 03 / 09 / 2025, page 51 / 1278 39 / 161 a specific composition used; age, weight, general health status, sex and diet of the patient; time of administration, route of administration and excretion rate of the specific compound used; duration of treatment; drugs used in combination or simultaneously with the specific compounds used; and similar factors known in the medical field.

[0192] The isomers mentioned in this disclosure include geometric isomers and stereoisomers, such as atropisomers, cis-trans isomers, enantiomers, diastereomers, tautomers, and racemic mixtures thereof and other mixtures, all of which fall 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 hydrogen bonding sites through the displacement of one or more double bonds. For example, a ketone and its enol form constitute keto-enol tautomers. The term diastereomer refers to stereoisomers in which the molecules have two or more chiral centers and the relationship between the molecules is not mirror image.The term cis-trans isomer refers to different spatial configurations in which a double bond or a single bond of a ring-forming carbon atom in a molecule cannot rotate freely. The term atropisomer refers to a stereoisomer that can be isolated due to hindered or extremely slow rotation around a single bond.

[0193] Stereoisomers of the compounds in this disclosure can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, an enantiomer of a certain compound in this disclosure can be prepared by an asymmetric catalysis technique or a chiral auxiliary derivatization technique. Alternatively, compounds with a single stereo configuration can be obtained from a mixture by a chiral resolution technique. Alternatively, it can be prepared directly from chiral starting materials. The separation of optically pure compounds in this disclosure is generally carried out by preparative chromatography, and a chiral chromatographic column is used to achieve the goal of separating chiral compounds.

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

[0195] The optionally replaced term means that an atom can be replaced by Petition 870250078555, dated 03 / 09 / 2025, p. 52 / 1278 40 / 161 whether or not a substituent is present, unless otherwise specified, the type and number of substituents may be arbitrary, provided they are chemically attainable. For example, the term optionally substituted by one or more R means that an atom may or may not be substituted by one or more R. When any variable occurs in the constitution or structure of the compound more than once, the definition of the variable in each occurrence is independent. For example, if a group is substituted by 0 to 2 Ra, the group may optionally be substituted by up to two Ra, where the definition of Ra in each occurrence is independent.

[0196] When the substituent structure contains -wwv», it indicates that the atom is an atom of The symbol ·~~ indicates that the C atom in the pyrimidine ring is the linking atom. The presence of a dash (-) in a substituent structure indicates a point of attachment for the substituent, for example, -CH3 is linked through a C atom. The symbols · and ·...... denote the absolute configuration of a stereocenter, i.e., the R or S configuration. < / ',',ou'''' denota a configuração cis ou trans, onde ligações sólidas duplas ou ligações tracejadas duplas representam a configuração cis e uma ligação sólida e uma ligação tracejada representam a configuração trans.

[0197] In the present disclosure, L is -(B1)ni-(B2)n2-(B3)n3-; when ni, n2 or n3 is 0, it indicates that the corresponding group is absent and the adjacent groups on either side are directly connected by a chemical bond. Specifically, for example: when only ni is 0, L is -(B2)n2-(B3)n3-; when only n2 is 0, L is -(B1)ni-(B3)n3-; when only n3 is 0, L is -(B1)ni-(B2)n2-.

[0198] When a substituent bond can be cross-linked to two atoms in a ring, the substituent can be bonded to any atom in the ring. For example, the fraction aR indicates that the substituent R can be substituted at any position in a benzene ring.

[0199] When a listed substituent does not specify the atom through which the substituent is attached to a given group or a given structural formula, the substituent may be attached through any of its bondable atoms. Petition 870250078555, dated 03 / 09 / 2025, p. 53 / 1278 41 / 161

[0200] The term alkyl mentioned in this disclosure refers to a group derived from a branched or linear saturated aliphatic alkane with a specified number of carbon atoms by removing one hydrogen atom. For example, C1-10 alkyl refers to including C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 alkyl, including C1-6 alkyl, C1-4 alkyl, C1-3 alkyl; specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc.

[0201] The term haloalkyl mentioned in this disclosure refers to an alkyl group in which the hydrogen is replaced by one or more halogens, such as fluoromethyl including monofluoromethyl, difluoromethyl and trifluoromethyl; preferably, the haloalkyl mentioned in this disclosure is halo C1-6 alkyl or halo C1-4 alkyl. The alkyl is as defined above.

[0202] The oxo mentioned in this disclosure refers to the substitution of the group by an =O structure, such as -CH2- being oxo-substituted to form -C(O)-, or S being oxo-substituted to form S(O) or S(O)2.

[0203] The term hydrocarbylene mentioned in this disclosure refers to a group derived from a branched or linear alkane, alkene or alkyne with a specified number of carbon atoms by removing two hydrogen atoms, including alkylene, alkenylene and alkynylene, wherein the hydrocarbylene may be further substituted by other groups; wherein alkenylene and alkynylene refer to unsaturated hydrocarbon chains containing at least one double bond or triple bond, respectively, in the hydrocarbon chain. The hydrocarbylene mentioned in this disclosure includes C115 hydrocarbylene, preferably C2-10 hydrocarbylene, C4-6 alkylene, C2-10 alkylene, C5-7 alkynylene, C7-10 alkylene, C5-7 alkenylene, C1-6 hydrocarbylene, C13 alkylene, C2-6 alkynylene, etc.Preferably, the alkylene mentioned in this disclosure is preferably a linear alkylene; specific examples of the alkylene chain include, but are not limited to: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH2)CH2-, CH2CH2CH2CH2-, -CH(CH2)CH2CH2-, -CH(CH2CH2)CH2-, -C(CH2)(CH2)CH2-, CH2CH2CH2CH2CH2-, etc. Preferably, the methylene unit mentioned in this disclosure refers to -CH2-. Specific examples of alkenylene mentioned in this disclosure include, but are not limited to: -CH=CH-, -CH=CHCH2-, -CH=C(CH3)CH2. Petition 870250078555, dated 03 / 09 / 2025, page 54 / 1278 42 / 161, -CH=CHCH2CH=CH-, -CH2CH=CHCH2-, -CH2CH=CHCH2CH2-; specific examples of alkynylene mentioned in this disclosure include, but are not limited to, -C=C-, -C=C-CH2-, -C=C-CH2CH2-, -CH2-C=C-CH2CH2-, -C=C-CH2C=C-, -C=C-CH2C=CH-, etc. Furthermore, the term "any methylene unit is optionally substituted" mentioned in this disclosure, such as any methylene unit in -CH2CH2CH2 being substituted by -C(O)-, may form, but is not limited to, the following structures: C(O)CH2CH2-, -CH2C(O)CH2-, -CH2CH2C(O)-, -C(O)CH2C(O)-, etc.

[0204] The ring mentioned in this disclosure includes, but is not limited to, cycloalkane, spirocycloalkane, bridged cycloalkane, heterocycle, heterocycloalkene, spiroheterocycle, bridged heterocycle, fused heterocycle, heteroaromatic ring, fused heteroaromatic ring, etc.; the monovalent rings derived from them may be cycloalkyl, spirocycloalkyl, bridged cycloalkyl, heterocyclyl, heterocycloalkenyl, spiroheterocyclyl, bridged heterocyclyl, heteroaryl or fused heteroaryl, respectively; and the divalent ring derived from them refers to a group derived from a ring structure by removing two hydrogen atoms, where the bonding sites may connect to different groups or different positions of the same group. The derived divalent rings can be cycloalkylene, bridged cycloalkylene, spirocycloalkylene, heterocyclene, heterocycloalkenylene, spiro-heterocyclene, bridged heterocyclene, fused heterocyclene, heteroarylene, etc., respectively.

[0205] The cycloalkane mentioned in this disclosure refers to a monocyclic saturated cyclic alkane structure in which the carbon atoms in the cycloalkane may be oxo-substituted, i.e., the carbon atoms are replaced by -C(O)-. It includes C3-8 cycloalkanes, C3-6 cycloalkanes, C3-5 cycloalkanes, etc., with specific examples including, but not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane.

[0206] The spirocycloalkane mentioned in this disclosure refers to a cyclic structure formed by two or more adjacent cycloalkanes sharing a ring atom, in which the carbon atoms in the cycloalkane may be oxo-substituted, that is, the carbon atoms are replaced by -C(O)-. Includes C7-11 spirocycloalkane, C7-9 spirocycloalkane Petition 870250078555, dated 03 / 09 / 2025, p. 55 / 1278 43 / 161, etc., with specific examples including, but not limited to: 00O, OOCO, 00, and 0X20.

[0207] The bridged cycloalkane mentioned in this disclosure refers to a cyclic structure formed by two or more adjacent cycloalkanes sharing two non-adjacent ring atoms, wherein the carbon atoms in the cycloalkane may be oxo-substituted, i.e., the carbon atoms are replaced by -C(O)-. Includes C6-10 bridged cycloalkanes, C6-10 bridged cycloalkanes, etc., with specific examples including, but not limited to: ^^, ^^, ^-—^, ^-^0, etc.

[0208] The heterocycle mentioned in this disclosure refers to a cyclic structure derived from a cycloalkane in which at least one carbon atom is replaced by a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from the group consisting of O, NR, N(O), S, S(O) and S(O)2, wherein R is H or any substituent group that may exist, and the cycloalkane is as defined above. The heterocycle preferably contains 1 to 2 heteroatoms selected from the group consisting of NR and / or O, more preferably containing 1 NR and 0 to 1 NR or O heteroatom. 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 heterocycle with 3 to 8 members, a heterocycle with 3 to 6 members, a heterocycle with 4 to 6 members, a heterocycle with 5 to 6 members, a nitrogen-containing heterocycle with 4 to 6 members, and a nitrogen-containing heterocycle with 5 to 6 members.Specific examples include, but are not limited to: tetraHN-a. O= / \ hydrofuran, pyrrolidine, piperidine, morpholine, piperazine '—' , etc.

[0209] The heterocycloalkene mentioned in this disclosure refers to a heterocyclic group containing at least one ring-forming double bond in the heterocycle and lacking aromaticity. The heterocycloalkene preferably contains 1 to 2 heteroatoms selected from the group consisting of NR and / or O, more preferably containing 1 NR and 0 to 1 NR or O heteroatom. The heterocycloalkene includes 5 to 8 heterocycloalkenes. Petition 870250078555, dated 03 / 09 / 2025, page 56 / 1278 44 / 161 members and 6- to 8-membered heterocycloalkenes. Specific examples include, but are not limited to:

[0210] The spiro-heterocycle mentioned in this disclosure refers to a cyclic structure derived from a spirocycloalkane in which at least one carbon atom is replaced by a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from the group consisting of O, NR, N(O), S, S(O) and S(O)2, wherein R is H or any substituent group that may exist, and the spirocycloalkane is as defined above. Includes, but is not limited to, heterocyclic spiroheterocycles and cyclic structures formed by heterocyclic spirocycloalkanes. The spiroheterocycle preferably contains 1 to 2 heteroatoms selected from the group consisting of NR and / or O, more preferably containing 1 NR and 0 to 1 NR or O heteroatom. The spiroheterocycle is preferably a nitrogen-containing spiroheterocycle, which refers to a spiroheterocycle in which at least one ring atom is NR. The spiroheterocycle includes a 7- to 11-membered spiroheterocycle, a 7- to 9-membered spiroheterocycle, a 7- to 11-membered nitrogen-containing spiroheterocycle, and a 7- to 9-membered nitrogen-containing spiroheterocycle. Specific examples of ÔCnh hnNH HNCXNH include, but are not limited to: v'x / ' , vv ,v\— / ,HN0θ,HN0θ,ΟΌνH, etc.

[0211] The bridging heterocycle mentioned in this disclosure refers to a cyclic structure derived from a bridging cycloalkane in which at least one carbon atom is replaced by a heteroatom / heteroatom group, wherein the heteroatom / heteroatom group is selected from the group consisting of O, NR, N(O), S, S(O) and S(O)2, wherein R is H or any substituent group that may exist, and the cycloalkane is as defined above. The bridging heterocycle is preferably a nitrogen-containing bridging heterocycle, which refers to a bridging heterocycle in which at least one ring atom is NR. The bridging heterocycle includes 6- to 10-membered bridging heterocycles, 6- to 8-membered bridging heterocycles, etc., with specific examples including, but not limited to Petition 870250078555, dated 03 / 09 / 2025, p. 57 / 1278 45 / 161 limited to: etc.

[0212] The fused heterocycle mentioned in this disclosure refers to a saturated cyclic 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. It includes, but is not limited to, fused heterocycles with heterocycles and structures formed by fused cycloalkanes with heterocycles. The fused heterocycle preferably contains 1 to 2 heteroatoms selected from the group consisting of NR and / or O, more preferably containing 1 NR and 0 to 1 NR or O heteroatom. 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. COcp CQ Specific examples include, but are not limited to, N, , and N

[0213] The heteroaromatic ring mentioned in this disclosure refers to a monocyclic or polycyclic aromatic hydrocarbon in which at least one ring atom is a heteroatom and the heteroatom is selected from the group consisting of N, O, and S. When the heteroaryl contains an N atom, a nitrogen oxide thereof is also included. The polycyclic heteroaromatic ring, i.e., a fused heteroaromatic ring, includes, but is not limited to, a 5- to 6-membered benzo heteroaromatic ring and a 5- to 6-membered fused heteroaromatic ring with a 5- to 6-membered heteroaromatic ring. The heteroaromatic ring includes a 5- to 6-membered heteroaromatic ring, a 7- to 10-membered fused bicyclic heteroaromatic ring, and an 8- to 14-membered fused heteroaromatic ring. A heteroaromatic ring is preferably a nitrogen-containing heteroaromatic ring, which refers to a heteroaromatic ring in which at least one ring atom is N.Examples of heteroaromatic rings include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, pyrazine, pyridazine, triazine, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, indazole, indole, isoquinoline, quinoxaline, benzoxazole, benzofuran, benzothiophene, benzothiazole. Petition 870250078555, dated 03 / 09 / 2025, page 58 / 1278 46 / 161 N / Γ^N S q benzimidazole, quinoline, quinazoline, ,N'- / , etc.

[0214] The combinations of substituents and / or variables described in this disclosure are permitted only when such combinations produce stable compounds or usable synthetic intermediates. A stable compound or stable structure refers to a compound that is sufficiently stable to undergo chemical reactions, can be isolated in useful purity, and can be formulated into an effective therapeutic agent.

[0215] As used in this document, the term degrader refers to a bifunctional compound capable of binding between IRAK4 kinase and an E3 ligase, leading to ubiquitination and subsequent degradation of IRAK4 kinase. In certain examples, the DC50 of the degrader is less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0216] Beneficial effects of the compounds in this disclosure:

[0217] (1) The compounds in this disclosure exhibit good degradation activity against the IRAK4 target and can effectively inhibit the secretion of inflammatory factors.

[0218] (2) The compounds in this disclosure exhibit favorable pharmacokinetic properties, such as high exposure, appropriate clearance rate and other superior properties.

[0219] (3) The compounds in this disclosure exhibit good safety, with lower cardiotoxicity. BRIEF DESCRIPTION OF THE DRAWINGS

[0220] 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 from Example 22 of this disclosure to mice at three different dose levels (15 mg / kg, 50 mg / kg and 150 mg / kg) in Test Example 6.

[0221] FIG. 2 shows the in vivo degradation levels of IRAK4 in mouse spleens after oral administration of KT-474 and the compound of Example 22 of this disclosure to mice at three different dose levels (15 mg / kg, 50 mg / kg and 150 mg / kg) in Example 22. Petition 870250078555, dated 03 / 09 / 2025, p. 59 / 1278 47 / 161 of Test 6. DETAILED DESCRIPTION OF THE PREFERRED MODALITY

[0222] The preparation methods of some compounds in this disclosure refer to the preparation methods of similar compounds mentioned above. Those skilled in the art should know that, when using or referring to the cited preparation methods, the reagent feed rate, reaction solvent, reaction temperature, etc., may be appropriately adjusted according to the different reagents.

[0223] The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods and equivalent alternatives known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0224] Unless otherwise specified, all reactions in this disclosure are conducted under continuous magnetic stirring in a dry nitrogen or argon atmosphere with the solvent being a dry solvent, wherein: (i) temperatures are given in degrees Celsius (°C) and operations are performed at room temperature, which generally refers to 15-35 °C, preferably 20-30 °C, more preferably 20-25 °C; (ii) the solvent is removed by evaporation under reduced pressure using a rotary evaporator; (iii) the progress of the reaction is monitored by LC-MS or thin-layer chromatography (TLC); (iv) the final products exhibit satisfactory hydrogen nuclear magnetic resonance (1H-NMR) and / or mass spectrometry (MS) data. The methods used to purify the products of this disclosure include, but are not limited to: high-performance preparative liquid chromatography, thin-layer chromatography, column chromatography, etc.The purification reagents used are conventional solvents in the art, such as dichloromethane, methanol, ethyl acetate, petroleum ether, acetonitrile, and water. The specific types and ratios used can be determined by conventional methods in the art.

[0225] Test instruments:

[0226] The structures of the compounds in this disclosure are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). Petition 870250078555, dated 03 / 09 / 2025, page 60 / 1278 48 / 161 NMR chemical shifts (δ) are given in parts per million (ppm) units. NMR is determined using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument, with deuterated dimethyl sulfoxide (DMSO-d5), deuterated methanol (CD3OD) and / or deuterated chloroform (CDCh) as solvents and tetramethylsilane (TMS) as an internal standard.

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

[0228] High-performance preparative liquid chromatography is performed using a Shimadzu FRC-40 equipped with LC-20AP and PDA-20A (chromatographic column: Synergi Max-RP, 150x30 mm, 4 μm) or a GILSON Trilution LC (chromatographic columns: SunFire Prep C18, 10 μm, 19 x 250 mm; XBridge Prep C18, 10 μm, 19 x 250 mm).

[0229] The starting materials or intermediate compounds used in this disclosure are commercially available or self-synthesized, and the structures and preparations of the self-synthesized intermediates have been registered in this disclosure. The chirality of a chiral intermediate or chiral product in this disclosure can be determined based on the chiral starting material used. When the reaction site is a non-chiral site, the chirality of the starting material is typically identical to that of the product.

[0230] The chemical abbreviations used in this disclosure and their corresponding chemical names are as follows: Chemical Abbreviations Chemical Name DHP Dihexyl phthalate TEA Triethanolamine DCM Dichloromethane DAST Diethylaminosulfur trifluoride (Dess-Martin reagent, 1,1,1-triacetoxy-1,1-di- Petition 870250078555, dated 03 / 09 / 2025, page 61 / 1278 49 / 161 hi dro-1,2-b enzyme odoxol -3 (1 H)-one PE Petroleum ether EtOAc Ethyl acetate DEAD Diethyl azodicarboxylate PMB / 2-Methoxybenzyl

[0231] Synthesis of Ogiva IRAK4 A:

[0232] Step 1: Aa hydrochloride (8.32 g, 36.88 mmol) and (17?,4Ã)-2-oxa-5 Petition 870250078555, of 03 / 09 / 2025, p. 62 / 1278 50 / 161 azabicyclo[2.2.1]heptane (5 g, 36.88 mmol) were dissolved in acetonitrile (60 mL) at room temperature under an argon atmosphere, and N,N-diisopropylethylamine (14.3 g, 110.63 mmol) was added slowly dropwise with stirring. The reaction mixture was then stirred overnight at 60°C. LC-MS showed complete consumption of the starting material, with the formation of a single product Ab. Water (100 mL) was added to the cooled reaction mixture, and then the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (3 x 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 obtain Ab (10.1 g).1H 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).

[0233] Step 2: Ab (10.1 g, 35.03 mmol) was dissolved in methanol / anhydrous water (100 mL / 25 mL) at room temperature, followed by the addition of lithium hydroxide monohydrate (8.82 g, 210.19 mmol) with stirring. The reaction mixture was then stirred overnight at 60°C. LC-MS showed that trace amounts of the starting material remained, and the main product was Ac. The cooled reaction mixture was diluted with water (100 mL) and the pH was adjusted to 5 with dilute hydrochloric acid (1 M) in an ice-cold water bath. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain Ac (8.7 g).1H NMR(400 MHz,CDCh) 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).

[0234] Step 3: 1H-Pyrazol-5-carbaldehyde (58.7 g, 610.89 mmol) and TsOH^H2O were dissolved in DCM (580 mL), cooled to 0°C, and DHP (61.6 g, 733.07 mmol) was added slowly. The ice bath was removed, and the reaction mixture was heated to room temperature and stirred overnight. TEA (23.5 mL) was added to the reaction mixture, and the mixture was concentrated by rotary evaporation. The residue was purified by silica gel column chromatography to obtain Ad (88 g).1H NMR (400 MHz,CDCh) 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). Petition 870250078555, dated 03 / 09 / 2025, page 63 / 1278 51 / 161 3.77 - 3.70 (m, 1H), 2.16 - 2.03 (m, 3H), 1.77 - 1.63 (m, 3H).

[0235] Step 4: Ad (88 g, 488.33 mmol) was dissolved in DCM (500 mL) and DAST (157 g, 976.65 mmol) was added dropwise at 0 °C. The ice bath was removed and the reaction was carried out overnight at room temperature. TLC (PE / EtOAc = 10 / 1) monitored that the reaction was not complete. The reaction mixture was slowly quenched with NaHCO3 (3 L). The organic phase was separated and the aqueous phase was further extracted with DCM (3 x 1 L). The organic phases were combined, dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue was purified by a silica gel column to obtain 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).

[0236] 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 carried out overnight at room temperature. The completion of the reaction was monitored by TLC. The reaction mixture was concentrated, followed by the addition of saturated NaHSO3 (420 mL) and EtOAc (420 mL). The mixture was stirred at room temperature for 1 h, then extracted with EtOAc (3 x 200 mL). The combined organic phases were dried over Na2SO4, concentrated by rotary evaporation to obtain Af (16.8 g). 1H 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).

[0237] Step 6: Af (14.0 g, 118.56 mmol) was dissolved in concentrated H2SO4 (140 mL), cooled to 0°C in an ice bath, and HNO3 (65%, 40.23 g, 414.95 mmol) was added dropwise. The temperature was slowly heated to room temperature, then gradually increased to 60°C, and the reaction was carried out overnight at 115°C. The reaction mixture was cooled to room temperature, poured into ice water (1 L), and extracted with EtOAc (3 x 1 L). The combined organic phases were dried over Na2SO4, concentrated by rotary evaporation, and purified to obtain Ag (7.79 g). 1H NMR (400 MHz, CDCh) δ 8.46 (s, 1H), 7.35 (t, J = 53.6 Hz, 1H).

[0238] Step 7: tert-butyl 2-oxo-7-azaspiro[3,5]nonane-7-carboxylate (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 added slowly in an ice water bath with Petition 870250078555, dated 03 / 09 / 2025, page 64 / 1278 52 / 161 stirring. The reaction mixture was slowly returned to room temperature and stirred for 1 hour. TLC showed that the starting material reacted completely. Saturated aqueous ammonium chloride solution (100 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to obtain Ah (9.14 g). 1H NMR(400 MHz, CDCh) 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).

[0239] Step 8: Ah (9.14 g, 37.87 mmol) was dissolved in toluene (90 mL) at room temperature, followed by the sequential addition of triphenylphosphine (14.90 g, 56.81 mmol), imidazole (5.16 g, 75.75 mmol), and iodine (14.42 g, 56.81 mmol) in an ice-cold water bath with stirring. The reaction mixture was slowly returned to room temperature and stirred for 1 hour, then heated to 60°C and stirred for another hour. LC-MS showed that the starting material reacted completely. Water (200 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (3 x 200 mL). The combined organic phases were washed with saturated brine (400 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the resulting residue was separated by silica gel column chromatography to obtain Ai (7.98 g).1H NMR(400 MHz, CDCh) 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).

[0240] 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, followed by the addition of potassium carbonate (3.58 g, 25.88 mmol) with stirring. The reaction mixture was then stirred overnight at 100°C. LC-MS showed that the starting material reacted completely. The reaction mixture was cooled to room temperature, then added with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to obtain Aj (3.8 g, yield: 76%). 1H NMR(400 MHz,DMSO-de) δ 9.13 (s, 1H), 7.32 (t, J = 53.0 Hz, Petition 870250078555, dated 03 / 09 / 2025, page 65 / 1278 53 / 161 1H) (s, 9H).

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

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

[0243] Step 12: Al (3.40 g, 5.68 mmol) was dissolved in dichloromethane (40 mL) at room temperature and a hydrochloric acid / 1,4-dioxane solution (4 M, 14 mL, 56 mmol) was added in an ice-cold water bath with stirring. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the starting material reacted completely. The reaction mixture was concentrated to obtain the desired crude product A (3.87 g, hydrochloride). MS (ESI) m / z: 499.6 [M+H+]. 1H NMR(400 MHz, DMSO-de) 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, Petition 870250078555, dated 03 / 09 / 2025, page 66 / 1278 54 / 161 2H).

[0244] Synthesis of intermediate B:

[0245] Step 1: Glutarimide (100 g, 884.0 mmol) was placed in a sealed 500 mL container at room temperature, then chloroform (200 mL) was added and liquid bromine (141 g, 884.0 mmol) was added slowly with stirring. After sealing, the reaction mixture was stirred overnight at 105°C. LC-MS showed that the starting material was almost completely reacted and the main product was Bb. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was dissolved in ethyl acetate (1 L), washed with saturated aqueous sodium bicarbonate solution (500 mL) and 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+], ^NMR^OO MHz, DMSO-óL) 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).

[0246] Step 2: α-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 mixture was then cooled to 0°C and diethyl azodicarboxylate (25.9 g, 148.9 mmol) was added slowly dropwise under an argon atmosphere. After the dropwise addition was complete, the reaction mixture was naturally warmed to room temperature and stirred overnight. LC-MS showed that the starting material reacted completely. The reaction mixture was concentrated and the Petition 870250078555, dated 03 / 09 / 2025, p. 67 / 1278 55 / 161 residue was purified by silica gel column chromatography to obtain the desired product Bc (29.7 g). 1H NMR (400 MHz, CDCh) 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).

[0247] Step 3: Bd (19.8 g, 87.4 mmol) was dispersed in dry tetrahydrofuran (400 mL) at room temperature, stirred, and cooled to 0°C, and potassium tert-butoxide (16.7 g, 148.5 mmol) was added under an argon atmosphere. The reaction mixture was stirred at this temperature for one more hour, then heated 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 complete, the reaction mixture was stirred at 45°C for another 3 hours. LC-MS showed that the starting material was almost completely reacted. The reaction mixture was cooled to 0°C, slowly quenched with saturated brine (300 mL), and the phases were separated. The organic phase was washed once with brine (300 mL), dried with 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). 1H NMR(400 MHz,DMSO-de) 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).

[0248] 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 hours. LC-MS showed that the starting material reacted completely. The reaction mixture 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) Hz, 1H), 3.64 (s, 3H), 2.96 - 2.82 (m, 1H), 2.77 - 2.59 (m, 2H), 2.10 - 1.98 (m, 1H).

[0249] Example 1 Petition 870250078555, dated 03 / 09 / 2025, page 68 / 1278 56 / 161 DIPEA. Kl MeCN Step 3

[0250] Step 1: B (300 mg, 0.89 mmol) and dry Α,Α-dimethylformamide (5 mL) were added to a dry 100 mL single-neck flask at room temperature, followed by the addition of hydroxyethyl propargyl ether (179 mg, 1.78 mmol), bis(triphenylphosphine)palladium(II) dichloride (62 mg, 0.089 mmol), copper(I) iodide (17 mg, 0.089 mmol), and cesium carbonate (870 mg, 2.67 mmol) under an argon atmosphere. The mixture was purged with argon three times and heated to 80°C and stirred for 2 hours under an argon atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was cooled to room temperature and saturated aqueous ammonium chloride solution (20 mL) was added with stirring. The resulting mixture was extracted with dichloromethane (3 x 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 ia (103 mg).

[0251] Step 2: La (250 mg, 699.56 pmol) 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 in an ice-cold water bath with stirring. The reaction mixture was then heated to 30°C and stirred for 1 hour under an argon atmosphere. LC-MS showed the disappearance of the starting material. Water (30 mL) was added to the cooled reaction mixture, and then the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (3 x 0 mL), dried over sulfate Petition 870250078555, dated 03 / 09 / 2025, page 69 / 1278 57 / 161 anhydrous sodium and filtered. The filtrate was concentrated and the resulting residue was purified by preparative thin-layer chromatography to obtain 1b (80 mg). MS (ESI) m / z: 436.1 [M+H+]; 434.1 [MH-]. 1H NMR(400 MHz,CDCh) 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).

[0252] Step 3: 1b (30 mg, 68.89 μmol) and A (crude hydrochloride, 51 mg, 103.34 μmol) were dissolved in acetonitrile (2 mL) at room temperature under an argon atmosphere, and potassium iodide (14 mg, 82.67 μmol) and N,N-diisopropylethylamine (44 mg, 344.47 μmol) were added with stirring. The reaction mixture was then reacted overnight at 85°C under an argon atmosphere. LC-MS showed that a small amount of the starting material remained and the major product was 1. The reaction mixture was cooled to room temperature, then saturated aqueous sodium bicarbonate solution (30 mL) was added, and the mixture was then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by preparative thin-layer chromatography to obtain 1 (7.93 mg).MS (ESI) m / z: 838,5 [M+H+]; 1H NMR (400 MHz,DMSO- de) 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).

[0253] Exemplo 2 Petição 870250078555, de 03 / 09 / 2025, pág. 70 / 1278 58 / 161

[0254] 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 A,A-dimethylformamide (60 mL) at room temperature and cesium carbonate (14.4 g, 44.4 mmol), bis(triphenylphosphine)palladium(II) chloride (1.25 g, 1.77 mmol) and copper(I) iodide (676 mg, 3.55 mmol) were added sequentially with stirring under an argon atmosphere. The reaction mixture was then stirred at 80°C under an argon atmosphere for 5 hours.

[0255] LC-MS showed that the starting material reacted completely. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and ethyl acetate (200 mL) and saturated brine (100 mL) were added to the resulting residue, followed by phase separation. The organic phase was washed with saturated brine (100 mL), dried with 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). Ή NMR(400 MHz,DMSO-t / 6) 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).

[0256] Step 2: 2a (95.0 mg, 255.8 pmol) was dissolved in dichloromethane (4 mL) at room temperature, cooled in an ice water bath, and Dess-Martin periodonane (162.7 mg, 383.7 pmol) was added with stirring. The reaction mixture was stirred to Petition 870250078555, dated 03 / 09 / 2025, page 71 / 1278 59 / 161 room temperature overnight. LC-MS showed the disappearance of the starting material. The reaction mixture was filtered and water (20 mL) and dichloromethane (20 mL) were added to the filtrate for phase separation. The aqueous phase was further extracted with dichloromethane (10 mL x 2). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the resulting crude product was purified by preparative thin-layer chromatography to obtain 2b (46 mg). MS (ESI) m / z: 370.1 [M+H+]. 1H NMR(400 MHz,DMSOd5)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).

[0257] 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-cold water bath with stirring. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed that the starting material reacted completely. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture and then the mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting crude residue was purified by preparative thin-layer chromatography to obtain the desired product 2 (10.79 mg). MS (ESI) m / z: 852 [M+H+].1H NMR(400 MHz,DMSO-d5)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).

[0258] Exemplo 3 Petição 870250078555, de 03 / 09 / 2025, pág. 72 / 1278 60 / 161

[0259] 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 mixture was then stirred at room temperature for 1 hour. TLC showed complete consumption of the starting material and the formation of a new point. The reaction mixture was slowly added dropwise to water and then extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the resulting residue was separated by silica gel column chromatography to obtain 3b (2.75 g, yield: 81%) as a colorless liquid.1HNMR(400 MHz,CDCh) 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, 4Hz, 2.69), 1.25 (t, J=7.l Hz, 3H). Petition 870250078555, of 03 / 09 / 2025, p. 73 / 1278 61 / 161

[0260] Step 2: 3b (2.03 g, 10.40 mmol) was dissolved in tetrahydrofuran (15 mL) at room temperature. A lithium aluminum hydride tetrahydrofuran solution (2.5 M, 12.48 mL, 31.2 mmol) was slowly added dropwise to the reaction mixture at 0°C with stirring, and the reaction mixture was then stirred at 0°C for 1 hour. TLC showed complete consumption of the starting material and formation of a product. The reaction mixture was quenched by slow dropwise addition of ice-cold water, and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to obtain 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).

[0261] Step 3: 3c (159 mg, 1.04 mmol) was dissolved in N,N-dimethylformamide (10 mL) at room temperature and B (422 mg, 1.25 mmol), copper(I) iodide (39.61 mg, 0.21 mmol) and cesium carbonate (1.36 g, 4.16 mmol) were added under an argon atmosphere. The reaction mixture was purged with argon three times and then bis(triphenylphosphine)palladium(II) dichloride (146 mg, 0.21 mmol) was added. The reaction mixture was then stirred at 80°C for 2 hours under an argon atmosphere. LC-MS showed complete consumption of the starting material and formation of a product. The cooled reaction mixture was diluted with water and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to obtain the desired 3d (178 mg).MS (ESI) m / z: 411.2 [M+H+].

[0262] Step 4: 3d (100 mg, 0.259 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature, cooled to 0°C in an ice water bath, and DessMartin periodonane (165 mg, 0.389 mmol) was added with stirring. The reaction mixture was stirred at room temperature for 4 hours. LC-MS showed complete consumption of the starting material and formation of a product. The reaction mixture was slowly added dropwise to saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (10 mL) and dried over sulfate. Petition 870250078555, dated 03 / 09 / 2025, page 74 / 1278 62 / 161 of anhydrous sodium and filtered. The filtrate was concentrated and the resulting residue was separated by preparative thin-layer chromatography to obtain 3e (48 mg). MS (ESI) m / z: 409.2 [M+H+]. 1H 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).

[0263] Step 5: 3e (24 mg, 0.058 mmol) and A (crude hydrochloride, 32 mg, 0.058 mmol) were dissolved in tetrahydrofuran (1 mL) at room temperature, stirred in an ice water bath for 20 minutes, and sodium triacetoxyborohydride (50 mg, 0.235 mmol) was added. The reaction mixture was then stirred at room temperature overnight. LC-MS showed complete consumption of the starting material and formation of a product. The reaction mixture was quenched by slow addition of water, and the resulting mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by preparative thin-layer chromatography to obtain 3 (13.8 mg, yield: 26%). MS (ESI) m / z: 891.4 [M+H+].1H 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).

[0264] Exemplo 4 Petição 870250078555, de 03 / 09 / 2025, pág. 75 / 1278 63 / 161

[0265] 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 mixture was then stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C and a solution of 3-bromopropine (3.0 g, 25.22 mmol) in tetrahydrofuran (10 mL) was added slowly dropwise with stirring. After the dropwise addition was complete, the reaction mixture was stirred overnight at room temperature. ATLC showed complete consumption of the starting material and the formation of a new point. The reaction mixture was diluted with water and then extracted with ethyl acetate (3 x 40 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated and the resulting residue was separated by silica gel column chromatography to obtain 4a (2.75 g). '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).

[0266] Subsequent reaction procedures were carried out with reference to Example 2. 4 (22.06 mg, yield: 42%) was obtained. MS (ESI) m / z: 866.5 [M+H+], 'H NMR(400 MHz,DMSO-t / 6) 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) 4.80 - 4.74 (m, 1H), 4.43 (s, 2H), Petition 870250078555, dated 03 / 09 / 2025, p. 76 / 1278 64 / 161 3,84 - 3,72 (m, 2H), 3,64 - 3,62 (m, 4H), 3,59 - 3,55 (m, 3H), 3,47 - 3,43 (m, 1H), 2,91 - 2,85 (m, 1H), 2,75 - 2,57 (m, 3H), 2,38 - 2,28 (m, 4H), 2,20 - 2,11 (m, 3H), 2,06 - 1,92 (m, 4H), 1,75 - 1,50 (m, 8H).

[0267] Exemplo 5 Etapa 3

[0268] Step 1: Ethyl 2-(hydroxymethyl)-2-methylpropanoate (5.0 g, mmol) was dissolved in Λζ / V-dimethylformamide (50 mL) at room temperature and sodium hydride (60%, 2.05 g, 51.3 mmol) was added in an ice-cold water bath with stirring. After 20 minutes, 3-bromopropyne (3.25 mL, 4.48 g, 37.62 mmol) was added to the reaction mixture. After 20 minutes, the ice-cold water bath was removed and the reaction mixture was stirred overnight at room temperature under an argon atmosphere. TLC showed the disappearance of the starting material and the formation of a new spot. Saturated aqueous ammonium chloride solution (approximately 50 mL) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate (3 x 00 mL). The combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the residue... Petition 870250078555, dated 03 / 09 / 2025, page 77 / 1278 65 / 161 resulting was separated by silica gel column chromatography to obtain 5a (2.12 g). 1HNMR(400 MHz,CDCl3) δ 4.17 - 4.11 (m, 4H), 3.53 (s, 2H), 2.41 (t, J = 2.2 Hz, 1H), 1.25 (t, J = 7.0 Hz, 3H), 1.20 (s, 6H).

[0269] 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 mixture was stirred at 100°C for 2 hours. TLC showed that the reaction was complete. The pH of the cooled reaction mixture was adjusted to 5 with concentrated hydrochloric acid and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain a crude product 5b (772 mg).1H NMR(400 MHz, CDCh) 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).

[0270] Step 3: 2-(7-Azabenzotriazol-1-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate (HATU, 72 mg, 0.56 mmol) was added 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. After 5 minutes, N,N-diisopropylethylamine (0.1 mL, 0.42 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. LC-MS showed that the reaction was complete. Water (approximately 5 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting crude residue was separated by silica gel column chromatography to obtain a crude product (106 mg). The crude product was further purified by preparative thin-layer chromatography to obtain 5c (58 mg). MS (ESI) m / z: 637.4 [M+H+].

[0271] Step 4: B (15 mg, 0.044 mmol) and 5c (58 mg, 0.091 mmol) were dissolved in N,N-dimethylformamide (2 mL) under an argon atmosphere, followed by the sequential addition of cesium carbonate (29 mg, 0.090 mmol), copper(I) iodide (2 mg, 0.0089 mmol), and bis(triphenylphosphine)palladium(II) dichloride (3 mg, 0.0046 mmol). The reaction mixture was then stirred at 80°C under an argon atmosphere for 6 hours. LC-MS showed the completion of the reaction. The cooled reaction mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (approximately 10 mL). The filtrate was added with water and then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine. Petition 870250078555, dated 03 / 09 / 2025, page 78 / 1278 66 / 161 saturated, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting residue was separated by preparative thin layer chromatography to obtain 5 (8.81 mg). MS (ESI) m / z: 894.3 [M+H+],1HNMR(400 MHz,DMSO-ó / ó) δ 11.11 (s, 1H), 9.51 (d, J= 5.6 Hz, 1H), 8.78 (d, J= Ί,β Hz, 1H), 8.39 (d, J= 4.0 Hz, 1H) 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).

[0272] Example 6 DMP DCM Step 2 2-methylpyr dine borane DCE / DMSO Step 3 Pd^PPhj)^^. Cul. 0$2^θ3 DMF Step 4

[0273] The desired product 6 (11.83 mg) was obtained with reference to Example 4. MS (ESI) m / z: 877.38 [M+H+],1HNMR(400 MHz,DMSO-t / 6) 11.11 (s, 1H), 9.50 (d, J= 5.2 Hz, 1H), 8.79 (d, J= Ί,β Hz, 1H), 8.40 (d, J= 2.8 Hz, 1H), 8.47 (d, J= 5.6 Hz, 1H), 7.28 - 7.00 (m, 4H), 6.87 - 6.44 (m, 1H), 5.44 - 5.07 (m, 2H), 4.98 - 4.74 (m, 2H), 4.45 (s, 2H), 3.84 - 3.72 (m, 2H), 3.66 - 3.59 (m, 4H), 3.47 - 3.35 (m, 3H), 2.92 - 2.60 (m, 4H), 2.42 - 1.93 (m, 12h), 1.79 - 1.48 Petition 870250078555, dated 03 / 09 / 2025, page 79 / 1278 67 / 161 (m, 4H), 0.49-0.31 (m, 4H).

[0274] Example 7

[0275] The desired product 7 (5.06 mg) was obtained with reference to Example 5. MS (ESI) m / z: 892.3 [M+H+], Ή NMR(400 MHz,DMSO-t / 6) 11.11 (s, 1H), 9.50 (d, J= 5.6 Hz, 1H), 8.79 (d, J= 8.0 Hz, 1H), 8.39 (d, d, J= 3.6 Hz, 1H), 8.27 (d, J= 5.6 Hz, 1H), 7.30 - 6.44 (m, 5H), 5.42 - 5.07 (m, 2H), 4.96 - 4.75 (m, 2H), 4.45 (s, 2H), 3.84 - 3.51 (m, 12h), 2.90 - 2.55 (m, 3H), 2.28 - 1.90 (m, 8H), 1.60 - 1.45 (m, 4H), 0.91 - 0.73 (m, 4H).

[0276] Example 8 Petition 870250078555, dated 03 / 09 / 2025, p. 80 / 1278 68 / 161

[0277] Step 1: w-Butyllithium (1.6 M in hexanes, 7 mL, 11.2 mmol) was added to a stirred solution of propargyl alcohol (6.4 mL, 110 mmol) in tetrahydrofuran (100 mL) via syringe at 0°C under an argon atmosphere. The reaction mixture was stirred at 0°C under an argon atmosphere for 10 minutes. tert-Butyl acrylate (14.6 mL, 110 mmol) was added slowly dropwise via syringe at 0°C. The reaction mixture was slowly returned to room temperature and stirred overnight under an argon atmosphere. TLC showed that the starting material was almost completely consumed. Acetic acid (1 mL) was added to the reaction mixture, and then the mixture was stirred for 10 minutes. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3.50 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered.The filtrate was concentrated and the resulting residue was separated by silica gel column chromatography to obtain 8a (14 g). 'H NMR(400 MHz,DMSO-t / 6) 54.12 - 4.10 (m, 2H), 3.62 (t, J= 6.2 Hz, 2H), 3.42 - 3.40 (m, 1H), 2.44 (t, J = 6.2 Hz, 2H), 1.40 (s, 9H). Petition 870250078555, dated 03 / 09 / 2025, p. 81 / 1278 69 / 161

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

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

[0280] Step 4: 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 sequentially added to a stirred solution of A (50 mg, 0.1 mmol) in N,N-dimethylformamide (3 mL) at room temperature under an argon atmosphere. The reaction mixture was slowly returned to room temperature and stirred for 1 hour under an argon atmosphere. LC-MS showed that the starting material reacted completely and the major product was 8 (34%). Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture, and then the mixture was extracted with Petition 870250078555, dated 03 / 09 / 2025, page 82 / 1278 70 / 161 ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by preparative thin-layer chromatography to obtain pure 8 (2.07 mg + 16.31 mg, yield: 22%). MS (ESI) m / z: 866.55 [M+H+]; 864.30 [M-H']. Ή NMR(400 MHz,DMSO-t / 6)ô 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).

[0281] Example 9

[0282] The desired product 9 (2.83 mg) was obtained with reference to Example 2. MS (ESI) m / z: 878.4 [M+H+]; 'HNMR (400 MHz,CDCl3) δ 9.61 (s, 1H), 8.47 - 8.41 (m, 2H), 8.32 (d, J = 8.0 Hz, 2H), 7.22 - 7.17 (m, 1H), 7.04 - 6.97 (m, 2H), 6.80 - 6.73 (m, 2H), 6.12 (d, J= Ί,β Hz, 1H), 5.45 (s, 1H), 5.35-5.17 (m, 2H), 4.84 - 4.60 (m, 3H), 4.40 (s, 2H), 4.10 - 4.07 (m, 1H), 4.00 - 3.95 (m, 2H), 3.81 (s, 3H), 3.68 - 3.64 (m, 2H), 3.61 - 3.56 (m, 2H), 3.51 - 3.48 (m, 2H), 2.98 - 2.92 (m, 2H), 2.88 - 2.67 (m, 4H), 2.48 - 2.36 (m, 8H), 2.12 - 2.09 (m, 2H), 2.03 1.97 (m, 2H).

[0283] Example 10 Petition 870250078555, dated 03 / 09 / 2025, page 83 / 1278 71 / 161

[0284] Step 1: Ethyl 2-bromo-2-methylpropanoate (1.0 g, 5.13 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature and cesium carbonate (3.34 g, 10.26 mmol) was added in an ice-cold water bath with stirring. After 20 minutes, propargyl alcohol (0.30 mL, 5.13 mmol) was added slowly. After 20 minutes, the reaction mixture was returned to room temperature and stirred overnight under an argon atmosphere. TLC showed complete consumption of the brominated starting material and formation of a new spot. Saturated aqueous ammonium chloride solution (approximately 20 mL) was added to the reaction mixture in an ice-cold water bath with stirring. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the resulting residue was purified by preparative thin-layer chromatography to obtain 10a (200 mg).Ή NMR(400 MHz,CDCl3) δ 4.27 - 4.15 (m, 4H), 2.42 (t, J= 2.4 Hz, 1H), 1.48 (s, 6H), 1.33 - 1.24 (m, 3H).

[0285] Subsequent procedures were performed with reference to Example 5 for Petition 870250078555, dated 0V09 / 2025, page 84 / 1278 72 / 161 obtain the desired product 10 (4.6 mg). MS (ESI) m / z: 880.5 [M+EE], 'H NMR(400 MHz,DMSO-t / 6)ô 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).

[0286] Example 11 Step 4

[0287] The desired product 11 (3.1 mg) was obtained with reference to Example 5. MS (ESI) m / z: 866.5 [M+H+], Ή NMR(400 MHz,DMSO-t / 6) 11.12 (s, 1H), 9.50 (d, J= 5.2 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 - 7.00 (m, 4H), 6.88 - 6.44 (m, 1H), 5.42 - 5.38 (m, 1H), 5.28 - 5.08 (m, 1H), 4.98 - 4.93 (m, 1H), 4.80 - 4.75 (m, 1H), 4.62 - 4.56 (m, 1H), 4.52 - 4.37 (m, 2H), 3.84 - 3.80 (m, 2H), 3.75 - 3.72 (m, 1H), Petition 870250078555, dated 03 / 09 / 2025, page 85 / 1278 73 / 161 3.64 - 3.63 (m, 3H), 3.59 (s, 1H), 3.54 - 3.43 (m, 4H), 2.92 - 2.84 (m, 1H), 2.76 - 2.59 (m, 3H), 2.49 - 2.15 (m, 4H), 2.07 - 1.93 (m, 3H), 1.66 - 1.49 (m, 4H), 1.29 - 1.27 (m, 2H).

[0288] Example 12

[0289] The desired product 12 (36.29 mg) was obtained with reference to Example 5. MS (ESI) m / z: 852.4 [M+H+]; 'HNMR (400 MHz, DMSO-óL) δ 11.12 (s, 1H), 9.50 (d, J= 5.2 Hz, 1H), 8.85 (s, 2H), 8.79 (d, J= Ί,β Hz, 1H), 8.69 (s, 1H), 8.41 (d, J= 3.6 Hz, 1H), 8.26 (d, J= 5.6Hz, 1H), 7.55 - 7.46 (m, 1H), 7.20 - 7.01 (m, 4H), 6.88 - 6.45 (m, 1H), 5.41 (dd, J= 12.6, 5.4Hz, 1H), 5.28 - 5.07 (m, 1H), 5.00 - 4.93 (m, 1H), 4.80 - 4.75 (m, 1H), 4.54 (s, 2H), 4.29 (d, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.63 - 3.57 (m, 4H), 3.55 - 3.30 (m, 1H), 2.95 - 2.55 (m, 3H), 2.40 - 2.35 (m, 2H), 2.24 - 2.19 (m, 2H), 2.06 - 1.93 (m, 2H), 1.69 - 1.50 (m, 4H).

[0290] Example 13 Petition 870250078555, dated 03 / 09 / 2025, p. 86 / 1278 74 / 161

[0291] Step 1: B (1.0 g, 2.96 mmol) was dissolved in Λζ / V-dimethylformamide (10 mL) at room temperature under an argon atmosphere and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.42 g, 5.91 mmol), cesium carbonate (1.93 g, 5.91 mmol), copper(I) iodide (112 mg, 591.43 pmol) and bis(triphenylphosphine)palladium(II) dichloride (207 mg, 295.72 pmol) were added sequentially. The reaction mixture was stirred at 80°C under an argon atmosphere for 2 hours. LC-MS showed that a small amount of the starting material B remained and the major product was 13a. The reaction mixture was cooled to room temperature, then added with water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (3 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to obtain 13a (1.03 g).'H NMR(400 MHz, CDCh) δ 8.26 (s, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.99 (t, J= 7.8 Hz, 1H), 6.76. Petition 870250078555, dated 03 / 09 / 2025, p. 87 / 1278 75 / 161 (d, J = 7.6 Hz, 1H), 5.20 (dd, J = 12.6, 5.4 Hz, 1H), 4.46 (s, 2H), 3.81 - 3.73 (m, 6H), 3.16 3.09 (m, 2H), 2.98 - 2.66 (m, 3H), 2.34 - 2.17 (m, 1H), 1.94 - 1.81 (m, 2H), 1.60 - 1.52 (m, 2H), 1.46 (s, 9H).

[0292] Step 2: 13a (300 mg, 604.15 μmol) was dissolved in dichloromethane (3 mL) in an ice-cold water bath and trifluoroacetic acid (1.17 g, 12.08 mmol) was added with stirring. The reaction mixture was then slowly returned to room temperature and stirred for 2 hours. LC-MS showed that the starting material was completely consumed and 13B was the major product. The reaction mixture was concentrated under reduced pressure to obtain 13b (236 mg, trifluoroacetate salt). 1H NMR(400 MHz, DMSO-de) 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).

[0293] Step 3: 13B (100 mg, 252.24 μmol) and p-nitrophenyl chloroformate (76 mg, 378.36 μmol) were dissolved in dichloromethane (3 mL), and triethylamine (76 mg, 756.72 μmol) was added at 0°C with stirring. The reaction mixture was stirred at room temperature under an argon atmosphere. LC-MS showed the disappearance of the starting material. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture, and then the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by preparative thin-layer chromatography to obtain 13c (77 mg).1H NMR(400 MHz, CDCh) 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).

[0294] Step 4: 13C (57 mg, 101.50 μmol) and A (61 mg, 121.81 μmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature under an argon atmosphere, and potassium carbonate (42 mg, 304.51 μmol) was added with stirring. The reaction mixture was then reacted overnight at 80°C under an argon atmosphere. LC-MS showed that a small amount of the starting material remained and the major product was 13A. Petition 870250078555, dated 03 / 09 / 2025, page 88 / 1278 76 / 161 The reaction mixture was cooled to room temperature, then a saturated aqueous solution of sodium bicarbonate (30 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were 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 obtain 13 (26.78 mg).MS (ESI) m / z: 921.4 [M+H+]; 'HNMR (400 MHz,DMSO-tÃ) δ 11.11 (s, 1H), 9.50 (d, J= 5.2 Hz, 1H), 8.78 (d, J= Ί,β 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).

[0295] Example 14

[0296] Step 1: Sodium hydride (60%, 2.80 g, 69.97 mmol) was added to a stirred solution of A-Boc-3-hydroxyazetidine (10.1 g, 58.31 mmol) in tetrahydrofuran (100 mL) in Petition 870250078555, dated 03 / 09 / 2025, page 89 / 1278 77 / 161 an ice water bath. The reaction mixture was stirred for 0.5 hours in an ice water bath, then returned to room temperature and stirred for another 0.5 hours. 3-Bromopropyne (8.32 g, 69.97 mmol, 6.03 mL) was added to the reaction mixture. The reaction mixture was then stirred overnight at 60°C under an argon atmosphere. LC-MS showed that the reaction was complete. The reaction mixture was cooled and then quenched by the addition of saturated aqueous ammonium chloride solution (approximately 100 mL) in an ice water bath with stirring. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with saturated brine, dried with 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 14a (11.60 g).1H NMR(400 MHz,DMSO-de) 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).

[0297] As reações subsequentes foram realizadas com referência ao Exemplo 13 para obter o produto desejado 14 (25,4 mg). MS (ESI) m / z: 893,2 [M+H+]; 1H NMR (400 MHz,CDCh) 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).

[0298] Exemplo 15 Petition 870250078555, dated 03 / 09 / 2025, page 90 / 1278 78 / 161

[0299] The desired product 15 (9.02 mg) was obtained with reference to Example 2. MS (ESI) m / z: 836.5 [M+H+]; Ή NMR (400 MHz,DMSO-t / 6) δ 11.11 (s, 1H), 9.50 (d, J= 5.2 Hz, 1H), 8.79 (d, J= Ί,β Hz, 1H), 8.42 - 8.40 (m, 1H), 8.26 (d, J= 5.6 Hz, 1H), 7.28 - 6.97 (m, 4H), 6.88 - 6.44 (m, 1H), 5.42 - 5.36 (m, 1H), 5.28 - 5.07 (m, 1H), 5.01 - 4.90 (m, 1H), 4.80 - 4.74 (m, 1H), 3.83 - 3.72 (m, 2H), 3.65 (s, 3H), 3.62 - 3.59 (m, 1H), 3.45 - 3.39 (m, 2H), 2.94 - 2.85 (m, 1H), 2.75 - 2.60 (m, 3H), 2.39 - 2.13 (m, 9H), 2.05 - 1.90 (m, 4H), 1.84 - 1.44 (m, 8H).

[0300] Example 16 Petition 870250078555, dated 03 / 09 / 2025, page 91 / 1278 79 / 161 DIPEA. DMF Step 3

[0301] The desired product 16 (134.24 mg) was obtained with reference to Example 13. MS (ESI) m / z: 852.3 [M+H+]; 'HNMR (400 MHz, DMSO-óh) δ 11.11 (s, 1H), 9.49 (d, J= 4.8 Hz, 1H), 8.78 (d, J= 8.0 Hz, 1H), 8.40 (d, J= 4.4 Hz, 1H), 8.26 (d, J= 5.6 Hz, 1H), 7.28 - 6.98 (m, 4H), 6.88 - 6.44 (m, 1H), 5.42 - 5.37 (m, 1H), 5.28 - 5.07 (m, 1H), 4.99 - 4.90 (m, 1H), 4.80 - 4.75 (m, 1H), 4.23 - 4.19 (m, 2H), 3.83 - 3.73 (m, 2H), 3.64 (s, 3H), 3.62 - 3.57 (m, 1H), 3.46 - 3.30 (m, 5H), 2.92 - 2.82 (m, 3H), 2.75 - 2.59 (m, 2H), 2.35 - 2.30 (m, 2H), 2.20 - 2.15 (m, 2H), 2.07 - 1.92 (m, 3H), 1.60 - 1.57 (m, 2H), 1.53 - 1.51 (m, 2H).

[0302] Example 17 Petition 870250078555, dated 03 / 09 / 2025, page 92 / 1278 80 / 161

[0303] The desired product 17 (72.51 mg) was obtained with reference to Example 1. MS (ESI) m / z: 822.4 [M+H+]; Ή NMR (400 MHz,DMSO-tÃ) δ 11.11 (s, 1H), 9.50 (d, J= 4.8 Hz, 1H), 8.78 (d, J= Ί,β Hz, 1H), 8.42 (d, J= 3.6 Hz, 1H), 8.26 (d, J= 5.6 Hz, 1H), 7.28 - 6.98 (m, 4H), 6.88 - 6.44 (m, 1H), 5.42 - 5.37 (m, 1H), 5.28 - 5.07 (m, 1H), 5.01 - 4.90 (m, 1H), 4.80 - 4.75 (m, 1H), 3.84 - 3.72 (m, 2H), 3.65 - 3.59 (m, 5H), 3.50 - 3.40 (m, 1H), 2.95 - 2.85 (m, 1H), 2.76 - 2.54 (m, 7H), 2.44 - 2.13 (m, 6H), 2.07 - 1.52 (m, 9H).

[0304] Example 18 Petition 870250078555, dated 03 / 09 / 2025, page 93 / 1278 81 / 161

[0305] The desired intermediate 18c (5.8 g) was obtained with reference to Example 14. 'H NMR(400 MHz,CDCl3) δ 4.28 - 4.20 (m, 1H), 4.18 - 4.11 (m, 2H), 3.51 - 3.35 (m, 4H), 2.44 (t, J= 2.4 Hz 1H), 2.10-1.89 (m, 2H), 1.46 (s, 9H).

[0306] Step 4: A (100 mg, 200.59 pmol) and dep-nitrophenyl chloroformate (61 mg, 300.88 pmol) were dissolved in dichloromethane (3 mL) in an ice-cold water bath with stirring, and triethylamine (61 mg, 601.76 pmol) was added in an ice-cold water bath with stirring. The reaction mixture was then heated to room temperature and stirred for 1 hour under an argon atmosphere. LC-MS showed the disappearance of the starting material. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture, and then the mixture was extracted with dichloromethane (3 x 10 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by preparative thin-layer chromatography to obtain 18d (85 mg).1HNMR(400 MHz,CDCh) 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 = 8,0Hz, 1H), 5,46 (s, 1H), 4,83 -4,77 (m, 2H), 4,01-3,96 (m, 2H), 3,69 - 3,48 (m, 6H), 2,54 - 2,37 (m, 4H), 2,13 - 2,09 (m, 1H), 2,05 - 1,97 (m, 1H),. Petição 870250078555, de 03 / 09 / 2025, pág. 94 / 1278 82 / 161 1,82 - 1,77 (m, 4H).

[0307] Step 5: 18D (70 mg, 105.48 pmol) and 18C (61 mg, 158.22 pmol) were dissolved in dimethyl sulfoxide (1 mL) at room temperature under an argon atmosphere, and N,N-diisopropylethylamine (136 mg, 1.05 mmol) was added with stirring. The reaction mixture was then stirred overnight at 100°C under an argon atmosphere. LC-MS showed that the major product was 18. The reaction mixture was cooled to room temperature, then saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were 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 obtain 18 (5.11 mg).MS (ESI) m / z: 907.4 [M+H+]; 'HNMR (400 MHz,DMSO-t / 6) 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).

[0308] Example 19

[0309] The desired product 19 (12.02 mg) was obtained with reference to Example 18. MS (ESI) Petition 870250078555, dated 03 / 09 / 2025, page 95 / 1278 83 / 161 m / z: 907,5 [M+H+], Ή 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= Ί,β 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= 16,0 Hz, 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).

[0310] Exemplo 20

[0311] The desired product 20 (1.96 mg) was obtained with reference to Example 12. MS (ESI) m / z: 892.6 [M+H+], Ή NMR(400 MHz,DMSO-t / 6) 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,lH), 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).

[0312] Example 21 Petition 870250078555, dated 03 / 09 / 2025, p. 96 / 1278 84 / 161

[0313] Step 1: B (300 mg, 891.84 pmol) was dissolved in MA-dim ethyl formamide (3 mL) at room temperature under an argon atmosphere, and propargyl alcohol (100 mg, 1.78 mmol), cesium carbonate (581 mg, 1.78 mmol), copper(I) iodide (34 mg, 1.78 pmol), and bis(triphenylphosphine)palladium(II) dichloride (62 mg, 89.18 pmol) were added sequentially. The reaction mixture was stirred at 80°C under an argon atmosphere for 2 hours. LC-MS showed that a small amount of the starting material B remained and the major product was 21a. The reaction mixture was cooled to room temperature, then added with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography to obtain 21a (81 mg, yield: 29%) as a yellow solid.'H NMR(400 MHz,DMSO-tÃ) δ 11.11 (s, 1H), 7.15 (d, J= Ί,β Hz, 1H), 7.08 (d, J= 8.0 Hz, 1H), 7.02 (t, J = Ί,β Hz, 1H), 5.42 - 5.36 (m, 2H), 4.36 (d, J= 6.0 Hz, 2H), 3.65 (s, 3H), 2.97 - 2.82 (m, 1H), 2.77 - 2.57 (m, 2H), 2.04 - 1.99 (m, 1H).

[0314] Step 2: Triethylamine (0.11 mL, 0.78 mmol) added to a solution of 21a (80 mg, 0.26 mmol) and 4-nitrophenyl chloroformate (105 mg, 0.52 mmol) and dichloromethane (2.0 Petition 870250078555, 03 / 09 / 2025, pág. 97 / 1278 85 / 161 mL) in an ice-cold water bath with stirring. The reaction mixture was returned to room temperature after 10 minutes and stirred for 2 hours under an argon atmosphere. LC-MS showed that the reaction was complete. Saturated aqueous sodium bicarbonate solution (15 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was separated by silica gel column chromatography and preparative thin-layer chromatography to obtain 21b (38 mg). MS (ESI) m / z: 479.1 [M+H+]. 1H NMR (400MHz, CDCl3) 1H), 5.22 - 5.17 (m, 1H), 5.14 (s, 2H), 3.78 (s, 3H), 2.99 - 2.93 (m, 1H), 2.87 - 2.70 (m, 2H), 2.26 - 2.22 (m, 1H).

[0315] Step 3: A (300 mg, 601.76 μmol) and 1-Boc-3-azetidinone (515 mg, 3.01 mmol) were dissolved in tetrahydrofuran (5 mL) in an ice-cold water bath, and sodium triacetoxyborohydride (510 mg, 2.41 mmol) was added in an ice-cold water bath with stirring. The reaction mixture was stirred at room temperature for 2 hours. LC-MS showed complete consumption of the starting material and formation of 21c. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (3 x 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 obtain 21c (240 mg). MS (ESI) m / z: 654.5 [M+H+].

[0316] Step 4: 21c (240 mg, 367.12 μmol) was dissolved in dichloromethane (4 mL) in an ice-cold water bath and trifluoroacetic acid (418 mg, 3.67 mmol) was added with stirring. The reaction mixture was slowly returned to room temperature and stirred for 1 hour. LC-MS showed that the starting material was completely consumed and 21D was the major product. The reaction mixture was concentrated under reduced pressure to obtain 21d (80 mg, crude trifluoroacetate salt).1H NMR (400 MHz, DMSO-de) 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 Petition 870250078555, dated 03 / 09 / 2025, page 98 / 1278 86 / 161 (m, 1H), 2.36 - 2.21 (m, 3H), 2.08 - 1.64 (m, 7H).

[0317] Step 5: 21d (60 mg, 108.69 pmol), 21b (40 mg, 83.61 qmol) and potassium carbonate (35 mg, 250.83 qmol) were dispersed in Λζ / V-dimethylformamide (2 mL) at room temperature. The reaction mixture was then heated to 60°C and stirred for 3 hours. LC-MS showed that a small amount of the starting material remained and a product was produced. The reaction mixture was cooled to room temperature, then saturated aqueous sodium bicarbonate solution (10 mL) was added and the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (6 x 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 obtain 21 (17.52 mg).MS (ESI) m / z: 893,4 [M+H+],1HNMR(400 MHz,DMSO-ó / ó) δ 11,12 (s, 1H), 9,49 (d, J= 5,2 Hz, 1H), 8,78 (d, J= Ί,β 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).

[0318] Exemplo 22

[0319] Etapa 1: 3-Butin-l-ol (0,5 g, 7,13 mmol) foi dissolvido em diclorometano (10 mL) à Petição 870250078555, de 03 / 09 / 2025, pág. 99 / 1278 87 / 161 at room temperature and p-toluenesulfonyl chloride (1.63 g, 8.56 mmol) and pyridine (850 mg, 10.70 mmol) were added sequentially in an ice-cold water bath with stirring. The reaction mixture was then stirred at room temperature for 26 hours. TLC showed that the starting material reacted completely. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with saturated brine (3 x 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). 1H NMR (400 MHz, CDCh) 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).

[0320] Step 2: 22a (201.8 mg, 0.90 mmol) was dissolved in N,N-dimethylformamide (4 mL) at room temperature and A (300 mg, 0.60 mmol) and cesium carbonate (586.5 mg, 1.80 mmol) were added with stirring. The reaction mixture was then stirred overnight at 60°C. LC-MS showed that the starting material reacted completely. Water (30 mL) was added to the cooled reaction mixture and then the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated aqueous sodium bicarbonate solution (2 x 30 mL), washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the resulting crude residue was separated by silica gel column chromatography to obtain the desired product 22b (123 mg).MS (ESI) m / z: 551.4 [M+H+]; 1H NMR (400 MHz, CDCh) 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).

[0321] Step 3: 22b (123 mg, 0.22 mmol) and B (50 mg, 0.15 mmol) were dissolved in dry N,N-dimethylformamide (2 mL) at room temperature under an argon atmosphere, and then cesium carbonate (122.2 mg, 0.38 mmol), bis(triphenylphosphine)palladium(II) dichloride (16 mg, 0.022 mmol), and copper(I) iodide (9.0 mg, 0.045 mmol) were added sequentially under an argon atmosphere. The reaction was then stirred at 80°C under an argon atmosphere for 5 hours. LC-MS showed the formation of product 22. The mixture Petition 870250078555, dated 03 / 09 / 2025, pp. 100 / 1278 88 / 161 of the cooled reaction was filtered and the filter cake was washed with ethyl acetate (20 mL). Saturated aqueous sodium bicarbonate solution (10 mL) was added to the filtrate and then the mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic phases were washed with saturated sodium chloride solution (5 x 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 obtain the desired product 22 (6.9 mg). MS (ESI) m / z: 808.6 [M+H+]; 'HNMR (400 MHz, CDCh) 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= Ί,β 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).

[0322] Exemplo 23

[0323] O produto desejado 23 (20,25 mg) foi obtido com referência ao Exemplo 16. MS (ESI) m / z: 838,4 [M+H+]; 'HNMR (400 MHz,DMSO-t / 6) δ 11,12 (s, 1H), 9,50 (d, J= 5,2 Hz, 1H), 8,78 (d, J= Ί,β Hz, 1H), 8,41 (d, J= 4,0 Hz, 1H), 8,26 (d, J= 5,6 Hz, 1H), 7,29 - 7,01 (m, 4H), 6,88 - 6,44 (m, 1H), 5,43 - 5,38 (m, 1H), 5,28 - 5,07 (m, 1H), 5,01 - 4,94 (m, 3H), 4,77 (d, J = 15,2 Hz, 1H), 3,84 - 3,72 (m, 2H), 3,65 - 3,59 (m, 5H), 3,47 - 3,39 (m, 3H), 3,39 - 3,32 (m, Petição 870250078555, de 03 / 09 / 2025, pág. 101 / 1278 89 / 161 1H), 2,94 - 2,85 (m, 1H), 2,76 - 2,60 (m, 2H), 2,43 - 2,37 (m, 2H), 2,26 - 2,20 (m, 2H), 2,08 1,95 (m, 3H), 1,67 - 1,57 (m, 4H).

[0324] Exemplo 24

[0325] Step 1: 4-Pentinoic acid (2 g, 19.04 mmol) and tert-butanol (21.16 g, 285.46 mmol) were dissolved in dichloromethane (40 mL) at room temperature, and dicyclohexylcarbodiimide (DCC, 6.31 g, 30.59 mmol) and 4-dimethylaminopyridine (DMAP, 0.5 g, 4.08 mmol) were added in an ice-cold water bath with stirring. The reaction mixture was then stirred at room temperature overnight. TLC showed that the starting material reacted completely. The reaction mixture was added with dilute hydrochloric acid (0.5 M, 50 mL) and then extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with saturated brine (3 x 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 24a (1.27 g). 'H NMR(400 MHz, CDC13) δ 2.45 (s, 4H), 1.97 (s, 1H), 1.46 (s, 9H).

[0326] Subsequent procedures were carried out with reference to Example 8 to obtain the desired product 24 (17.05 mg). MS (ESI) m / z: 836.6 [M+H+], 'H NMR(400 MHz, CDCh) δ 11.11 (s, 1H), 9.50 (d, J= 5.2 Hz, 1H), 8.79 (d, J= Ί,β 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), Petition 870250078555, dated 03 / 09 / 2025, p. 102 / 1278 90 / 161 2.25 - 2.19 (m, 2H), 2.09 - 1.90 (m, 3H), 1.70 - 1.50 (m, 4H).

[0327] Example 25

[0328] The desired product 25 (2.25 mg) was obtained with reference to Example 24. MS (ESI) m / z: 850.6 [M+H+]; 'HNMR (400 MHz,DMSO-t / 6) 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).

[0329] Example 26 Petition 870250078555, dated 03 / 09 / 2025, page 103 / 1278 91 / 161

[0330] Step 1: Dess-Martin periodinane (4.22 g, 9.94 mmol) was added to a stirred solution of tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (1.0 g, 4.97 mmol) in dichloromethane (20 mL) in an ice-cold water bath. The reaction mixture was returned to room temperature after 10 minutes and stirred for 1 hour under an argon atmosphere. TLC showed that the reaction was complete. The reaction mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (30 mL) and the combined filtrates were added with water and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated and the resulting residue was separated by silica gel column chromatography to obtain the desired 26a (567 mg).1H NMR (400 MHz, CDCh) 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).

[0331] Step 2: Dimethyl (l-diazo-2-oxopropyl)phosphonate (682 mg, 3.55 mmol) and potassium carbonate (670 mg, 4.85 mmol) were added to a stirred solution of 26a (630 mg, 3.23 mmol) in methanol (10 mL) at room temperature. The reaction mixture was stirred overnight at room temperature under an argon atmosphere. TLC showed that the starting material reacted completely. Water (30 mL) was added to the cooled reaction mixture, and then the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 26b (600 mg).1H NMR (400 MHz, DMSO-0 / 0) 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, Petition 870250078555, dated 03 / 09 / 2025, page 104 / 1278 92 / 161 2H), 1.37 (s, 9H).

[0332] Subsequent procedures were performed with reference to Example 18 to obtain the desired product 26 (14.70 mg). MS (ESI) M / Z:877.3 [M+H+]; Ή NMR (400 MHz,DMSO-tÃ) 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).

[0333] Example 27

[0334] The desired product 27 (6.33 mg) was obtained with reference to Example 26. MS (ESI) m / z: 905.4 [M+H+], Ή NMR(400 MHz,DMSO-tÃ) δ 11.13 (s, 1H), 9.51 (d, J= 5.2 Hz, 1H), 8.79 (d, J= Ί,β Hz, 1H), 8.41 (d, J= 4.0 Hz, 1H), 8.26 (d, J= 5.6 Hz, 1H), 7.30 - 6.97 (m, 4H), 6.89 - 6.44 (m, 1H), 5.42 - 5.37 (m, 1H), 5.28 - 5.08 (m, 1H), 5.00 - 4.95 (m, 1H), 4.80 - 4.75 (m, 1H), 3.84 - 3.72 (m, 2H), 3.64 - 3.43 (m, 7H), 3.13 - 3.04 (m, 4H), 2.95 - 2.84 (m, 1H), 2.77 - 2.60 (m, 4H), 2.41 - 2.33 (m, 2H), 2.24 - 2.16 (m, 2H), 2.08 - 1.95 (m, 4H), 1.79 - 1.58 (m, 7H), 1.38 - 1.25 (m, 3H).

[0335] Example 28 Petition 870250078555, dated 03 / 09 / 2025, p. 105 / 1278 93 / 161

[0336] Step 1: 2-(Prop-2-en-l-yloxy)tetrahydro-2H-pyran (312 mg, 2.22 mmol), B (300 mg, 0.9 mmol), cesium carbonate (876.6 mg, 2.7 mmol), copper(I) iodide (618 mg, 0.09 mmol) and bis(triphenylphosphine)palladium(II) dichloride (60 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (6 mL) at room temperature. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred in an oil bath at 85°C for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL * 3) and the organic phases were combined, 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 obtain 28a (140 mg).MS (ESI) m / z: 398,1 [M+EE], 'H NMR(400 MHz, CDC13) 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. Petição 870250078555, de 03 / 09 / 2025, pág. 106 / 1278 94 / 161 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).

[0337] Step 2: 28a (140 mg, 0.352 mmol) and p-toluenesulfonic acid (72 mg, 0.704 mmol) were dissolved in methanol (5 mL). The reaction system was purged with nitrogen and stirred at 25°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first diluted by the addition of dichloromethane (30 mL). The reaction mixture was washed with water (30 mL x 3) three times and the organic phase was extracted. The organic phase was washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 28b (70 mg). MS (ESI) m / z: 314.1 [M+H+]. 1H NMR (400MHz, DMSO) 1H), 4.36 (s, 2H), 2.96 - 2.83 (m, 1H), 2.65 (s, 2H), 1.99 (s, 1H), 1.17 (s, 1H).

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

[0339] Step 4: (S)-Pyrrolidin-3-ylmethanol (1.5 g, 14.5 mmol), di-tert-butyl dicarbonate (4.6 g, 22 mmol), 4-dimethylaminopyridine (180 mg, 1.45 mmol), and triethylamine (3.0 g, 29 mmol) were dissolved in dichloromethane (10 mL) at room temperature. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred in an oil bath at 25°C for 12 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3) and the organic phases were combined and washed. Petition 870250078555, dated 03 / 09 / 2025, page 107 / 1278 95 / 161 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 obtain 28d (1.8 g).

[0340] Step 5: 28d (300 mg, 1.5 mmol) and triethylamine (450 mg, 4.5 mmol) were dissolved in dichloromethane (5 mL) at room temperature. The reaction system was cooled to 0°C and methanesulfonyl chloride (258 mg, 2.25 mmol) was added slowly dropwise. The system was then evacuated and purged with nitrogen several times. The reaction mixture was stirred in an oil bath at 25°C for 12 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (15 mL χ 3) and the organic phases were combined, washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 28e (340 mg).

[0341] Step 6: 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) at room temperature. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred in an oil bath at 90°C for 12 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL χ3), and the organic phases were combined, 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 obtain 28f (270 mg). MS (ESI) m / z: 583.1 [M+H+].

[0342] Step 7: 28f (270 mg, 0.39 mmol) was dissolved in dioxane (3 mL) at room temperature, and then dioxane hydrochloride (3 mL) was added dropwise at 0 °C. The reaction mixture was stirred in an oil bath at 25 °C for 2 hours. After LCMS monitoring showed the disappearance of the starting material, the mixture was concentrated under reduced pressure, and then the pH was adjusted to 7-8. 28 g (170 mg) were then obtained by preparative reversed-phase chromatography. MS (ESI) m / z: 583.1 [M+H+].

[0343] Step 8: 28 g (300 mg, 0.9 mmol), cesium carbonate (876.6 mg, 2.7 mmol), iodide Petition 870250078555, dated 03 / 09 / 2025, page 108 / 1278 96 / 161 of copper(I) (618 mg, 0.09 mmol) and bis(triphenylphosphine)palladium(II) dichloride (60 mg, 0.09 mmol) were dissolved in M ​​A-dimethylformamide (6 mL) at room temperature. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred in an oil bath at 85°C for 3 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL χ 3) and the organic phases were combined, 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 obtain 28 (140 mg).MS (ESI) m / z: 398.1 [M+H+],1HNMR(400 MHz, CDC13) 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).

[0344] Example 29

[0345] Step 1: Methyl (lR,3R)-3-hydroxycyclobutane-l-carboxylate (5.0 g, 38.4 mmol) was dissolved in dry tetrahydrofuran (32 mL) and placed in an ice water bath. After the reaction system was cooled to 0°C, lithium aluminum hydride (2.5 M, 30.7 mL) was slowly added dropwise to the reaction mixture under a nitrogen atmosphere and the Petition 870250078555, dated 03 / 09 / 2025, p. 109 / 1278 The reaction was stirred at 0°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first diluted by the addition of tetrahydrofuran (300 mL) and then O₂(-1001 hO₂) 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 to obtain 29A (2.7 g). 1H 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).

[0346] 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 system was purged with nitrogen and placed in an ice water bath. After the reaction system was cooled to 0°C, tert-butyldiphenylsilyl chloride (8.1 g, 29.4 mmol) was slowly added dropwise to the reaction mixture under a nitrogen atmosphere, and the reaction was stirred at 25°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first diluted by the addition of dichloromethane (30 mL). The reaction mixture was washed with water (30 mL x 3) three times, and the organic phase was extracted. The organic phase was washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 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).

[0347] Step 3: 29b (220 mg, 0.65 mmol) was dissolved in dry tetrahydrofuran (3.5 mL) and the reaction system was purged with nitrogen and placed in an ice water bath. After the reaction system was cooled to 0°C, sodium hydride (52 mg, 1.30 mmol) was slowly added to the reaction mixture under a nitrogen atmosphere. After the reaction had been stirred at 0°C for 1 hour, propargyl bromide (153.4 mg, 1.29 mmol) was slowly added dropwise to the reaction system and the reaction was slowly returned to room temperature and stirred overnight. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first quenched by the addition of aqueous solution. Petition 870250078555, dated 03 / 09 / 2025, page 110 / 1278 98 / 161 saturated ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 29c (190 mg). 1H 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).

[0348] 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 mixture. The reaction mixture was stirred at room temperature for another 2 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (15 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 29d (70 mg). 1H 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).

[0349] Step 5: 29D (31.1 mg, 0.22 mmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1Hbenzo[d]imidazol-1-yl)piperidine-2,6-dione (50.0 mg, 0.15 mmol), cesium carbonate (344.3 mg, 0.75 mmol), copper(I) iodide (2.8 mg, 0.015 mmol), and bis(triphenylphosphine)palladium(II) 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 purged with nitrogen several times. The reaction mixture was stirred in a sealed tube in an oil bath at 85°C for 3 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL χ 3) and the organic phases were combined, 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 obtain 29e (12 mg).1H NMR(400. Petition 870250078555, dated 03 / 09 / 2025, p. 111 / 1278 99 / 161 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).

[0350] Step 6: 29E (110 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL) at room temperature. Triethylamine (85 mg, 0.84 mmol) and p-toluenesulfonyl chloride (47.8 mg, 0.42 mmol) were added at 0°C and the reaction mixture was stirred at room temperature for 2 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with dichloromethane (30 mL x 3) and the organic phases were combined, 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 obtain 29f (100 mg). MS (ESI) m / z: 476.2 [M+H+].

[0351] Step 7: 29F (100 mg, 0.21 mmol) and A (115.0 mg, 0.23 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature. Potassium carbonate (86.9 mg, 0.63 mmol) was then added. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred at 50°C for 18 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3) and the organic phases were combined, washed with saturated brine (30 mL), 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 obtain 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), 2,21 - 2,11 (m, 3H), 2,07 - 1,93 (m, 7H), 1,58 (dd, J = 16,5 Hz, 4H). Petição 870250078555, de 03 / 09 / 2025, pág. 112 / 1278 100 / 161

[0352] Exemplo 30

[0353] O produto desejado 30 (8,5 mg) foi obtido com referência ao Exemplo 29. MS (ESI) M / Z:878,4 [M+H+], Ή NMR(400 MHz, DMSO) δ 11,12 (s, 1H), 9,50 (d, J= 5,3 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), 7,29 - 6,97 (m, 4H), 6,87 (d, J= 7,9 Hz, 0,5H), 6,45 (d, J= 7,8 Hz, 0,5H), 5,40 (dd, J= 12,6, 5,3 Hz, 1H), 5,27 (s, 0,5H), 5,07 (s, 0,5H), 4,98 - 4,88 (m, 1H), 4,77 (d, J= 16,0 Hz, 1H), 4,43 (s, 2H), 3,85 - 3,72 (m, 3H), 3,63 (d, J= 3,8 Hz, 3H), 3,59 (s, 1H), 3,45 (d, J= 9,8 Hz, 0,5H), 3,33 (s, 0,5H), 2,88 (m, J= 20,3, 9,5 Hz, 1H), 2,78 - 2,57 (m, 2H), 2,31 (m, J= 12,5, 5,1 Hz, 4H), 2,22 (s, 1H), 2,19 - 2,12 (m, 2H), 2,10 - 1,90 (m, 6H), 1,79 (m, J= 10,7 Hz, 2H), 1,64 (m, 2H), 1,58 (m, 3H), 1,46 (m, J= 12,9 Hz, 4H), 1,25 - 1,18 (m, 2H).

[0354] Exemplo 31 Petição 870250078555, de 03 / 09 / 2025, pág. 113 / 1278 101 / 161

[0355] Step 1: (lr,4r)-4-hydroxycyclohexane-1-carboxylate methyl (5.0 g, 31.6 mmol) was dissolved in dry tetrahydrofuran (50 mL) and placed in an ice water bath. After the reaction system was cooled to 0°C, lithium aluminum hydride (2.5 M, 25.2 mL) was slowly added dropwise to the reaction mixture under a nitrogen atmosphere, and the reaction was stirred at 0°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first diluted by the addition of tetrahydrofuran (300 mL), and then Na₂SO₄·1OH₂O 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 to obtain 31a (2.6 g).^NMRIDO 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).

[0356] 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 system was purged with nitrogen and placed in an ice water bath. After the reaction system was cooled to 0°C, tert-chloride Petition 870250078555, dated 03 / 09 / 2025, page 114 / 1278 102 / 161 butyldiphenylsilyl (5.8 g, 21.2 mmol) was added slowly dropwise to the reaction mixture under a nitrogen atmosphere, and the reaction was stirred at 25°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first diluted by the addition of dichloromethane (50 mL). The reaction mixture was washed with water (50 mL χ 3) three times, and the organic phase was extracted. The organic phase was washed with saturated brine (300 mL χ 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 31b (3.8 g). 1H 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).

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

[0358] Step 4: 31c (1.8 g, 4.4 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and then tetrabutylammonium fluoride (1.0 M, 8.8 mL) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature for another 2 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, first washed with saturated brine (50 mL), then dried. Petition 870250078555, dated 03 / 09 / 2025, pages 115 / 1278 103 / 161 on anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 31d (670 mg). 1H 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).

[0359] Step 5: 31d (364.9 mg, 2.25 mmol), B (500.0 mg, 1.5 mmol), cesium carbonate (2.4 g, 7.5 mmol), copper(I) iodide (28.5 mg, 0.15 mmol), and bis(triphenylphosphine)palladium(II) dichloride (105.1 mg, 0.15 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred in a sealed tube in an oil bath at 85°C for 3 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (200 mL). The mixture was extracted with ethyl acetate (200 mL x 3) and the organic phases were combined, 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 obtain 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).

[0360] Step 6: 31e (270 mg, 0.63 mmol) was dissolved in dichloromethane (8 mL) at room temperature. Triethylamine (318.8 mg, 3.1 mmol) and ptoluenesulfonyl chloride (291.9 mg, 2.5 mmol) were added at 0°C and the reaction mixture was stirred at room temperature for 2 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with dichloromethane (30 mL x 3) and the organic phases were combined, 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 obtain 31f (160 mg). MS (ESI) m / z: 504.0 [M+H+].

[0361] Step 7: 31f (160 mg, 0.32 mmol) and A (207.2 mg, 0.42 mmol) were dissolved in Petition 870250078555, dated 03 / 09 / 2025, pp. 116 / 1278 104 / 161 Λζ / V-dimethylformamide (4 mL) at room temperature. Potassium carbonate (176.6 mg, 1.28 mmol) was then added. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred at 50°C for 18 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL * 3) and the organic phases were combined, 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 obtain the final product 31 (18.9 mg).MS (ESI) m / z: 906.8 [M+H+],1HNMR(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= 22.8Hz, 4H), 1.52- 1.38 (m, 1H), 1.21-1.07 (m, 2H), 0.95 - 0.76 (m, 2H).

[0362] Example 32

[0363] The desired product 32 (12.39 mg) was obtained with reference to Example 31. MS (ESI) Petition 870250078555, dated 03 / 09 / 2025, pp. 117 / 1278 105 / 161 M / Z:906,5 [M+H+], Ή NMR(400 MHz, DMSO) δ 11,12 (s, 1H), 9,50 (d, J= 5,3 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), 7,29 - 6,97 (m, 4H), 6,87 (d, J= 7,9 Hz, 0,5H), 6,45 (d, J= 7,8 Hz, 0,5H), 5,40 (dd, J= 12,6, 5,3 Hz, 1H), 5,27 (s, 0,5H), 5,07 (s, 0,5H), 4,98 - 4,88 (m, 1H), 4,77 (d, J= 16,0 Hz, 1H), 4,43 (s, 2H), 3,85 - 3,72 (m, 3H), 3,63 (d, J= 3,8 Hz, 3H), 3,59 (s, 1H), 3,45 (d, J= 9,8 Hz, 0,5H), 3,33 (s, 0,5H), 2,88 (m, J = 20,3, 9,5 Hz, 1H), 2,78 - 2,57 (m, 2H), 2,31 (m, J = 12,5, 5,1 Hz, 4H), 2,22 (s, 1H), 2,19 - 2,12 (m, 2H), 2,10 - 1,90 (m, 6H), 1,79 (m, J= 10,7 Hz, 2H), 1,64 (m, 2H), 1,58 (m, 3H), 1,46 (m, J= 12,9 Hz, 4H), 1,25 - 1,18 (m, 2H).

[0365] The desired product 33 (2.4 mg) was obtained with reference to Example 4. MS (ESI) m / z: 892.4 [M+H+],1HNMR(400 MHz, DMSO) δ 11.12 (s, 1H), 9.49 (d, J = 5.2 Hz, 1H), 8.79 (d, J = 7.7 Hz, 1H), 8.39 (d, J = 3.8 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.19 - 7.08 (m, 2.5H), 7.03 (t, J = 7.9 Hz, 1.4H), 6.87 (d, J = 7.8 Hz, 0.49H), 6.45 (d, J = 7.8 Hz, 0.53H), 5.40 (dd, J = 12.6, 5.4 Hz, 1H), 5.27 (s, 0.5H), 5.08 (s, 0.5H), 4.97 - 4.87 (m, 1H), 4.77 (d, J = 15.5 Hz, 1H), 4.47 - 4.41 (m, 2H), 3.82 (d, J=9.9Hz, 1.4H), 3.74 (d, J=7.2Hz, 1H), 3.65 - 3.63 (m, 3.64H), 3.59 (s, 1H), 3.48 - 3.39 (m, 1H), 3.29 (s, 1H), 2.93 - 2.84 (m, 1H), 2.75 - 2.60 (m, 2H), 2.46 - 2.42 (m, 1H), 2.38 - 2.23 (m, 5H), 2.07 - 1.98 (m, 3H), 1.94 - 1.86 (m, 2H), 1.75 (d, 1H), 1.65 - 1.65 (m, 3H), 1.49 - 1.42 (m, 2H), 1.21 (m, 1H). Petition 870250078555, dated 03 / 09 / 2025, pp. 118 / 1278 106 / 161

[0366] Example 34

[0367] The desired product 34 (13.58 mg) can be found in Example 3. MS (ESI) M / Z:919.2 [M+H+], ΉΝΜΚ^ΟΟ 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), 7.30 - 6.96 (m, 4H), 6.87 (d, J= 8.0 Hz, 0.5H), 6.45 (d, J= 7.8 Hz, 0.5H), 5.39 (dd, J= 12.8, 5.2 Hz, 1H), 5.27 (s, 0.5H), 5.07 (s, 0.5H), 4.99 - 4.88 (m, 1H), 4.77 (d, J= 17.4 Hz, 1H), 3.84 - 3.72 (m, 2H), 3.65 (d, J= 3.6 Hz, 3H), 3.60 (d, J= 11.7 Hz, 1H), 3.45 (d, J= 10.3 Hz, 1H), 3.11 (d, J= 10.0 Hz, 2H), 2.97 - 2.83 (m, 1H), 2.77 - 2.60 (m, 3H), 2.39 - 2.27 (m, 5H), 2.17 (t, J= 10.3 Hz, 6H), 2.09 - 1.86 (m, 4H), 1.79 - 1.58 (m, 6H), 1.43 (s, 6H), 1.18 - 1.03 (m, 2H).

[0368] Example 35 Petition 870250078555, 03 / 09 / 2025, pág. 119 / 1278 107 / 161

[0369] Step 1: Sodium hydride (8.6 g, 38.4 mmol) was dissolved in dry tetrahydrofuran (50 mL). The reaction system was purged with nitrogen and placed in an ice water bath. After the reaction system was cooled to 0°C, l,4-dioxaspiro[4.5]decan-8-one (5.0 g, 32.0 mmol dissolved in 10 mL of tetrahydrofuran) was slowly added to the reaction mixture under a nitrogen atmosphere. After the reaction was stirred at 0°C for 1 hour, the reaction mixture was cooled to -20°C and ethyl 2-(dimethoxyphosphoryl)acetate (8.6 g, 38.4 mmol dissolved in 8 mL of tetrahydrofuran) was slowly added dropwise to the reaction system. The reaction mixture was then slowly returned to room temperature and stirred for 2.5 hours. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first quenched by the addition of water (500 mL). The mixture was extracted with ethyl acetate (500 mL x 3).The organic phases were combined, first washed with saturated brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 35a (4.4 g). Ή NMR (400 MHz, DMSO) δ 5.45 - 5.32 (m, 1H), 4.05 (dt, J= 12.3, 4.2 Hz, 2H), 3.86 (s, 4H), 2.97 (s, 2H), 2.20 - 2.07 (m, 4H), 1.65 (t, J= 6.5 Hz, 2H), 1.17 (t, J= 7.1 Hz, 3H).

[0370] Step 2: 35a (4.0 g, 17.6 mmol) and palladium on carbon (4.0 g, 17.6 mmol) were dissolved in ethanol (25 mL) and the reaction system was stirred under an atmosphere of Petition 870250078555, dated 03 / 09 / 2025, pp. 120 / 1278 108 / 161 hydrogen at room temperature for 3 hours. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first diluted by the addition of ethanol (100 mL) and the black solid was filtered through a Büchner funnel. The filter cake was washed twice with ethanol and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to obtain 35b (2.2 g). MS (ESI) m / z: 229.1 [M+H+].

[0371] Step 3: 35B (2.2 g, 9.6 mmol) was dissolved in dry tetrahydrofuran (30 mL) and the reaction system was placed in an ice water bath. After the reaction system was cooled to 0°C, lithium aluminum hydride (2.5 M, 7.7 mL) was slowly added dropwise to the reaction mixture under a nitrogen atmosphere and the reaction was stirred at 0°C for 3 hours. After TLC monitoring showed the disappearance of the starting material, the reaction mixture was first diluted by the addition of tetrahydrofuran (300 mL) and then Ni-uSO-tiOI l:O 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, followed by distillation and drying in suspension under reduced pressure to obtain 35°C (1.45 g).1H 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).

[0372] Step 4: Oxalyl chloride (0.2 mL, 2.42 mmol) was dissolved in dry dichloromethane (3 mL). The reaction system was purged with nitrogen and placed in a dry ice-acetone bath. After the reaction system was cooled to -78°C, 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 the reaction had been stirred at -78°C for 0.5 hours, 35C (300 mg, 1.61 mmol dissolved in 3 mL of dichloromethane) was slowly added dropwise to the reaction system and the reaction was stirred at -78°C for another hour. After TLC monitoring showed the disappearance of the starting material, triethylamine (12 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 0.5 hours. Next, water (50 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with brine. Petition 870250078555, dated 03 / 09 / 2025, pages 121 / 1278 109 / 161 saturated (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 obtain 35d (250 mg, yield: 84.4%). 1H 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).

[0373] Step 5: 35d (250 mg, 1.36 mmol) and potassium carbonate (563.1 mg, 4.08 mmol) were dissolved in methanol (5 mL) at room temperature. Then, dimethyl (1-diazo-2-oxopropyl)phosphonate (313.0 mg, 4.08 mmol) was added and the reaction mixture was stirred at room temperature for 18 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was concentrated under reduced pressure and water (30 mL) was added to the residue for quenching. The mixture was extracted with ethyl acetate (30 mL χ 3) and the organic phases were combined, 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 obtain 35e (220 mg, yield: 89.8%).1H 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).

[0374] Step 6: 35e (167.1 mg, 0.93 mmol), B (200.0 mg, 0.62 mmol), cesium carbonate (1.0 g, 3.1 mmol), copper(I) iodide (11.8 mg, 0.062 mmol), and bis(triphenylphosphine)palladium(II) dichloride (43.5 mg, 0.062 mmol) were dissolved in N,N-dimethylformamide (16 mL) at room temperature. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred in a sealed tube in an oil bath at 85°C for 3 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (200 mL). The mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, 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 obtain 35f (100 mg). MS (ESI) m / z: 438.3 [M+H+].

[0375] Step 7: At room temperature, 35f (100 mg, 0.23 mmol) was dissolved in Petition 870250078555, dated 03 / 09 / 2025, pages 122 / 1278 110 / 161 dichloromethane / acetone (4 mL / 1 mL) and then iron(III) chloride hexahydrate (216.5 mg, 0.8 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 35 g (62 mg). MS (ESI) m / z: 394.0 [M+H+].

[0376] Step 8: At room temperature, 35 g (60 mg, 0.15 mmol) were dissolved in a mixture of tetrahydrofuran / N,N-dimethylformamide (0.8 mL / 0.4 mL), and then A (83.4 mg, 0.17 mmol) and potassium acetate (16.2 mg, 0.17 mmol) were added to the reaction mixture. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred at 25°C for 2 hours. Then, sodium cyanoborohydride (18.9 mg, 0.30 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred at room temperature for another 2 hours. After LC-MS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (50 mL x 3).The organic phases were combined, first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography to obtain 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).

[0377] Example 36 Petition 870250078555, dated 03 / 09 / 2025, pages 123 / 1278 111 / 161

[0378] O produto desejado 36 (11,4 mg) foi obtido com referência ao Exemplo 20. MS (ESI) m / z: 892,4 [M+H+],1HNMR(400 MHz, DMSO) δ 11,12 (s, 1H), 9,50 (d, J = 5,1 Hz, 1H), 8,79 (d, J = 7,7 Hz, 1H), 8,41 (d, J = 4,1 Hz, 1H), 8,26 (d, J = 5,7 Hz, 1H), 7,35 - 6,94 (m, 4H), 6,87 (d, J = 7,9 Hz, 0,5H), 6,46 (d, J = 7,7 Hz, 0,5H), 5,40 (dd, J = 12,6, 5,3 Hz, 1H), 5,28 (s, 0,5H), 5,08 (s, 0,5H), 5,03 - 4,91 (m, 1H), 4,77 (d, J = 17,3 Hz, 1H), 4,37 (s, 2H), 4,23 - 4,13 (m, 1H), 3,87 - 3,71 (m, 2H), 3,64 (s, 3H), 3,63 - 3,57 (m, 1,5H), 3,52 - 3,37 (m, 2,5H), 3,26 3,17 (m, 1H), 2,96 - 2,81 (m, 1H), 2,77 - 2,60 (m, 2H), 2,43 - 2,34 (m, 4H), 2,26 - 2,18 (m, 5H), 2,06 - 1,91 (m, 4H), 1,65 - 1,50 (m, 4H)

[0379] Exemplo 37 Petição 870250078555, de 03 / 09 / 2025, pág. 124 / 1278 112 / 161 NaBH4. MeOH 0 °C to rt MsCITEA DCM Etapa 1 Etapa 2

[0380] The desired product 37 (2.44 mg) was obtained with reference to Example 1. MS (ESI) m / z: 866.3 [M+H+]; 'HNMR (400 MHz, CDCh) δ 9.61 (s, 1H), 8.69 (s, 1H), 8.54 - 8.27 (m, 3H), 7.18 (d, J= 7.9 Hz, 1H), 6.99 (t, J= 7.9 Hz, 1H), 6.92 - 6.61 (m, 2H) 3.54 (dd, J= 36.4, 9.4 Hz, 2H), 3.02 - 2.57 (m, 7H), 2.25 (s, 1H), 2.09 (s, 1H), 2.01 - 1.59 (m, 12h), 1.30 - 1.20 (m, 4H).

[0381] Example 38 Petition 870250078555, dated 03 / 09 / 2025, pages 125 / 1278 113 / 161

[0382] The desired product 38 (1.96 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 892.1 [M+H+];1H NMR (400 MHz,DMSO-de) δ 11.15 (s, 1H), 10.03 (s, 1H), 9.51 (s, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.20 - 6.99 (m, 5H), 6.88 6.47 (m, 1H), 5.50 - 5.05 (m, 2H), 4.80 - 4.75 (m, 1H), 4.43 (s, 2H), 4.20 - 4.15 (m, 1H), 3.88 - 3.55 (m, 5H), 2.89 - 2.66 (m, 8H), 2.23 - 2.10 (m, 5H), 2.03 - 1.88 (m, 10H), 1.55 - 1.40 (m, 5H).

[0383] Example 39 o2n

[0384] The desired product 39 (1.22 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 921.3 [M+H+]; 1H NMR (400 MHz, Methanol-d4 )δ 9.74 (s, 1H), 8.52 (d, J =7.9 Hz, 1H), 8.43 - 8.23 ​​(m, 3H), 7.50 - 7.32 (m, 3H), 7.27 - 7.12 (m, 4H), 7.11 - 6.68 (m, 2H), 6.44 (d, J = 8.4 Hz, 1H), 5.46 - 5.29 (m, 2H), 4.73 - 4.45 (m, 3H), 4.27 - 4.17 (m, 2H), 4.00 - 3.94 (m, 3H), 3.83 - 3.63 (m, 6H), 2.95 - 2.75 (m, 6H), 2.23 - 1.85 (m, 11H).

[0385] Example 40 Petition 870250078555, dated 03 / 09 / 2025, pp. 126 / 1278 114 / 161

[0386] The desired product 40 (1.52 mg) was obtained with reference to the examples mentioned above. MS (ESI) M / Z: 906.2 [M+H]+; 'HNMR (400 MHz, Methanol-íZ / ) δ 8.51 (d, J = 7.8 Hz, 1H), 8.41 - 8.26 (m, 3H), 7.19 - 7.12 (m, 3H), 7.10 - 6.97 (m, 2H), 6.87 (d, J= 8.5 Hz, 1H), 6.73 (d, J= 8.0 Hz, 1H), 6.43 (d, J= 7.8 Hz, 1H), 5.46 - 5.30 (m, 2H), 4.79 (d, J= 7.2 Hz, 1H), 4.38 (d, J= 3.9 Hz, 2H), 4.16 - 4.14 (m, 2H), 3.93 (d, J= 3.9 Hz, 2H), 3.74 (s, 4H), 3.73 - 3.62 (m, 2H), 3.50 (d, J= 9.8 Hz, 1H), 2.82 - 2.79 (m, 8H), 2.58 - 2.53 (m, 2H), 2.23 2.13 (m, 3H), 2.07 (d, J= 18.9 Hz, 2H), 2.01 - 1.95 (m, 5H), 1.56 (s, 3H).

[0387] Example 41 Petition 870250078555, dated 03 / 09 / 2025, pp. 127 / 1278 115 / 161

[0388] The desired product 41 (2.38 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 921.3 [M+H+]; 'HNMR (400 MHz, DMSO-óL) δ 11.13 (s, 1H), 9.50 (d, J= 6.0 Hz, 1H), 8.78 (d, J= 7.7 Hz, 1H), 8.40 (d, J= 4.8 Hz, 1H), 8.26 (d, J= 5.4 Hz, 1H), 7.27 - 7.02 (m, 4H), 6.88 - 6.43 (m, 1H), 5.44 - 5.36 (m, 1H), 5.28 - 5.06 (m, 1H), 4.77 (d, J = 17.3 Hz, 1H), 4.51 (s, 2H), 4.26 - 4.15 (m, 1H), 3.82 - 3.51 (m, 14H), 3.03 - 2.83 (m, 3H), 2.78 - 2.60 (m, 3H), 2.08 - 1.89 (m, 8H), 1.81 - 1.71 (m, 2H), 1.65 - 1.55 (m, 2H), 1.45 1.36 (m, 2H).

[0389] Example 42

[0390] The desired product 42 (24.29 m, salt format) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 893.2 [M+H+]; Ή NMR (400 MHz, DMSO-óL) δ 11.13 (s, 1H), 9.56 - 9.44 (m, 1H), 8.78 (d, J= 7.8 Hz, 1H), 8.45 - 8.37 (m, 1H), 8.26 (d, J= 5.4 Hz, 1H), 7.27 - 7.02 (m, 4H), 6.89 - 6.43 (m, 1H), 5.45 - 5.36 (m, 1H), 5.28 - 5.07 (m, 1H), 4.77 (d, J= 17.4 Hz, 1H), 4.47 (s, 2H), 4.26 - 4.16 (m, 1H), 4.14 - 4.05 (m, 2H), 3.85 - 3.74 (m, 4H), 3.70 - 3.53 (m, 8H), 2.96 - 2.83 (m, 1H), 2.78 - 2.58 (m, 3H), 2.08 - 1.84 (m, 8H), 1.81 Petition 870250078555, dated 03 / 09 / 2025, page 128 / 1278 116 / 161 1.67 (m, 2H), 1.66 - 1.54 (m, 2H).

[0391] Example 43

[0392] The desired product 43 (4.1 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 949.1 [M+H+]; 'HNMR (400 MHz, DMSO-óL) δ 11.13 (s, 1H), 9.50 (d, J= 5.9 Hz, 1H), 8.79 (d, J= 7.7 Hz, 1H), 8.42 (d, J= 4.7 Hz, 1H), 8.26 (d, J= 5.7 Hz, 1H), 7.25 - 7.00 (m, 4H), 6.88 - 6.44 (m, 1H), 5.41 (dd, J= 12.7, 5.3 Hz, 1H), 5.28 - 5.07 (m, 1H), 4.77 (d, J= 16.4 Hz, 1H), 4.50 (s, 2H), 4.22 - 4.18 (m, 1H), 3.86 - 3.79 (m, 1H), 3.74 (d, J= 7.9 Hz, 1H), 3.65 (s, 3H), 3.59 (s, 1H), 3.45 - 3.30 (m, 4H), 3.14 (s, 4H), 2.93 - 2.86 (m, 3H), 2.80 - 2.58 (m, 3H), 2.11 - 1.94 (m, 4H), 1.94 - 1.75 (m, 8H), 1.65 - 1.20 (m, 6H).

[0393] Example 44 Petition 870250078555, dated 03 / 09 / 2025, pages 129 / 1278 117 / 161 LiAIH* THF Step 1 Br Step 3 DMP, DCM Pd(PPh3)2CI2, Cul CS2CO3 Step 4 NaH Step 2

[0394] The desired product 44 (11.14 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 878.60 [M+H+]; Ή NMR (400 MHz, CDCh) δ 10.39 (s, 1H), 9.67 (d, J= 12.4 Hz, 1H), 8.69 - 8.56 (m, 2H), 8.33 (dd, J= Ί,β, 2.0 Hz, 1H), 7.20 (d, J= 8.0 Hz, 1H) 4.52 - 4.46 (m, 1H), 4.32 - 4.22 (m, 1H), 3.97 (s, 3H), 3.80 (d, J= 6.8 Hz, 4H), 3.58 (d, J= 9.6 Hz, 1H), 3.49 (d, J= 9.6 Hz, 1H), 3.39 - 3.20 (m, 2H), 2.95 - 2.80 (m, 4H), 2.40 - 2.16 (m, 8H), 2.11 - 2.08 (m, 2H), 2.00 - 1.97 (m, 1H), 1.46 - 1.43 (m, 2H), 1.29 - 1.24 (m, 3H), 1.07 - 0.84 (m, 2H).

[0395] Example 45 Petition 870250078555, dated 03 / 09 / 2025, page 130 / 1278 118 / 161

[0396] The desired product 45 (2.19 mg, salt formate) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 907.2 [M+H+]; 'HNMR (400 MHz, CDCh) δ 9.60 (s, 1H), 8.42 (s, 2H), 8.31 (s, 1H), 8.21 (s, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.98 (d, J= Ί,β Hz, 1H), 6.91 - 6.57 (m, 2H), 6.15 - 6.11 (m, 1H), 5.45 (s, 1H), 5.36 - 5.18 (m, 2H), 4.79 (s, 1H), 4.33 (s, 3H), 4.21 (d, J= 7.4 Hz, 1H), 4.05 - 3.95 (m, 3H), 3.77 (s, 3H), 3.69 (s, 2H), 3.65 - 3.45 (m, 4H), 2.95 - 2.72 (m, 4H), 2.50 (s, 1H), 2.25 - 2.20 (m, 2H), 2.15 - 1.95 (m, 7H), 1.85 - 1.15 (m, 6H).

[0397] Example 46 Petition 870250078555, dated 03 / 09 / 2025, page 131 / 1278 119 / 161

[0398] The desired product 46 (14.13 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 934.3 [M+H+]; 'HNMR (400 MHz, DMSO-tfc) δ 11.12 (s, 1H), 9.49 (d, J= 5.4 Hz, 1H), 8.79 (d, J= 7.7 Hz, 1H), 8.41 (d, J= 4.2 Hz, 1H), 8.25 (d, J= 5.6 Hz, 1H) 4.77 (d, J= 17.9 Hz, 1H), 4.47 (s, 2H), 4.19 (s, 1H), 3.86 - 3.70 (m, 2H), 3.64 (s, 3H), 3.62 - 3.57 (m, 1H), 3.50 - 3.40 (m, 1H), 3.30 - 3.27 (m, 1H), 2.95 - 2.80 (m, 1H), 2.78 - 2.56 (m, 3H), 2.36 - 2.25 (m, 3H), 2.05 - 1.80 (m, 16H), 1.57 - 1.10 (m, 9H).

[0399] Example 47 Petition 870250078555, dated 03 / 09 / 2025, page 132 / 1278 120 / 161

[0400] The desired product 47 (2.06 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 813.3 [M+H+]; 'HNMR (400 MHz, DMSO-δ) δ 11.10 (s, 1H), 11,08 (s, 1H), 9,24 (s, 1H), 8,71 (d, J= 3,4 Hz, 1H), 8,65 (s, 1H), 8,60 (s, 1H), 8,22 (d, J= 9,2 Hz, 1H), 8,12 (s, 1H), 7,68 (d, J= 8,6 Hz, 1H), 7,36 (s, 1H), 7,32 (dd, J= 9,3, 4,3 Hz, 1H), 7,26 (s, 2H), 5,07 (dd, J= 12,8, 5,2 Hz, 1H), 4,49 (s, 1H), 4,13 (s, 3H), 4,08 (s, 2H), 3,08 - 3,02 (m, 7H), 2,98 - 2,79 (m, 1H), 2,69 - 2,55 (m, 2H), 2,35 - 2,14 (m, 4H), 2,06 - 1,95 (m, 5H), 1,90 - 1,82 (m, 3H), 1,65 - 1,50 (m, 4H), 1,33 - 1,20 (m, 3H).

[0401] Exemplo 48 Petição 870250078555, de 03 / 09 / 2025, pág. 133 / 1278 121 / 161 48a 48b MsO

[0402] The desired product 48 (2.07 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 813.2 [M+H+]; 'HNMR (400 MHz, DMSO-óL) δ 11.08 (s, 1H), 10.53 (s, 1H), 9.38 (dd, J= 7.0, 1.5 Hz, 1H), 8.96 (dd, J= 4.2, 1.5 Hz, 1H), 8.70 (s, 1H), 8.68 (s, 1H) (dd, J= 12.9, 5.4 Hz, 1H), 4.37 - 4.33 (m, 1H), 4.07 4.02 (m, 1H), 4.02 (s, 3H), 3.00 - 2.82 (m, 3H), 2.65 - 2.33 (s, 5H), 2.28 - 2.10 (m, 1H), 2.05 1.80 (m, 11H), 1.66 - 1.30 (m, 6H), 1.25 - 1.16 (m, 4H).

[0403] Example 49 Petition 870250078555, dated 03 / 09 / 2025, page 134 / 1278 122 / 161 TBDPSCI NaH THF 0°C Step 3 Step 2 49b

[0404] The desired product 49 (23 mg) was obtained with reference to Example 31. MS (ESI) m / z: 908.1 [M+H+]; Ή NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.50 (d, J= 5.2 Hz, 1H), 8.79 (d, J= 7.7 Hz, 1H), 8.42 (s, 1H), 8.26 (d, J= 5.6 Hz, 1H), 7.31 - 6.96 (m, 4H) 1H), 4.77 (d, J= 18.3 Hz, 1H), 4.48 (s, 2H), 3.86 - 3.71 (m, 2H), 3.66 (s, 3H), 3.63 - 3.56 (m, 1.5H), 3.49 - 3.41 (m, 1.5H), 2.95 - 2.82 (m, 1H), 2.76 - 2.63 (m, 2H), 2.37-2.25 (m, 4H), 2.24-2.14 (m, 2H), 2.11 - 1.88 (m, 7H), 1.88 - 1.74 (m, 3H), 1.68 - 1.55 (m, 2H), 1.49 - 1.39 (m, 1H), 1.09 - 0.97 (m, 2H), 0.81 - 0.68 (m, 2H).

[0405] Example 50 Petition 870250078555, dated 03 / 09 / 2025, p. 135 / 1278 123 / 161

[0406] The undesirable product 50 (6 mg) can be found in the aforementioned examples. MS (ESI) m / z: 905.6 [M+H+]; Ή NMR (400 MHz, DMSO-cL) δ 11.12 (s, 1H), 9.45 (d / =6, 1H), 8.78 (d, J=7.6, 1H), 8.41 (d, J=2.8, 1H), 8.26 (d, J=5.2, 1H), 7.14 (t, <7=6.6, 3H), 7.04-6.86 (m, 2H), 6.46 (d, J=8, 1H), 5.42-5.37 (m, 1H), 5.28 (s, 1H), 5.07(s, 1H), 4.97-4.95 (m, 1H), 4.79-4.75 (m, 1H), 3.81 (s,lH), 3.75-3.73 (m,lH), 3.67-3.59 (m, 5H), 2,892.85 (m, 1H), 2.73-2.61 (m, 3H), 2.39-2.33 (m, 3H), 2.23-2.18 (m,2H), 2.05-1.95 (m, 4H), 1.61-1.45 (m, 5H), 1.22 (s, 9H).

[0407] Exemplo 51 OH AgNOy NaOH y I acetone, rt. 2h y 1 ' H Etapa 1 ' jf O Õ 51a Λ.ΑΖ NaH DMF rt 12 h O ÇAg eu Ζ=ν°Η 1 dh V \ NaOH H2O YJ TMSCHNs, MeOH^ 0 --:110 C. 4h * HOyQz DCM rt. 16 h EtaPa2 S Etapa 3 0 Etapa 4 51c 51b LiOH THF H2O Í^V0 A Jc J rt 12 h ' ΜΛ r HATU. DIEA. Step 5 q 51 <t 51e p -oB N-N _________________________. Pd(PPh2)2CI2. Cul. Cs2CO3 Γ HN^P DMF. 90 °C 4 h <tn nD0 Etapa8 ° 51o j DMF, rt, 12 h Etapa 6 0 51f Etapa 7 O O 0 x J1 Vnh r / v.—ò--^· Fy-Çj / LJ HN o U^N-n 51 Petition 870250078555, dated 03 / 09 / 2025, page 136 / 1278 124 / 161

[0408] Step 1: 4-(Methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid (1.22 g, 5.75 mmol) and acetone (10 mL) were added to a reaction flask and stirred, then 1 M sodium hydroxide solution (5.8 mL, 5.8 mmol) was added dropwise at room temperature. After the formation of a clear solution, 4 M aqueous silver nitrate solution (1.5 mL, 6.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filter cake was washed with water, methyl tert-butyl ether, and acetone. The solvent was removed under reduced pressure to obtain 51 a (1.82 g).

[0409] Step 2: 51A (1.82 g, 5.75 mmol) was added to a reaction flask, which was then purged with N2. n-Hexane (12 mL) was added, followed by the dropwise addition of liquid bromine (920 mg, 5.75 mmol), and the mixture was stirred for 4 hours. The reaction mixture was filtered, and the filtrate was collected. The filter cake was washed with methyl tert-butyl ether (15 mL x 3) and saturated sodium bicarbonate solution (20 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and subjected to rotary evaporation to dryness to obtain 51b (909 mg). 1H NMR (400 MHz, Chloroform-d) δ 3.63 (s, 3H), 2.29 - 2.19 (m, 6H), 2.00 - 1.93 (m, 6H).

[0410] Step 3: 51b (13.3 g, 53.8 mmol), sodium hydroxide (12.9 g, 323 mmol) and water (300 mL) were added to a reaction flask. The reaction was carried out at 110°C for 24 hours. After the reaction was complete, the pH was adjusted to 3-4 with 4 M hydrochloric acid solution and the mixture was extracted with EA (50 mL x 3). The organic phase was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and concentrated to obtain 51c (4.5 g). 1H NMR (400 MHz, DMSO-d5) δ 11.96 (s, 1H), 4.21 (s, 1H), 1.79 - 1.72 (m, 6H), 1.55 - 1.44 (m, 6H).

[0411] Step 4: 51c (4.5 g, 26.5 mmol) was added to a reaction flask, which was then purged with nitrogen. Anhydrous dichloromethane (10 mL) and anhydrous methanol (10 mL) were added until the solution became clear. Trimethylsilyldiazomethane (2 M, 53 mmol, 26.5 mL) was added dropwise under a nitrogen atmosphere and the reaction was carried out overnight at room temperature. After completion of the reaction, the reaction mixture was separated by column chromatography to obtain 51d (2.0 g). 1H NMR (400 MHz, Chloroform-d) δ 3.63 (s, 3H), 1.94 - 1.88 (m, 6H), 1.70 - 1.62 (m, 6H).

[0412] Step 5: 51d (2.0 g, 10.9 mmol) was added to a reaction flask, which was then Petition 870250078555, dated 03 / 09 / 2025, page 137 / 1278 125 / 161 purged with nitrogen. Anhydrous DMF (10 mL) and sodium hydride (60% by weight, 872 mg, 21.8 mmol) were added and the reaction was carried out at room temperature for 30 minutes. Subsequently, propargyl bromide (2.59 g, 21.8 mmol) was added and the reaction was carried out overnight at room temperature. After the reaction was complete, the reaction mixture was quenched by the addition of water (30 mL) and extracted with EA (30 mL x 4). The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and separated by column chromatography to obtain 51e (720 mg). 1H 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).

[0413] Step 6: 51e (100 mg, 0.45 mmol), LiOH (54 mg, 2.25 mmol), THF (2 mL), and water (0.4 mL) were added to a reaction flask, and the reaction was carried out overnight at room temperature. After the reaction was complete, the pH was adjusted to 3-4 by adding 1 M aqueous hydrochloric acid solution. The mixture was extracted with EA (10 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and subjected to rotary evaporation to dryness to obtain 51f (85 mg). 1H NMR (400 MHz, DMSO-d5) 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).

[0414] Step 7: 51f (20 mg, 0.096 mmol) was added to a reaction flask, which was then purged with nitrogen. Anhydrous DMF (2 mL) and HATU (40 mg, 0.106 mmol) were added and the reaction was carried out at room temperature for 30 minutes. A (48 mg, 0.096 mmol) was added and the reaction was stirred overnight at room temperature. 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 subjected to rotary evaporation to dryness to obtain compound 51g (38 mg). [M+H]+ = 689.5.

[0415] Step 8: B (110 mg, 0.32 mmol), 51 g (450 mg, 0.65 mmol), cesium carbonate (212 mg, 0.65 mmol), Cul (12 mg, 0.06 mmol) and Pd(PPh3)2Ch (46 mg, 0.06 mmol) were dissolved in ultradry DMF (3 mL) at room temperature and the system was thoroughly purged with N2. The mixture was stirred at 90°C for 12 hours. The reaction was monitored by LC-MS. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The Petition 870250078555, dated 03 / 09 / 2025, pp. 138 / 1278 126 / 161 organic phases were combined, dried over anhydrous sodium sulfate and purified by preparative TLC to obtain the desired product 51 (4.5 mg). MS (ESI) m / z: 946.7 [M+EF]; 'H NMR (400 MHz, DMS04) 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).

[0416] Example 52

[0417] Step 1: 51e (260 mg, 1.17 mmol) was dissolved in ultradry THF (4 mL) at room temperature and lithium aluminum hydride (1.75 mL, 1.75 mmol) was added slowly at 0 °C. The reaction mixture was heated to room temperature and stirred for 3 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with EA (5 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate to obtain 52a (170 mg, 74.9%).

[0418] Step 2: 52a (170 mg, 0.87 mmol), B (300 mg, 0.62 mmol), cesium carbonate (395 mg, 1.24 mmol), Cul (24 mg, 0.12 mmol) and Pd(PPh3)2C12 (89 mg, 0.12 mmol) were dissolved Petition 870250078555, dated 03 / 09 / 2025, page 139 / 1278 127 / 161 in ultradry DMF (5 mL) at room temperature and the system was completely purged with N2. The mixture was stirred at 90°C for 4 hours. The reaction was monitored by LC-MS. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (5 mL χ 3). The organic phases were combined, dried over anhydrous sodium sulfate and purified by preparative TLC to obtain 52b (120 mg). MS (ESI) m / z: 452.3 [M+H+].

[0419] Step 3: 52b (120 mg, 0.26 mmol) was dissolved in DCM (3 mL) at room temperature and Dess-Martin periodinan (124 mg, 0.29 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction was quenched with water and extracted with DCM (5 mL χ 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by preparative TLC to obtain 52c (90 mg, 75.6%). MS (ESI) m / z: 450.1 [M+H]+.

[0420] Step 4: 52c (32 mg, 0.07 mmol) and A (32 mg, 0.07 mmol) were dissolved in DCM (3 mL) at room temperature and NaBH(OAc)3 (18 mg, 0.08 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS. The reaction was quenched with water (5 mL) and extracted with DCM (5 mL χ 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by preparative TLC to obtain a crude product (30 mg). The crude product was further purified by preparative high-performance liquid chromatography to obtain the desired product 52 (13.8 mg).MS (ESI) m / z: 932,8 [M+H+]; 1H NMR (400 MHz, DMSO- de) 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).

[0421] Exemplo 53 Petição 870250078555, de 03 / 09 / 2025, pág. 140 / 1278 128 / 161

[0422] The desired product 53 (6.4 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 905.7 [M+H+]; 'H NMR (400 MHz, Chloroform-d) δ 9.63 (s, 1H), 8.54 (d, J = 9.2 Hz, 2H), 8.33 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.02 - 6.94 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.13 (s, 1H), 5.51 (s, 1H), 5.20 (d, J = 40.7 Hz, 1H), 4.80 (d, J = 10.5 Hz, 1H), 4.70 (t, J = 8.5 Hz, 1H), 3.96 (d, J = 7.4 Hz, 2H), 3.91 - 3.70 (m, 4H), 3.54 (dd, J = 33.2, 14.8 Hz, 2H), 3.18 - 2.57 (m, 8H), 2.53 - 1.89 (m, 17H), 1.64 (s, 6H).

[0423] Example 54

[0424] The desired product 54 (2.5 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 919.6 [M+H+]; 'HNMR (400 MHz, CDCh) δ: 9.46 (s, 1H), 8.53 - 8.41 (m, 2H), 8.35 - 8.24 (m, 1H), 7.11 - 7.08 (m, 1H), 6.93 - 6.87 (m, 1H), 6.71 - 6.65 (m, Petition 870250078555, dated 03 / 09 / 2025, page 141 / 1278 129 / 161 1H), 6.05 (d, J = 2.8 Hz, 1H), 5.38 (s, 1H), 5.17 - 5.03 (m, 1H), 4.76 - 4.60 (m, 2H), 3.95 3.86 (m, 2H), 3.72 (s, 3H), 3.57 - 3.37 (m, 4H), 3.31 - 3.04 (m, 4H), 2.96 - 2.83 (m, 5H), 2.81 - 2.61 (m, 2H), 2.45 - 2.15 (m, 7H), 2.06 - 1.91 (m, 5H), 1.47 - 1.42 (m, 6H).

[0425] Example 55

[0426] The desired product 55 (16.1 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 919.7 [M+H+]; 'H NMR (400 MHz, Chloroform-tZ) δ 9.56 (s, 1H), 8.57 - 8.35 (m, 2H), 8.25 (d, J= Ί,β Hz, 1H), 7.10 (d, J= 7.5 Hz, 1H), 6.95 - 6.87 (m, 1H), 6.70 (d, J= 7.8 Hz, 1H), 6.06 (d, J= 7.7 Hz, 1H), 5.37 (s, 1H), 5.18 (d, J= 40.4 Hz, 1H), 4.76 - 4.52 (m, 2H), 3.90 (s, 2H), 3.72 (s, 3H), 3.54 - 3.40 (m, 3H), 3.29 (s, 1H), 3.16 - 3.07 (m, 6H), 3.00 - 2.72 (m, 6H), 2.44 - 1.88 (m, 11H), 1.45 (s, 6H).

[0427] Example 56 Petition 870250078555, dated 03 / 09 / 2025, page 142 / 1278 130 / 161

[0428] 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-butane (0.53 g, 5.2 mmol) and TEA (881 mg, 8.73 mmol) were added, and the mixture was stirred for 10 minutes. CuI (66 mg, 0.349 mmol) was added to the system, and the mixture was stirred for 0.5 hours. Then, 40 mL of water and 80 mL of ethyl acetate were added, and the mixture was extracted three times. The organic phase was collected and dried over anhydrous sodium sulfate. After rotary evaporation to dryness, product 56a (470 mg) was obtained. 1H NMR (400 MHz, Chloroform-d) δ3.61 (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).

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

[0430] Step 3: 56b (47 mg, 0.1 mmol) was dissolved in a mixed solvent of THF / MeOH = 1 / 1 (6 mL) at room temperature and LiOH (36 mg, 1.5 mmol) was added. The reaction mixture was stirred at 40°C for 1 hour, then 40 mL of dichloromethane were added. After filtration to remove excess salts, the product was purified by preparative TLC to obtain 56C (25 mg). MS (ESI) m / z: 453.3 [M+H+].

[0431] 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 the mixture was stirred at room temperature for 5 minutes. Then, A (22 mg, 0.044 mmol) and TEA (13 mg, 0.13 mmol) were dissolved in dichloromethane (0.5 mL) and added to the reaction system, which was stirred at 40°C for 2 hours. After completion of the reaction, the reaction mixture was purified by preparative TLC to obtain 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), Petition 870250078555, dated 03 / 09 / 2025, page 143 / 1278 131 / 161 1.43 (s, 6H).

[0432] Example 57

[0433] The desiccated product 57 (2.5 mg) was obtained with reference to the previously mentioned examples. MS (ESI) m / z: 900.5[M+H+]; 'HNMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.49 (d, J= 5.2 Hz, 1H), 8.78 (d, J= Ί,β Hz, 1H), 8.39 (d, J= 4.0 Hz, 1H), 8.25 (d, J= 5.2 Hz, 1H), 7.24 (d, J= 8.4 Hz, 2H), 7.14 (dd, J= 26.4, 7.8 Hz, 2H), 7.02 (dt, J= Ί,β, 3.6 Hz, 3H), 6.86 (d, J= 7.8 Hz, 1H), 6.45 (d, J= Ί,β Hz, 1H), 5.38 (dd, J= 12.8, 5.4 Hz, 1H), 5.27 (s, 1H), 5.11 (d, J= 7.4 Hz, 2H), 5.07 (s, 1H), 4.98 - 4.88 (m, 1H), 4.77 (d, J= 17.2 Hz, 1H), 3.82 (d, J= 10.4 Hz, 2H), 3.74 (d, J= Ί,β Hz, 1H), 3.66 - 3.56 (m, 2H), 3.45 (s, 2H), 3.39 - 3.36 (m, 2H), 2.87 (t, J= 14.8 Hz, 1H), 2.68 - 2.59 (m, 2H), 2.33 (d, J= 8.8 Hz, 4H), 2.16 (d, J= 19.6 Hz, 3H), 1.99 (dd, J= 20.8, 10.3 Hz, 3H), 1.62 (d, J= 23.2 Hz, 4H), 1.23 (s, 2H).

[0434] Example 58 Petition 870250078555, 03 / 09 / 2025, pág. 144 / 1278 132 / 161

[0435] The desired product 58 (1.8 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 877.7 [M+H+]; 'HNMR (400 MHz, DMSO-ó / 6) δ 11.12 (s, 1H), 9.51 (d, J= 5.6 Hz, 1H), 8.79 (d, J= 7.8 Hz, 1H), 8.41 (d, J= 4.2 Hz, 1H), 8.26 (d, J= 5.6 Hz, 1H), 7.15 (dd, J= 13.2, 8.0Hz, 2H), 7.03 (t, J= 7.8Hz, 1H), 6.87 (d, J= 8.0Hz, 1H), 6.46 (d, J= 8.0Hz, 1H), 5.40 (dd, J= 12.4, 5.6Hz, 1H), 4.98 (t, J= 8.4 Hz, 1H), 4.78 (d, J= 17.2 Hz, 1H), 3.82 (d, J= 9.6 Hz, 1H), 3.67 (s, 2H), 3.60 (s, 1H), 3.49 (d, J= 19.2 Hz, 4H), 3.17 (s, 2H), 2.88 (d, J= 17.2 Hz, 2H), 2.80 - 2.70 (m, 1H), 2.61 (s, 1H), 2.39 (t, J= 10.0 Hz, 2H), 2.33 (t, J= 2.0 Hz, 1H), 2.22 (t, J= 10.0 Hz, 2H), 2.00 (dd, J= 19.6, 10.1 Hz, 3H), 1.59 (d, J= 18.0 Hz, 2H), 1.51 (s, 1H), 1.25 (d, J= 10.7 Hz, 6H), 0.86 (s, 1H).

[0436] Example 59 Petition 870250078555, dated 03 / 09 / 2025, pp. 145 / 1278 133 / 161

[0437] The desired product 59 (5.3 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 891.6 [M+H+]; 'HNMR (400 MHz, CDCh) δ 9.55 (s, 1H), 8.47 - 8.39 (m, 2H), 8.27 - 8.25 (m, 1H), 7.13-7.11 (m, 1H), 6.92 (t, J= 8 Hz, 1H), 6.84 - 6.57 (m, 2H), 6.05 (d, J= Ί,β Hz, 1H), 5.38 (s, 1H), 5.16 - 5.12 (m, 1H), 4.76-4.66 (m, 2H), 3.93-3.89 (m, 2H), 3.82 - 3.75 (m, 5H), 3.56 - 3.50 (m, 2H), 3.44 - 3.29 (m, 5H), 3.10 - 2.97 (m, 2H), 2.90 - 2.64 (m, 4H), 2.36 - 2.24 (m, 4H), 2.18 - 2.08 (m, 4H), 2.05 - 1.98 (m, 5H).

[0438] Example 60

[0439] The desired product 60 (8.0 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 891.6 [M+H+]; 'HNMR (400 MHz, DMSO-ó / 6) δ 11.12 (s, 1H), 9.50 (d, J= 5.3 Hz, 1H), 8.79 (d, J= 7.8 Hz, 1H), 8.42 (d, J= 4.1 Hz, 1H), 8.26 (d, J= 5.5 Hz, Petition 870250078555, dated 03 / 09 / 2025, pp. 146 / 1278 134 / 161 1H), 8,13 (s, 0,6H), 7,17 (dd, J= 18,6, 7,3 Hz, 3H), 7,08 - 7,00 (m, 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), 5,18 (d, J = 79,8 Hz, 1H), 4,99 (q, J= 7,7 Hz, 1H), 4,77 (d, J= 17,9 Hz, 1H), 4,02 (s, 2H), 3,78 (d, J= 25,0 Hz, 2H), 3,63 (d, J= 23,6 Hz, 5H), 3,52-3,43 (m, 4H), 3,11- 2,80 (m, 4H), 2,79 - 2,58 (m, 3H), 2,46 - 2,30 (m, 3H), 2,19 - 2,12 (m, 3H), 2,06 - 1,91 (m, 4H), 1,72 - 1,70 (m, 4H).

[0440] Exemplo 61 DMP.DCM 0°C. 2 h Etapa 6

[0441] The desiccated product 61 (2.1 mg) was obtained with reference to the previously mentioned examples. MS (ESI) m / z: 906.7 [M+H+]; 'H NMR (400 MHz, Chloroform-ó / ) δ 9.60 (s, 1H), 8.47 - 8.41 (m, 2H), 8.32 (d, J= Ί,β Hz, 1H), 8.22 (s, 1H), 7.15 (d, J= Ί,β Hz, 1H), 7.00 (t, J= Ί,β Hz, 1H), 6.79 (s, 1H), 6.77 (d, J= 2.8 Hz, 1H), 6.12 (d, J= Ί,β Hz, 1H), 5.46 (s, 1H), 5.20 (dd, J= 12.4, 5.2 Hz, 1H), 4.81 (d, J= 11.2 Hz, 1H), 4.68 (p, J= 8.4 Hz, 1H), 4.44 (s, 2H), 3.97 (d, J= 9.2 Hz, 2H), 3.81 (s, 1H), 3.77 (s, 3H), 3.58 (d, J= 9.2 Hz, 1H), 3.49 (d, J = 9.2 Hz, 1H), 2.89 - 3.01 (m, 3H), 2.89 - 2.68 (m, 4H), 2.51 (s, 2H), 2.36 - 2.45 (m, 1H), 2.32 -2.21 (m, 5H), 1.78 - 1.86 (m, 4H), 1.58 - 1.73 (m, 4H), 1.36- 1.36 (m, 2H), 1.31 - 1.30 (m, 1H), 1.95-1.15 (m, 2H).

[0442] Example 62 Petition 870250078555, 03 / 09 / 2025, pág. 147 / 1278 135 / 161 62f Stage 7

[0443] The desired product 62 (63.1 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 905.7 [M+H+]; 'HNMR (400 MHz, DMSO-ó / 6) δ 11.12 (s, 1H), 9.50 (d, J= 5.3 Hz, 1H), 8.78 (dd, J= Ί,Ί, 1.0 Hz, 1H), 8.40 (d, J= 4.0 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.27 (s, 0.3H), 7.19 - 7.06 (m, 2.6H), 7.05 - 6.99 (m, 1.3H), 6.87 (d, J= 7.9 Hz, 0.5H), 6.45 (d, J= 7.8 Hz, 0.5H), 5.40 (dd, J= 12.7, 5.4 Hz, 1H), 5.28 (s, 0.5H), 5.07 (s, 0.5h), 4.99 - 4.87 (m, 1H), 4.77 (d, J= 16.5 Hz, 1H), 4.50 - 4.35 (m, 2H), 3.85 - 3.70 (m, 2H), 3.67 - 3.57 (m, 4H), 3.50 - 3.39 (m, 3H), 3.17 (d, J= 5.2 Hz, 1H), 2.96 - 2.84 (m, 1H), 2.78 - 2.66 (m, 1H), 2.68 - 2.59 (m, 1H), 2.43 - 2.20 (m, 7H), 2.20 - 2.10 (m, 4H), 2.07 - 2.07 (m, 2H), 1.99 - 1.89 (m, 3H), 1.51 - 1.54 (m, 1H).

[0444] Example 63 Petition 870250078555, dated 03 / 09 / 2025, pp. 148 / 1278 136 / 161

[0445] The desired product 63 (1.93 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 877.5 [M+H+]; 'HNMR (400 MHz, CD3OD) δ 8.52 - 8.48 (m, 1H), 8.36 - 8.30 (m, 2H), 7.19 - 7.17 (m, 1H), 7.13 - 7.10 (m, 1H), 7.07 - 7.03 (m, 1H), 6.90 6.72 (m, 1H), 6.43 (d, J = 2.8 Hz, 1H), 5.44 (s, 1H), 5.36 - 5.32 (m, 1H), 3.94 - 3.92 (m, 1H), 3.77 (s, 3H), 3.74 - 3.72 (m, 1H), 3.70 - 3.68 (m, 2H), 3.52 - 3.47 (m, 2H), 3.13 - 3.12 (m, 1H), 3.03 - 2.96 (m, 1H), 2.93 - 2.73 (m, 6H), 2.53 - 2.52 (m, 3H), 2.43 - 2.39 (m, 7H), 2.32 - 2.27 (m, 2H), 2.20 - 2.17 (m, 1H), 2.09 - 2.05 (m, 3H), 1.77 - 1.70 (m, 4H), 1.60 - 1.53 (m, 1H).

[0446] Example 64 38c Step 1

[0447] The desired product 64 (4.4 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 825.1 [M+H+]; 'HNMR (400 MHz, CDCh) δ 11.22 (s, 1H), 8.82 (s, 1H), 8.37 (s, 2H), 8.25 (s, 1H), 8.08 (s, 1H), 7.96 (d, J= 9.0 Hz, 1H), 7.18 - 7.15 (m, 2H), 7.04 - 6.94 (m, 2H), 6.76 (d, J= 7.8 Hz, 1H), 5.20 (dd, J= 12.4, 5.2 Hz, 1H), 4.35 (s, 2H), 4.27 (s, 3H), 3.99 - 3.96 (m, 1H), 3.77 (s, 3H), 3.06 - 2.64 (m, 4H), 2.61 - 2.53 (m, 3H), 2.43 - 2.30 (m, 3H), 2.25 - 2.22 (m, 2H), 2.12 - 2.07 (m, 5H), 2.00 - 1.87 (m, 4H), 1.85 - 1.78 (m, 2H), Petition 870250078555, dated 03 / 09 / 2025, page 149 / 1278 137 / 161 1.53 - 1.51 (m, 1H), 1.37 - 1.33 (m, 2H).

[0448] Example 65

[0449] The desired product 65 (6.7 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 811.0 [M+H+]; Ή NMR (400 MHz, DMSO-δ / δ) δ 11.26 (s, 1H), 11,13 (s, 1H), 10,71 (brs, 1H), 8,99 (d, J= 3,8 Hz, 1H), 8,66 (s, 1H), 8,59 (s, 1H), 8,45 (d, J = 9,2 Hz, 1H), 8,38 (s, 1H), 7,69 (dd, J= 9,2, 4,5 Hz, 1H), 7,31 (s, 1H), 7,20 (d, J= 7,8 Hz, 1H), 7,13 (d, J= 7,7 Hz, 1H), 7,04 (t, J= 7,9 Hz, 1H), 5,43 (dd, J= 12,7, 5,4 Hz, 1H), 5,28 - 5,18 (m, 1H), 4,37 (s, 2H), 4,14 (s, 3H), 4,10 - 3,95 (m, 1H), 3,65 (s, 3H), 3,38 - 3,17 (m, 3H), 3,15 - 3,06 (m, 2H), 3,01 - 2,82 (m, 3H), 2,76 - 2,60 (m, 3H), 2,48 - 2,30 (m, 4H), 2,27 - 2,13 (m, 1H), 2,12 - 1,84 (m, 6H), 1,82 - 1,68 (m, 2H).

[0450] Exemplo 66

[0451] The desired product 66 (19 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 904.4 [M+H+]; Ή NMR (400 MHz, CDCh) δ 9.60 (s, 1H), 8.40 (d, J= 6.8 Hz, 2H), 8.32 (d, J= Ί,β Hz, 1H), 7.16 (d, J= 7.2 Hz, 1H), 6.99 (t, J= Ί,β Hz, 1H), 6.90 - 6.58 (m, 2H), 6.12 (d, J= Ί,β Hz, 1H), 5.44 (s, 1H), 5.20 (dd, J= 12.4, 5.2 Hz, 1H), 4.79 (s, 1H), 4.39 (s, 2H), 4.06 - 3.92 (m, 3H), 3.90 - 3.72 (m, 5H), 3.68 - 3.45 (m, 5H), 2.96 - 2.94 Petition 870250078555, dated 03 / 09 / 2025, page 150 / 1278 138 / 161 (m, 1H), 2.87 - 2.71 (m, 4H), 2.35 - 2.24 (m, 3H), 2.17 - 2.09 (m, 4H), 2.00 - 1.92 (m, 4H), 1.78 - 1.69 (m, 4H), 1.68 - 1.66 (m, 2H), 1.56 - 1.37 (m, 4H).

[0452] Example 67

[0453] The desired product 67 (5.3 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 813.4 [M+H+]; 'HNMR (400 MHz, DMSO-6 / o) 1H) 5.4Hz, 1H), 4.65 - 4.54 (m, 1H), 4.13 (s, 3H), 4.09 - 3.99 (m, 2H), 3.29 (s, 1H), 3.08 - 2.76 (m, 4H), 2.41 - 2.30 (m, 4H), 2.21 - 1.93 (m, 8H), 1.85 - 1.72 (m, 6H), 1.67 - 1.61 (m, 2H), 1.40 - 1.33 (m, 4H).

[0454] Example 68 Petition 870250078555, dated 03 / 09 / 2025, page 151 / 1278 139 / 161 TCFH. NMI MeCN rt at 50°C, o / n Step 3

[0455] The desired product 68 (40 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 934.3 [M+H+]; 'HNMR (400 MHz, DMSO-ó / ó) δ 11.13 (s, 1H), 9.49 (d, J= 5.2 Hz, 1H), 8.78 (d, J= Ί,β Hz, 1H), 8.41 (d, J= 4.4 Hz, 1H), 8.25 (d, J= 5.6 Hz, 1H), 7.26 - 6.98 (m, 4H), 6.88 - 6.44 (m, 1H), 5.41 (dd, J= 12.6, 5.4 Hz, 1H), 5.17 (d, J= 80.8 Hz, 1H), 4.77 (d, J= 17.6 Hz, 1H), 4.49 (s, 2H), 4.19 - 4.16 (m, 1H), 3.84 - 3.72 (m, 2H), 3.65 - 3.56 (m, 5H), 3.49 - 3.43 (m, 1H), 2.94 - 2.85 (m, 2H), 2.77 - 2.61 (m, 3H), 2.33 - 1.75 (m, 14H), 1.66 - 1.49 (m, 4H), 1.44 - 1.20 (m, 6H), 1.14 - 0.93 (m, 4H).

[0456] Example 69 Step 5 Petition 870250078555, dated 03 / 09 / 2025, page 152 / 1278 140 / 161

[0457] The desired product 69 (1 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 851.2 [M+H+]; 'HNMR (400 MHz, CDCh) δ 9.60 (s, 1H), 8.42 (d, J = 6.4Hz, 2H), 8.31 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 4.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 6.99 (t, J= 8.0 Hz, 1H), 6.91 - 6.63 (m, 2H), 6.12 (d, J= Ί,β Hz, 1H), 5.46 (s, 1H), 5.36 - 5.33 (m, 1H), 5.22 - 5.17 (m, 1H), 4.82 - 4.79 (m, 1H), 4.40 (s, 2H), 4.07 - 3.95 (m, 3H), 3.79 (s, 3H), 3.57 (d, J= 9.2 Hz, 1H), 3.49 (d, J= 9.2 Hz, 1H), 3.43 (d, J= 6.0 Hz, 2H), 2.98 - 2.71 (m, 3H), 2.26 - 2.20 (m, 1H), 2.12 - 1.85 (m, 8H), 1.67 - 1.61 (m, 1H), 1.49 - 1.45 (m, 1H), 1.39 - 1.30 (m, 4H), 1.12 - 0.98 (m, 4H).

[0458] Example 70

[0459] The desired product 70 (19 mg) was obtained with reference to the examples mentioned above. MS (ESI) m / z: 850.4 [M+H+]; 'HNMR (400 MHz, DMSO-0 / 0) δ 11.12 (s, 1H), 9.50 (d, J= 5.2 Hz, 1H), 8.78 (d, J= 8.0 Hz, 1H), 8.40 (d, J= 3.6 Hz, 1H), 8.25 (d, J= 5.6 Hz, 1H) 3.72 (m, 4H), 3.65 - 3.59 (m, 5H), 3.51 - 3.43 (m, 2H), 2.93 - 2.85 (m, 1H), 2.72 - 2.60 (m, 2H), 2.44 - 2.38 (m, 2H), 2.27 - 2.21 (m, 2H), 2.05 1.95 (m, 3H), 1.76 - 1.64 (m, 4H), 1.51 (s, 6H).

[0460] Example 71 Petition 870250078555, dated 03 / 09 / 2025, page 153 / 1278 141 / 161

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

[0462] Pi1HNMR(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).

[0463] P21HNMR(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).

[0464] Step 2: 71A (200 mg, 1.1 mmol) was dissolved in tetrahydrofuran / water (4 mL / 0.8 mL) at room temperature and lithium hydroxide (230 mg, 5.49 mmol) was added. The reaction system was stirred overnight at 50°C. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was extracted with ethyl acetate (30 mL χ²). The aqueous phase was adjusted to pH 3-4 with 1 M hydrochloric acid and then extracted. Petition 870250078555, dated 03 / 09 / 2025, page 154 / 1278 142 / 161 with ethyl acetate (30 mL x 2) to obtain intermediate 71b. (160 mg, pale yellow solid). 1H 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).

[0465] Step 3: 71B (101 mg, 0.554 mmol), intermediate A (230 mg, 0.462 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (263 mg, 0.693 mmol) were dissolved in N,N-dimethylformamide (4 mL) and N,N-diisopropylethylamine (150 mg, 1.155 mmol) was added. The reaction system was stirred at room temperature for 1 hour.

[0466] After TLC monitoring showed the disappearance of the starting material, ethyl acetate (30 mL) was added to the reaction mixture. 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 obtain 71c (150 mg). MS (ESI) m / z: 663.3 [M+H+].

[0467] Step 4: 71C (150 mg, 0.226 mmol), intermediate B (92 mg, 0.271 mmol), cesium carbonate (220 mg, 0.679 mmol), copper(I) iodide (5 mg, 0.0226 mmol), and bis(triphenylphosphine)palladium(II) dichloride (16 mg, 0.0226 mmol) were dissolved in N,N-dimethylformamide (4 mL) at room temperature. The reaction system was evacuated and purged with nitrogen several times. The reaction mixture was stirred in an oil bath at 85°C for 3 hours. After LCMS monitoring showed the disappearance of the starting material, the reaction mixture was quenched by the addition of water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3) and the organic phases were combined, washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and the product was collected to obtain 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,. Petição 870250078555, de 03 / 09 / 2025, pág. 155 / 1278 143 / 161 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, 7=25,0, 11,6 Hz, 2H), 1,27 (d, J= 10,9 Hz, 2H).

[0468] Exemplo 72 LrOH / THF / HjO Ν·Η. THF Etapa 1 Etapa 2 HATU. DiPEA Etapa 3 0469 Ή NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.50 (d, J= 5.2 Hz, 1H), 8.79 (d, J= 7.8 Hz, 1H), 8.41 (d, J= 4.1 Hz, 1H), 8.26 (d, J= 5.6 Hz, 1H), 7.19 - 7.00 (m, 4H), 6.87 (d, J= 7.9 Hz, 0.5H), 6.46 (d, J= 7.7 Hz, 0.5H), 5.40 (dd, 7= 12.7, 5.4 Hz, 1H), 5.28 (s, 0.5H), 5.08 (s, 0.5H), 4.99 (s, 1H), 4.77 (d, 7= 15.3 Hz, 1H), 4.45 (s, 2H), 3.82 (d, 7= 8.9 Hz, 2H), 3.74 (d, 7= 7.7 Hz, 0.5H), 3.64 (s, 3H), 3.58 (d, 7= 11.3 Hz, 1.5H), 3.45 (d, 7= 9.8 Hz, 3H), 3.37 (s, 2H), 2.88 (dd, 7= 20.6, 9.4 Hz, 1H), 2.75 - 2.62 (m, 3H), 2.40 (t, 7= 9.3 Hz, 2H), 2.23 (t, 7=10.0 Hz, (2H), 2.08 - 1.85 (m, 6H), 1.66 (s, 2H), 1.58 (d, 7= 9.8 Hz, 3H), 1.52 (s, 2H), 1.41 (s, 2H).

[0470] Examination of tests of biological biology

[0471] The control molecule used in this test example was KT-474, which was prepared with reference to the preparation method of compound 1-417 in patent WO2020113233AI. Its structure is as follows: Petition 870250078555, dated 03 / 09 / 2025, page 156 / 1278 144 / 161 KT-474

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

[0473] (1) Experimental objective

[0474] The level of IRAK4 protein degradation in the SU-DHL-2 cell line by the compounds was detected by flow cytometry.

[0475] (2) Experimental materials

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

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

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

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

[0480] (3) Experimental instruments

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

[0482] (4) Experimental method

[0483] Step 1: The SU-DHL-2 cell line was cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% dual antibiotics.

[0484] Step 2: On day 1, cells were seeded at a density of 2 *10⁵ cells per well in 100 μL in a 96-well plate. Compounds were dissolved in DMSO to a final concentration of 10 mM and then diluted with culture medium at a 1:5 concentration gradient to prepare 10 concentrations. The diluted solutions were added to the cells to obtain a maximum final concentration of 2 μM. Wells containing cells treated with 0.1% DMSO served as a positive control. Cells were incubated at 37°C in a 5% CO₂ incubator for 24 hours. Petition 870250078555, dated 03 / 09 / 2025, page 157 / 1278 145 / 161

[0485] Step 3: After centrifugation, the cells were washed with FACS buffer. The cells were stained for viability discrimination using the LIVE / Dead™ Blue Fixable Dead Cell Staining Kit, and surface staining of monocytes was performed with CD14 Anti-Human Mouse PE, followed by incubation at 4°C for 30 minutes.

[0486] Step 4: After centrifugation, the cells were washed with FACS buffer. FIX I buffer, equal in volume to the cultured cells, was added, and the cells were fixed at 37°C for 10 minutes.

[0487] Step 5: After centrifugation, the cells were washed with FACS buffer. 150 μL of Perm III reagent was added and the cells were incubated at 4°C for 30 minutes to permeabilize the membranes. After centrifugation, the cells were washed with FACS buffer.

[0488] Step 6: Cells were stained with Alexa Fluor 647 mouse anti-IRAK4 human antibody and incubated at 4°C for 1 hour. Flow cytometry analysis was performed using a flow cytometer.

[0489] (5) Data processing

[0490] Flow cytometry data were analyzed using Flowjo software. Data presentation and DC50 (half the maximum degradation concentration) calculation were performed using Prism 8.0.2 (GraphPad).

[0491] (6) Experimental results

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

[0493] The Dmax values ​​of the compounds in this disclosure for SU-DHL-2 and OCI-LY3 cells were generally 50% or higher, with the highest reaching approximately 90%.

[0494] The results indicate that the compounds in this disclosure have good degradation activity against the IRAK4 target in SU-DHL-2 and OCI-LY3 cells.

[0495] Table 1. IRAK4 degradation results in SU-DHL-2 and OCI-LY3 cells Compound No. SU-DHL-2 DC50 (nM) OCI-LY3 DC50 (nM) Example 1 1.4 0.4 Petition 870250078555, dated 03 / 09 / 2025, pp. 158 / 1278 146 / 161 Example 2 1.1 0.4 Example 3 11 8 Example 4 8 5 Example 5 27 28 Example 6 10 4 Example 7 12 10 Example 8 4 2 Example 9 2.7 2.3 Example 10 17 13 Example 11 3 4 Example 12 5 5 Example 13 5.7 5 Example 14 4.6 4.4 Example 15 5 1.5 Example 16 5 5 Example 17 1 1 Example 18 6 4 Example 19 7 6 Example 20 4 4 Example 21 3 4 Example 22 1.4 1.3 Example 24 4 3 Example 25 6 4 Example 26 2.9 3.5 Example 27 22 32 Example 28 4 2 Example 29 3 1 Example 30 3 1 Example 31 3.3 2.8 Petition 870250078555, dated 03 / 09 / 2025, page 159 / 1278 147 / 161 Example 32 3.4 2.7 Example 33 6.5 Example 34 21 Example 35 5 Example 36 5.6 Example 37 24 Example 38 68 Example 39 17 Example 40 33 Example 43 61 Example 44 5.4 Example 46 13 Example 47 0.5 Example 48 1 Example 49 4 Example 50 4 Example 51 7 Example 52 3 Example 53 6 Example 54 17 Example 55 7 Example 56 5 Example 57 22 Example 58 5 Example 59 3 Example 60 2.5 Example 61 4 Example 62 1.2 Example 63 6.5 Petition 870250078555, dated 03 / 09 / 2025, page 160 / 1278 148 / 161 Example 64 1 Example 65 2.8 Example 66 13 Example 67 45 Example 68 24 Example 70 16 Example 71 5 Example 72 4

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

[0497] (1) Experimental objective

[0498] The level of IRAK4 degradation in monocytes from human peripheral blood mononuclear cells (hPBMCs) was detected by flow cytometry.

[0499] (2) Experimental materials

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

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

[0502] LIVE / DEAD™ Fixable Blue Dead Cell Stain Kit, for UV Excitation, Thermo Fisher, L34962

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

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

[0505] (3) Experimental instruments

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

[0507] (4) Experimental method

[0508] Cryopreserved hPBMCs were thawed and cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% Pen + Strep, followed by recovery at 37°C for 1 hour.

[0509] On day 1, cells were seeded at a density of 2 *105 cells per well in 100 μL in a 96-well plate.

[0510] The compounds were dissolved in DMSO to a final concentration of 10 mM and Petition 870250078555, dated 03 / 09 / 2025, page 161 / 1278 149 / 161 then diluted with culture medium to a concentration gradient of 1:5 to prepare 10 concentrations. The diluted solutions were added to the cells to obtain a final maximum concentration of 2 μM. Wells containing cells treated with 0.1% DMSO served as a positive control.

[0511] The cells were incubated at 37°C in a 5% CO2 incubator for 24 hours.

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

[0513] Cells were stained for viability discrimination using the LIVE / Dead™ Fixable Blue Dead Cell Staining Kit, and surface staining of monocytes was performed with Mouse Anti-Human CD14 PE, followed by incubation at 4°C for 30 minutes.

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

[0515] FIX I buffer, equal in volume to the cultured cells, was added, and the cells were fixed at 37°C for 10 minutes.

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

[0517] 150 pL of Perm III reagent were added and the cells were incubated at 4°C for 30 minutes to permeabilize the membranes.

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

[0519] The cells were stained with Alexa Fluor 647 mouse anti-IRAK4 human antibody and incubated at 4°C for 1 hour.

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

[0521] (5) Data processing method

[0522] Flow cytometry data were analyzed using Flowjo software. Data presentation and DC50 calculation were performed using Prism 8.0.2 (GraphPad).

[0523] (6) Experimental results

[0524] The results of the degradation activity of the compounds in this disclosure against IRAK4 are shown in Table 2.

[0525] The results indicate that the compounds in this disclosure have good degradation activity against the IRAK4 target in human PBMC cells.

[0526] Table 2. IRAK4 degradation results in human PBMC cells Petition 870250078555, dated 03 / 09 / 2025, page 162 / 1278 150 / 161 DC50 Compound No. in PBMC (nM) Example 13 2.22 Example 22 0.13 Example 31 0.3 Example 36 0.8 Example 49 0.5 Example 52 0.65 Example 56 1.1 KT-474 0.6

[0527] Example of Test 3: Inhibition of inflammatory factor secretion induced in human PBMCs by compounds

[0528] (1) Experimental objective

[0529] The effect of small PROTAC molecules on inflammatory factors in PBMCs downstream of TLR- and IL-1-induced IRAK4 was detected based on the CBA (cytometric bead array) method.

[0530] (2) Experimental materials Table 3 Manufacturer Name Cat NO. 1640 GIBCO 11875093 FBS GIBCO 10091-148 pBMC human Allcells FPB004F-C Plate 3799 Corsta 3799 IL-6 Kit CBA BD 558276 TNFa Kit CBA BD 558273 Buffer CBA BD 558264 IL-1e novoprotein GMP-CG93 R848 Invivogen tlrl-r848 LPS Invivogen tlrl-b5lps Petition 870250078555, dated 03 / 09 / 2025, page 163 / 1278 151 / 161

[0531] (3) Experimental instruments

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

[0533] (4) Experimental method

[0534] Step 1: Thawing Human PBMC

[0535] Step 2: The density of PBMCs was adjusted to 1 E6 / mL, and 150 μL of PBMCs in 1640 complete medium were seeded in a 96-well plate, followed by incubation at 37°C for 1 hour.

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

[0537] Step 4: 10 μL of stimulants were added respectively, with final concentrations of 100 ng / mL for LPS, 1 μg / mL for R848 and 100 ng / mL for IE-1β.

[0538] Step 5: CBA Assay. The concentrations of IL-6 and TNF-α in the cell culture supernatant were determined using Hu IL-6 CBA Flex Set A7 and Hu TNF-α CBA Flex Set D9.

[0539] Step 6: Standard samples were prepared: 2500 pg / mL, 1250 pg / mL,...0. A 1:2 serial dilution was performed to obtain 10 concentrations.

[0540] Step 7: The mixed capture beads were resuspended in capture bead diluent (1:50) and cell culture supernatant (50 uL) was added, followed by incubation at room temperature for 10 minutes.

[0541] Step 8: The detection reagent prepared with detection diluent was added and the mixture was incubated in the dark at room temperature for 3 hours. At the end of the incubation, the samples were washed once with washing buffer and resuspended for detection.

[0542] (5) Data processing

[0543] IL-6 and TNFα concentrations were calculated using the standard curve method. The data presentation and IC50 calculation were performed using Prism 8.0.2.

[0544] (6) Experimental results

[0545] The inhibitory effects of the compounds in this disclosure on the secretion of inflammatory factors induced in human PBMCs are shown in Tables 3 and 4. Petition 870250078555, dated 03 / 09 / 2025, page 164 / 1278 152 / 161

[0546] The results indicate that the compounds in this disclosure can effectively inhibit the secretion of inflammatory factors, exhibiting potential therapeutic value for inflammatory diseases.

[0547] Table 3-1. TNFα secretion induced by LPS, R848, and ΓE-1β in human PBMCs Compound No. IC50 (nM) LPS R848 JL-1p Example 13 22.3 20 13 Example 22 1.2 1.4 0.16 Example 31 7.7 8.2 2.1 KT474 31 52 13

[0548] Table 3-2. TNFα secretion induced by LPS, R848, and ΓE-1β in human PBMCs Compound No. IC50 (nM) LPS R848 ΊΣ-1β Example 52 8.5 21.5 13.9

[0549] Table 4-1. IL-6 secretion induced by LPS, R848, and ΓE-1β in human PBMCs Compound No. IC50 (nM) of compounds against LPS-induced secretion R848 ΊΣ-1β Example 13 19.7 10 13.2 Example 22 0.5 0.16 1 Example 31 4.6 0.9 9.3 KT-474 41 14 18

[0550] Table 4-2. IL-6 secretion induced by LPS, R848 and IL-1β in human PBMCs Compound No. IC50 (nM) of compounds against LPS-induced secretion R848 ΊΣ-1β Example 52 8.4 20.3 8.9

[0551] Example Test 4: Inhibition of the hERG potassium channel by compounds Petition 870250078555, dated 03 / 09 / 2025, page 165 / 1278 153 / 161

[0552] (1) Experimental objective

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

[0554] (2) Experimental materials

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

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

[0557] CHO-hERG cell line (Chinese hamster ovary): Chinese hamster ovary cells that stably express the hERG channel.

[0558] Formula of the extracellular solution (mM): 140 NaCl, 5 KCl, 1 CaCh, 1.25 MgCh, 10 HEPES and 10 Glucose, adjusted to pH 7.4 with NaOH.

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

[0560] (3) Experimental instruments

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

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

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

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

[0565] Micromanipulator (MX7600R, Syskiyou, USA)

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

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

[0568] Vibration isolation table and Faraday cage (63-534, TMC, USA)

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

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

[0571] Biosafety cabinet (MODEL 1384, Thermo, USA)

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

[0573] (4) Experimental method Petition 870250078555, dated 03 / 09 / 2025, page 166 / 1278 154 / 161

[0574] (4.1) Cell culture and treatment

[0575] CHO cells that stably express hERG were cultured in 35 mm diameter cell culture plates and incubated at 37°C in a 5% CO2 incubator. Cells were passed at a 1:5 ratio every 48 hours. The culture medium was formulated as follows: 90% F12 (Invitrogen), 10% fetal bovine serum (Gibco), 100 g / mL G418 (Invitrogen), and 100 g / mL Hygromycin B (Invitrogen). On the day of the experiment, the cell culture medium was aspirated and the cells were rinsed once with extracellular solution. Then, 0.25% trypsin-EDTA solution (Invitrogen) was added and the cells were digested for 3-5 minutes at room temperature. The digestion solution was aspirated and the cells were resuspended in extracellular solution and then transferred to experimental plates for electrophysiological recording for later use.

[0576] (4.2) Preparation of compounds

[0577] On the day of testing, the compounds were prepared as 10 mM stock solutions in DMSO, then diluted to 1 mM with DMSO and further diluted 1000 times with extracellular solution to obtain the desired final test concentration. Preparation of the cisapride positive control compound: 10 μE of a 150 μM cisapride DMSO stock solution were added to 4990 μE of extracellular solution and diluted 500 times to obtain the desired final test concentration of 300 nM. The DMSO content in the final test concentration did not exceed 0.2%, and DMSO at this concentration had no effect on the hERG potassium channel.

[0578] (4.3) Electrophysiological recording process

[0579] hERG potassium channel currents were recorded at room temperature using the whole-cell patch-clamp technique in CHO cells that stably express the hERG channel. The glass microelectrode was prepared by pulling the blank glass electrode (BF150-86-10, Sutter) with an extractor, and the tip resistance after filling with the inner electrode solution was approximately 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe and then connected to the patch-clamp amplifier. The clamping voltage and data recording were controlled and recorded by the pClamp software via a computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining the whole-cell recording, the cells were clamped to Petition 870250078555, dated 03 / 09 / 2025, page 167 / 1278 155 / 161 -100 mV. The hERG potassium current (IhERG) was evoked by applying a 2 s depolarization voltage step from -100 mV to +20 mV, followed by repolarization at -50 mV for 1 s before returning to -100 mV. This voltage stimulus was applied every 5 s, and the drug administration process was initiated after the hERG potassium current was confirmed as stable (1 minute). Each test concentration of the compounds was applied for at least 1 minute to achieve the steady-state effect or for a maximum of 3 minutes, and at least two cells (n > 2) were tested for each concentration.

[0580] (5) Data processing

[0581] The data were analyzed and processed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of the potassium hERG current (peak hERG tail current induced at -50 mV) by different concentrations of the compound was calculated using the following formula:

[0582] % inhibition = [1 — (I / Io)] x 100%

[0583] where % inhibition represents the percentage inhibition of the hERG potassium current by the compound, and I and Io represent the amplitudes of the hERG potassium current after and before drug administration, respectively.

[0584] (6) Experimental results

[0585] Table 5. Results of hERG potassium channel inhibition hERG Compound (% inhibition) Example 22 36% @ 1 μM Example 52 16% @ 1 μM KT-474 47% @ 1 μM

[0586] Note: @ 1 μM refers to the concentration of the test compound.

[0587] Experimental results show that the compounds in this disclosure do not have significant inhibitory activity on hERG, indicating that the compounds in this disclosure have good safety.

[0588] Example Test 5: Determination of the in vivo pharmacokinetics of compounds

[0589] Experiment 1:

[0590] C57BL / 6 mice were used as test animals to study the Petition 870250078555, dated 03 / 09 / 2025, pp. 168 / 1278 156 / 161 Pharmacokinetic behavior of the compounds in this disclosure in mouse plasma after oral administration at a dose of 100 mg / kg.

[0591] 1. Experimental scheme

[0592] 1.1 Test drugs:

[0593] Examples 13, 22 and 31 of this disclosure.

[0594] 1.2 Test animals

[0595] C57BL / 6, male, transferred from the laboratory's animal repository (999M-018).

[0596] 1.3 Administration:

[0597] Three male C57BL / 6 mice were fasted overnight (1014 hours) with free access to water one day before administration. The mice were fed 4 hours after administration. The dose for PO administration was 100 mg / kg, with an administration volume of 20 mL / kg.

[0598] 1.4 Experimental equipment

[0599] The centrifuge (5810 R) was purchased from the Eppendorf Company, the pipette was purchased from the Eppendorf Company, and the vortex mixer was purchased from the Scientific Industries Company.

[0600] 1.5 Sample Collection

[0601] After administration, blood samples (0.03 mL) were collected from mice by venipuncture at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours. Samples were placed in EDTA-K2 tubes and centrifuged at 6800 rpm for 5 minutes at 2-8°C. Plasma was separated and stored at -80°C.

[0602] 1.6 Sample processing

[0603] 1) 10 μL of plasma sample were added to 200 μL of methanol for precipitation. After mixing, the mixture was centrifuged at 18000 g for 10 minutes.

[0604] 2) The processed supernatant solution was taken for LC / MS / MS analysis to determine the concentration of the test compound.

[0605] 1.7 Liquid Phase Analysis

[0606] Liquid phase conditions: Shimadzu LC-30AD pump

[0607] Mass spectrometry conditions: AB Sciex API 5500 mass spectrometer

[0608] Chromatographic column: Phenomenex Kinetex 2.6 μm C18 50 3.0 mm Petition 870250078555, dated 03 / 09 / 2025, page 169 / 1278 157 / 161

[0609] Mobile phase: Solution A was 0.1% formic acid in water and solution B was 0.1% formic acid in acetonitrile

[0610] Flow rate: 0.6 mL / min.

[0611] Elution time: Gradient elution for 0-1.6 minutes.

[0612] 2. Experimental results and analysis

[0613] The main pharmacokinetic parameters were calculated using WinNonlin 8.0.

[0614] Experimental results show that the compounds in the examples of this disclosure have good pharmacokinetic properties.

[0615] Table 6. Pharmacokinetic parameters of some compounds from this disclosure administered orally to mice Example Dose (mpk) T1 / 2 (hr) Tmax (hr) Cmax (ng / mL) MRTinf (hr) AUClast (hr*ng / mL) AUClnf (hr*ng / mL) Example 13 100 7.6 1 2158 10.9 16306 19243 Example 22 100 5.4 1.7 1396 8 17628 18423 Example 31 100 7.3 3.3 364 10.4 4892 5463

[0616] Experiment 2:

[0617] 1.1 Test drugs:

[0618] Example 52 of this disclosure.

[0619] 1.2 Test animals

[0620] C57BL / 6J, male, acquired from JH Laboratory Animal Co. LTD. Qualification No: SCXK (SH) 2022-0009 20220009007223

[0621] 1.3 Administration:

[0622] Two male C57BL / 6 mice had free access to food and water. The dose for PO administration was 100 mg / kg, with an administration volume of 10 mL / kg.

[0623] 1.4 Experimental equipment

[0624] The centrifuge (5810 R) was purchased from the Eppendorf Company, the pipette was purchased from the Eppendorf Company, and the vortex mixer was purchased from the Scientific Industries Company.

[0625] 1.5 Sample Collection

[0626] After administration, blood samples (0.025 mL) were collected from Petition 870250078555, dated 03 / 09 / 2025, pp. 170 / 1278 158 / 161 mice were obtained by venipuncture at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours. Samples were placed in EDTA-K2 tubes and centrifuged at 2000 g for 5 minutes at 4°C. Plasma was separated and stored at -70°C.

[0627] 1.6 Sample processing

[0628] 1) 5 μL of plasma sample were added to 100 μL of acetonitrile for precipitation. After mixing, the mixture was centrifuged at 5800 rpm for 10 minutes.

[0629] 2) The processed supernatant solution was taken for LCMS / MS analysis to determine the concentration of the test compound.

[0630] 1.7 Liquid Phase Analysis

[0631] LC-MS / MS Instrument: LCMS / MS-45 (Triple Quad 6500+)

[0632] Chromatographic column: Waters BEH C18 (2.1 χ 50 mm, 1.7 μm)

[0633] Mobile phase: Solution A was H2O-0.025% FA-1 mM NH4OAc and solution B was MeOH-0.025% FA-1mMNH4OAc.

[0634] Flow rate: 0.6 mL / min.

[0635] Elution time: gradient elution for 0-2.5 minutes.

[0636] 2. Experimental results and analysis

[0637] The main pharmacokinetic parameters were calculated using WinNonlin 8.2. The pharmacokinetic parameters of the drug administered orally to mice are shown in Table 7 below. The experimental results indicate that compound 52 of this disclosure has good pharmacokinetic properties.

[0638] Table 7. Pharmacokinetic parameters of some compounds from this disclosure administered orally to mice Example Dose (mpk) T1 / 2 (hr) Tmax (hr) Cmax (ng / mL) MRTinf (hr) AUClast (hr*ng / mL) Example 52 100 NA 8 2205 NA 40075

[0639] Experiment 3:

[0640] 1.1 Test drugs:

[0641] Examples 13, 22, 31 and 52 of this disclosure.

[0642] 1.2 Test animals Petition 870250078555, dated 03 / 09 / 2025, p. 171 / 1278 159 / 161

[0643] Healthy male Beagle dogs, weighing approximately 8-10 kg, 3 animals per group.

[0644] 1.3 Experimental setup:

[0645] Beagle dogs (3 animals per group) were administered the compound at 2.5 mg / kg by oral gavage, with a dosage volume of 5 mL / kg, which was prepared with 10% DMSO + 50% PEG400 + 40% water (w / v). The animals were not fasting and had free access to water.

[0646] Venous blood (0.5-0.8 mL) was collected at 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration by oral gavage, placed in K2EDTA tubes, and centrifuged at 4°C to separate the plasma. The concentration of the compound in the plasma was determined by liquid chromatography-tandem mass spectrometry.

[0647] 1.4 Experimental results:

[0648] The main pharmacokinetic parameters were calculated using WinNonlin. The pharmacokinetic parameters of the drug administered orally to dogs are shown in Table 8 below. The experimental results indicate that the compounds of the examples in this disclosure have good pharmacokinetic properties.

[0649] Table 8. Pharmacokinetic parameters of some compounds from this disclosure administered orally to dogs Example Dose (mpk) T1 / 2 (hr) Cmax (ng / mL) MRTlnf (hr) AUClast (hr*ng / mL) Example 13 2.5 2.1 102 4.5 521 Example 22 2.5 7.6 100 11.2 1194 Example 31 2.5 8 15 12 198 Example 52 2.5 13.4 78 20.2 1156 KT-474 2.5 6.7 31 10.3 380

[0650] Example Test 6: Evaluation of the efficacy of compounds in acute inflammation induced by IL-33 in mice

[0651] (1) Experimental objective

[0652] IL-33, a member of the IL-1 cytokine family, is the ligand for IL-1-like receptor 1 or ST2. IL-33 transgenic mice, which specifically express IL-33 in Petition 870250078555, dated 03 / 09 / 2025, page 172 / 1278 160 / 161 keratinocytes can spontaneously develop AD-like eczema (atopic dermatitis), indicating that the IL-33 pathway plays a key role in AD. The effect of compounds on inflammation in the IL-1R signaling pathway was investigated using an acute inflammatory model in mice induced by intraperitoneal injection of IL-33.

[0653] (2) Materials and experimental methods

[0654] Experimental animals: 6-8 weeks old SPF grade male C57BL / 6J mice.

[0655] Preparation of the compound: 10% DMSO + 50% PEG400 + 40% sterile water for injection. The compound was dissolved in DMSO, followed by the addition of PEG400 and sterile water for injection, and the solution was adjusted for clarity with 6N hydrochloric acid.

[0656] IL-33 inducer preparation: Recombinant mouse IL-33 powder was prepared as a 1 μg / μL stock solution. When using, 40 μL of the 1 μg / μL IL33 solution were added to 3960 pL of PBS, thoroughly mixed by inversion, to obtain 4 mL of IL-33 solution with a concentration of 1 pg / 100 pL, which was freshly prepared before use.

[0657] Administration of the compound and IL-33 inflammatory induction: Mice were randomly grouped according to body weight and administered orally with the compound at final doses of 15 mg / kg, 50 mg / kg, and 150 mg / kg, twice daily. Four hours after the last administration of the compound, mice were injected intraperitoneally with 1 pg / 100 pL of IL-33 PBS for inflammatory induction.

[0658] Termination, sample collection and data: plasma, peritoneal lavage fluid and spleen were collected for subsequent detection of the sample index.

[0659] The experiment was terminated 8 hours after the last administration. The mice were anesthetized and cardiac blood was collected. Blood samples were anticoagulated with EDTA-K2, centrifuged at 3500 rpm for 15 minutes, and the upper plasma was collected. Sacrificed mice were disinfected by immersion in 75% ethanol for 3 minutes in a sterile biosafety cabinet. 2.5 mL of PBS pre-cooled to 4°C was injected intraperitoneally, and the abdominals of the mice were massaged for 5 minutes. The abdominal skin was cut with sterile scissors and forceps to expose the peritoneum. The sternum at the xiphoid process was lifted with sterile forceps, and an incision of Petition 870250078555, dated 03 / 09 / 2025, page 173 / 1278 161 / 161 A 1 mm² peritoneal lavage was performed at the xiphoid process. A pipette was inserted into the peritoneal cavity for gentle aspiration and blowing, and 2 mL of lavage fluid were collected and divided into 1.5 mL aliquots in centrifuge tubes for storage at -80°C. The expression levels of inflammatory factors in mouse plasma and peritoneal lavage fluid were detected by ELISA, and the expression level of the IRAK4 protein in mouse spleen was detected by LC-MS.

[0660] (3) Experimental results and analysis

[0661] Table 9. Drug concentrations in plasma and end tissues C8hr KT474 Example 22 Dose (mpk) 15 50 150 15 50 150 Plasma (ng / mL) 100 262 578 54 517 1392 Spleen (ng / mL) 896 1,740 7262 369 6135 16257

[0662] The results in Table 9 show that Example 22 at a dose of 50 mpk achieves the same concentration levels in plasma and spleen as KT-474 at 150 mpk, indicating that Example 22 requires a lower dosage.

[0663] FIG. 1 shows the concentration-dependent reduction of inflammatory factors in mouse plasma and peritoneal lavage fluid after three PO doses of Example 22. At comparable drug concentrations in plasma, the anti-inflammatory effect of Example 22 is superior to that of KT474.

[0664] FIG. 2 shows the in vivo degradation of IRAK4 in mouse spleen after three PO doses of Example 22. At comparable drug concentrations in the spleen, the degradation effect of Example 22 at 50 mpk is 2-3 times better than that of KT-474 at 150 mpk.

[0665] The above description merely represents preferred examples of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present application shall be within the scope of protection of the present application. Petition 870250078555, dated 03 / 09 / 2025, page 174 / 1278

Claims

1 / 24 CLAIMS 1. Bifunctional compound represented by general formula (I), an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof, Target Structure Formula (I) characterized in that ring C is phenyl, 5- to 6-membered heteroaryl or 9- to 10-membered fused heteroaryl;R1 is selected from the group consisting of -CN, -NRlaRlb, -OH, halogen, C1-6 alkyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 7- to 9-membered bridging 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, bridging heterocyclyl, fused heterocyclyl, cycloalkyl, heteroaryl and fused heteroaryl are optionally replaced by one or more Rx, and Rx is selected from the group consisting of -NH2, -NRlaRlb, -CN, -OH, halogen, C1-6 alkyl and halo-C1-6 alkyl; Rla and Rlb are each independently selected from the group consisting of H, C1-6 alkyl, halo-C1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkyl-C1-6 alkyl-, 3 to 6-membered heterocyclyl and 3 to 6-membered heterocyclyl-C1-6 alkyl-;m is selected from the group consisting of 0, 1, 2, 3 and 4; ring B is selected from the group consisting of 5- to 6-membered heteroaryl and 9- to 10-membered fused heteroaryl; R2 is selected from the group consisting of H, halogen, C1-6 alkyl, halo-C1-6 alkyl, hydroxy-C1-6 alkyl, C1-6 alkoxy and halo-C1-6 alkoxy; q is selected from the group consisting of 0, 1, 2, 3 and 4; Lx is -C(O)-NRLa-; RLa is selected from the group consisting of H, C1-6 alkyl, halo-C1-6 alkyl and cycloalkyl. Petition 870250078555, dated 03 / 09 / 2025, page 235 / 1278 2 / 24 of 3- to 6 members;Ring A is selected from the group consisting of divalent groups optionally substituted by one or more Rz: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridging cycloalkylene and 7- to 9-membered bridging heterocyclylene, wherein Rz is selected from the group consisting of halogen, -OH, -NH2, C16 alkyl, halo-C1-6 alkyl, C1-6 alkoxy, halo-C1-6 alkoxy, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclyl; L is -(B1)ni-(B2)n2-(B3)n3-; B1 is a C1-6 alkylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(Ra)(Rb)-, -N(Rc)- or -S-; ni is selected from the group consisting of 0 and 1;B2 is selected from the group consisting of the following divalent rings optionally substituted by one or more Ry: C3-6 cycloalkylene, C5-8 bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene and 6- to 8-membered heterocycloalkenylene, wherein Ry is selected from the group consisting of oxo, halogen, C1-6 alkyl and halo-C1-6 alkyl; n2 is selected from the group consisting of O and 1; B3 is a saturated or unsaturated C1-6 hydrocarbylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(Ra)(Rb)-, -N(Rc)- or -S-; n3 is selected from the group consisting of O and 1; Ra and Rb are each independently selected from the group consisting of H, deuterium, halogen, C1-6 alkyl and halo-C1-6 alkyl, and Ra and Rb are not simultaneously H;Alternatively, Ra and Rb on the same carbon atom, together with the carbon atom to which they are attached, form a 3- to 6-membered cycloalkyl ring or a 3- to 6-membered heterocyclyl ring; Rc is selected from the group consisting of H and C1-6 alkyl;Degron is a ligand that binds to an E3 enzyme.

2. Bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof, according to claim 1, characterized by Petition 870250078555, dated 03 / 09 / 2025, p. 236 / 1278 3 / 24 fact that the bifunctional compound is represented by the following formula (IA), Degron Target Structure Formula (IA) wherein R1 is selected from the group consisting of -CN, halogen, C1-4 alkyl, halo-C1-4 alkyl, C1-4 alkoxy, 5- to 6-membered heterocyclyl, 7- to 9-membered bridging heterocyclyl, 6- to 10-membered fused heterocyclyl and 3- to 6-membered cycloalkyl-NH-, wherein heterocyclyl, bridging heterocyclyl, fused heterocyclyl and cycloalkyl are optionally replaced by one or more Rx, and Rx is selected from the group consisting of -NBE, -OH, halogen, C1-4 alkyl and halo-C1-4 alkyl; m is selected from the group consisting of O, 1, 2, 3 and 4;R2 is selected from the group consisting of C1-4 alkyl and halo-C1-4 alkyl; ring A is selected from the group consisting of the following divalent groups: 7- to 11-membered spirocycloalkylene, 7- to 11-membered spiroheterocyclylene, 7- to 9-membered bridging cycloalkylene and 7- to 9-membered bridging heterocyclylene; L is -(B1)m-(B2)n2-(B3)n3-; B1 is a C1-3 alkylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(Ra)(Rb)-, -N(RC)- or -S-; m is selected from the group consisting of O and 1; B2 is selected from the group consisting of the following divalent rings optionally substituted by one or more Ry: C3-6 cycloalkylene, C5-8 bridged cycloalkylene, 4- to 6-membered heterocyclylene, 6- to 8-membered bridged heterocyclylene, phenylene and 6- to 8-membered heterocycloalkenylene, wherein Ry is selected from the group consisting of oxo, halogen, C1-4 alkyl and halo-C1-4 alkyl; m is selected from the group consisting of O and I;B3 is a saturated or unsaturated C1-6 hydrocarbylene chain, any methylene unit of which is optionally substituted by -O-, -C(O)-, -C(Ra)(Rb)-, -N(Rc)- or -S-; n3 is selected from the group consisting of O and 1; Ra and Rb are each independently selected from the group consisting of H, deuterium, halogen, C1-4 alkyl and halo-C1-4 alkyl, and Ra and Rb are not simultaneously H; alternatively, Ra and Rb on the same carbon atom, together with the carbon atom to which they are attached, form a 3- to 6-membered cycloalkyl ring;Rc is selected from the group consisting of H and C1-4 alkyl.

3. Bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized in that the bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) the heteroatom in heterocyclyl, bridged heterocyclyl, fused heterocyclyl, heteroaryl, fused heteroaryl or spiro-heterocyclyl is independently selected from the group consisting of one, two or three types of N, O and S, and the number of heteroatoms is independently 1, 2, 3 or 4; (2) R1 is selected from the group consisting of -CN, halogen, C1-6 alkyl, halo-C1-6 alkyl, C1-6 alkoxy, 3- to 6-membered heterocycle, 7- to 9-membered bridging heterocycle, 6- to 10-membered fused heterocycle and 3- to 6-membered cycloalkyl-NH-; preferably, R1 is a 7- to 9-membered bridging heterocycle; (3) Rx is selected from the group consisting of -NH2 and C1-6 alkyl; (4) m is selected from the group consisting of 1 and 2, preferably 1; (5) ring B is heteroaryl with 5 to 6 members; (6) R2 is C1-6 alkyl or halo-C1-6 alkyl, preferably halo-C1-6 alkyl; (7) q is 1; (8) Lx is -C(O)-NRLa-*, where the terminal * is connected to ring B; (9) in L, the terminal -(B3)n3- is connected to the degron; (10) ring A is selected from the group consisting of the following unsubstituted divalent groups: 7 to 11 membered spirocycloalkylene, 7 to 11 membered spiroheterocyclylene, 7 to 9 membered bridging cycloalkylene and 7 to 9 membered bridging heterocyclylene, preferably ring A is a 7 to 9 membered nitrogenated spiroheterocyclylene.

4. Bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, characterized in that L is selected from any one of the following conditions: (1) L is selected from the group consisting of -B1-B2-B3-, -B1-B3- and -B2-B3-; (2) L is -B1-B2-B3-; more preferably, the -B3- terminal is connected to the degron;(3) L is-B3-.

5. Bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, characterized in that the bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) B1 is a C1-3 alkylene chain, in which 1 to 2 methylene units are optionally substituted by -O-, -C(O)-, -C(Ra)(Rb)-, or -N(Rc)-; preferably, 1 methylene unit is optionally substituted by -C(O); (2) B3 is an unsaturated C2-6 hydrocarbylene chain, in which 1 to 2 methylene units are optionally substituted by -O-, -C(O)- or -C(Ra)(Rb)-; The hydrocarbylene chain is connected to the degron via the alkyne terminal; preferably, 1 methylene unit is optionally replaced by -O;(3) Ra and Rb are each independently selected from the group consisting of H, deuterium and -CH3; and Ra and Rb are not simultaneously H; alternatively, Ra and Rb on the same carbon atom, together with the carbon atom to which they are attached, form a cyclopropyl ring or a cyclobutyl ring; (4) Rc is selected from the group consisting of H and -CH3; preferably H; Petition 870250078555, 03 / 09 / 2025, p. 239 / 1278 6 / 24 (5) B2 is selected from the group consisting of the following groups: ; preferably consisting of the following groups: preferably, B2 is selected from the group and connected to -(B3)n3-;preferably b, wherein the b-terminal is 6. Bifunctional compound, the isomer thereof, the deuterated compound thereof or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, characterized in that B3 satisfies any one of the following conditions: (1) B3 is a C2-6 alkynylene chain, wherein 1 to 2 methylene units are optionally replaced by -O- or -C(O)-; the alkynylene chain is connected to the degron via the alkyne terminal; (2) B3 is a C2-6 alkynylene chain containing only one triple bond at the terminal;Petition 870250078555, dated 03 / 09 / 2025, p. 240 / 1278 7 / 24 (3) B3 is a C2-4 alkynylene chain containing only one triple bond at the terminal.

7. Bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, characterized in that B1 is selected from the group consisting of -CH2-, -CD2- and C(O)-; B2 is selected from the group consisting of the following divalent rings: C56 cycloalkylene, C0-8 bridged cycloalkylene, 6-membered heterocyclylene and 6- to 8-membered bridged heterocyclylene;B3 is selected from the group consisting of 8. The bifunctional compound, the isomer thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, characterized in that the isomer thereof, the deuterated compound thereof, or the pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) R1 is selected from the group consisting of -F, -CH3, -CN, -CHF2, -CF3, -OCH3, ; preferably m is selected from the group consisting of 1 and 2; (2) R2 is selected from the group consisting of -CH3, -CH2F, -CHF2, and -CF3; preferably -CHF2; (3) ring A is selected from the group consisting of Petition 870250078555, dated 03 / 09 / 2025, page 241 / 1278 8 / 24 general (IA);, where the terminal “a” denotes the end connected to L in the formula preferably, the ring A is (4) L is selected from the group consisting of Petition 870250078555, dated 03 / 09 / 2025, page 242 / 1278 9 / 24 Petition 870250078555, dated 03 / 09 / 2025, page 243 / 1278 10 / 24 preferably, L is selected from the group consisting of more preferably, the alkyne terminal of L is connected to the degron.

9. Bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, characterized in that the bifunctional compound, isomer thereof, deuterated compound thereof or pharmaceutically acceptable salt thereof satisfies one or more of the following conditions: (1) each fused heteroaryl of 9 to 10 members is pyrazolopyrimidinyl, for example, (2) each halogen is fluorine, chlorine, bromine or iodine, for example, fluorine;(3) each C1-6 alkyl is C1-4 alkyl, for example, methyl; (4) each C1-6 alkoxy is C1-4 alkoxy, for example, methoxy; (5) the heteroatom in each 3- to 6-membered heterocyclyl is independently selected from the group consisting of one, two or three types of N, O and S, and the number of heteroatoms is independently 1 or 2, for example, ; (6) the heteroatom in each 7- to 9-membered bridging heterocyclyl is independently selected from the group consisting of one, two or three types of N, O and S, and the number of heteroatoms is independently 1 or 2, for example, H®»; or (7) the heteroatom in each fused heterocyclyl of 6 to 10 members is independently selected from the group consisting of one, two or three types of N, O and S, and the number of heteroatoms is independently 1 or 2, for example, (8) each cycloalkyl of 3 to 6 members is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclohexyl;(9) each 5- to 6-membered heteroaryl is a pyrazolyl, for example, (10) each 7- to 11-membered spirocycloalkylene is Petition 870250078555, dated 03 / 09 / 2025, page 245 / 1278 12 / 24 or 7- to 11-membered; (11) each N-I spiroheterocycline is \— / (12) each 7- to 9-membered bridged cycloalkylene (13) each 7- to 9-membered bridge heterocycline is (14) each C1-6 alkylene chain is a C1-4 alkylene chain, for example, methylene or ethylene; (15) each C3-6 cycloalkylene is or (16) each C5-8 bridged cycloalkylene is , or I—N (17) each 4- to 6-membered heterocycline is 5, or νΛ. \ (18) each 6- to 8-membered bridge heterocycline is VN / or O (19) each 6- to 8-membered heterocycloalkenylene is (20) each saturated or unsaturated C1-6 hydrocarbylene chain is an alkynylene chain Petition 870250078555, dated 03 / 09 / 2025, page. 246 / 1278 13 / 24 C3-6 unsaturated, preferably 10. Bifunctional compound, an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, characterized in that the bifunctional compound has a structure represented by the following general formula: Formula (IA-1) Formula (lA-la) rings A and L are as defined in any one of claims 1 to 9.

11. Bifunctional compound, characterized in that it is, as shown below, an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof: Petition 870250078555, dated 03 / 09 / 2025, p. 247 / 1278 14 / 24 Petition 870250078555, dated 03 / 09 / 2025, p. 248 / 1278 15 / 24 Petition 870250078555, dated 03 / 09 / 2025, page.249 / 1278 16 / 24 Petition 870250078555, dated 03 / 09 / 2025, page 250 / 1278 17 / 24 Petition 870250078555, dated 03 / 09 / 2025, page 251 / 1278 18 / 24 Petition 870250078555, dated 03 / 09 / 2025, page 252 / 1278 19 / 24 Petition 870250078555, dated 03 / 09 / 2025, page 253 / 1278 20 / 24 Petition 870250078555, dated 03 / 09 / 2025, page 254 / 1278 21 / 24 or 12. Pharmaceutical composition, characterized in that it comprises the bifunctional compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 11, and one or more pharmaceutically acceptable excipients; preferably, in the pharmaceutical composition, the content of the compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof is from 1% to 95%; preferably, in the pharmaceutical composition, the pharmaceutically acceptable excipient comprises one or more of a filler, a disintegrant, a binder, a glide, or a lubricant. 13.Use of the bifunctional compound, the isomer thereof, the deuterated compound of Petition 870250078555, dated 03 / 09 / 2025, page 255 / 1278 22 / 24 itself or the pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 11, or the composition, as defined in claim 12, characterized in that it is used in the manufacture of a medicament to prevent and / or treat an IRAK4-mediated related disease; preferably, the IRAK4-mediated related disease is selected from the group consisting of immune inflammatory diseases; preferably, the IRAK4-mediated related disease is selected from the group consisting of hidradenitis suppurativa, rheumatoid arthritis, atopic dermatitis, lupus erythematosus, gouty arthritis, psoriasis, asthma, chronic obstructive pulmonary disease, polypoid sinusitis and inflammatory bowel disease. 14.Compound represented by formula (Z) or formula (X), an isomer thereof, a deuterated compound thereof or a pharmaceutically acceptable salt thereof: Formula (Z) characterized in that in formula (Z) ring A is as defined in any one of claims 1 to 9 wherein in formula (X), L is B1-1-B2-B31-; B11 is hydroxyl, amino, carboxyl or hydroxy-substituted C1-3 alkyl; B31 is a C1-3 alkylene chain, any one methylene unit of which is optionally substituted by -O-, -C(O)-, -C(Ra)(Rb)-, -N(RC)- or -S-; Ra and Rb are each independently selected from the group consisting of H, deuterium, halogen, C1-6 alkyl and halo-C1-6 alkyl, and Ra and Rb are not simultaneously H; B2 is as defined in any one of claims 1 to 9; or a compound as shown below, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: Petition 870250078555, dated 03 / 09 / 2025, p.256 / 1278 23 / 24 Petition 870250078555, dated 03 / 09 / 2025, p. 257 / 1278 24 / 24 15. IRAK4 Degrader characterized in that it comprises the compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, as defined in claim 14; preferably, the IRAK4 Degrader is the bifunctional compound, an isomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, as defined in claim 1. Petition 870250078555, dated 03 / 09 / 2025, p. 258 / 1278.

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