Compound for targeted degradation of IRAK4 protein and use thereof

Abstract

Provided in the present application are a compound for the targeted degradation of an IRAK4 protein and the use thereof. Specifically provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound has the substituents and structural features of the present application. The present application further describes a pharmaceutical composition containing the compound of formula (I) or the pharmaceutically acceptable salt thereof, and the pharmaceutical use of the compound or pharmaceutically acceptable salt thereof. PTM-L-CLM Formula (I).

Description

Compounds that target and degrade IRAK4 protein and their applications

[0001] This application requests applications filed on January 26, 2025 (application number 2025101244302), March 10, 2025 (application number 2025102781329), April 21, 2025 (application number 2025105022096), May 23, 2025 (application number 2025106688403), July 10, 2025 (application number 2025109530919), and September 3, 2025. Priority is claimed in Chinese patent applications No. 2025112516654, No. 202511344462X (filed September 19, 2025), No. 2025114178775 (filed September 30, 2025), No. 202511530213X (filed October 24, 2025), and No. 2025120373578 (filed December 31, 2025), the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure belongs to the field of pharmaceutical technology, specifically relating to a compound that targets and degrades IRAK4 protein and its applications. Background Technology

[0003] PROTACs (Proteolysis-Targeting Chimeras) are an emerging therapeutic strategy for targeting and degrading proteins. They bring the target protein (POI) to the vicinity of an E3 ligase, utilizing the ubiquitin-proteasome system (UPS) to promote protein degradation. Compared to traditional protein activity inhibitors, PROTACs selectively remove specific proteins from cells, providing an event-driven degradation mechanism that avoids simple occupancy dependence. PROTACs employ a completely different mechanism of action than small molecule inhibitors. First, the ligand of the E3 ubiquitin ligase recruits the E3 ubiquitin ligase to the vicinity of the target protein, thereby ubiquitinizing the target protein by bringing it closer. The labeled target protein is then degraded by the proteasome system in vivo, thus inhibiting the corresponding protein pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared to traditional small molecule drugs, due to the altered binding mechanism, PROTACs only require transient binding to the target protein to complete the ubiquitin transfer process and achieve irreversible degradation of the target protein. Therefore, PROTACs have the following advantages: 1) stronger degradation and longer-lasting efficacy; 2) higher selectivity for target proteins; 3) can overcome the drug resistance caused by target protein mutations of traditional small molecule inhibitors (Cell Chem. Biol. 2018, 25, 67-77).

[0004] IRAK4 (interleukin-1 receptor-associated kinase 4) is a widely expressed serine / threonine kinase involved in the regulation of innate immunity and associated with various inflammatory and autoimmune diseases, including rheumatoid arthritis, atopic dermatitis, and hidradenitis suppurativa. IRAK4 plays a crucial role in downstream signaling pathways of the interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR), and is an important component of the myddosome complex. Activation of IRAK4 can trigger a series of inflammatory responses, including inducing the expression of inflammatory factors, cytokines, and chemokines. IRAK4 has two main functions: 1) Kinase function: IRAK4 phosphorylates downstream proteins through its kinase activity, activating transcription factors such as NF-κB and AP-1, thereby promoting the expression of inflammatory factors; 2) Scaffold function: As part of the myddosome complex, IRAK4 participates in the assembly and transmission of signal transduction, a function crucial for NF-κB activation. IRAK4 is central to all MyD88 (myeloid differentiation primary response gene 88)-dependent signaling pathways, playing a crucial role in the TLR / IL-1 signaling pathway. Overactivation, or abnormal activation due to mutations, leads to sustained activation of downstream signaling molecules, thereby stably inducing the sustained expression of cytokines and chemokines, causing related inflammatory and immune responses, and contributing to autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, and gout. Therefore, inhibiting IRAK4 has become a highly anticipated therapeutic target for suppressing autoimmune and inflammatory diseases.

[0005] There remains a need to develop PROTAC compounds that can target and degrade the IRAK4 protein. Summary of the Invention

[0006] This disclosure provides novel interleukin-1 receptor-associated kinase 4 (IRAK4) protein degradation-targeting chimeric compounds (PROTACs). These compounds exhibit significant activity as IRAK4 degraders in the treatment of IRAK4-mediated or dependent diseases.

[0007] In one aspect of this disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided.

[0008] PTM-L-CLM Formula (I)

[0009] In equation (Ⅰ), L is the key or connector sub-part that connects CLM and PTM;

[0010] CLM has a structure selected from the following equations (I-1), (I-2), and (I-3):

[0011] In this case, G and Z are each independently selected from O and S each time they appear;

[0012] W1 is independently CR each time it appears. c1 Or N;

[0013] W2 and W3 are each selected independently from C(R) each time they appear. c1 2. NR c1 O and S;

[0014] R W Each occurrence is independently selected from single bonds, C(O), O, S, S(O)2, NR. c1 Combinations of one or more of the following: C1-C6 alkylene, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 ynynylene, and C1-C6 heteroalkylene;

[0015] W4 and W5 are each independently selected from N, CH, and C each time they appear. Indicates either a single or double key; and One of them is a double bond, and the other is a single bond;

[0016] W6 is either N or CR each time it appears. c1 ;

[0017] W7 is independently assigned to CR each time it appears. c2 R c3 C(O), S(O)2 or NR c2 ;

[0018] R 1 Each occurrence is independently selected from hydrogen and C1-C. 10 alkyl;

[0019] R 1a R 1b R 1c R 1d and R 1e The definition is selected from one of the following groups:

[0020] (i-1)R 1a and R 1b Forming a ring Cy1, and R 1c R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0021] (i-2)R 1band R 1c Forming a ring Cy1, and R 1a R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0022] (i-3)R 1c and R 1d Forming a ring Cy1, and R 1a R 1b and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0023] (i-4)R 1d and R 1e Forming a ring Cy1, and R 1a R 1b and R 1c Each time it appears, it is independently selected from the substituents of group S1;

[0024] (i-5)R 1c for Wherein, “*Ph” represents the linking site of the benzene ring in formula (I-1);

[0025] R 1b and R 1f The atoms bonded to it together form 4 to 9-membered heterocycles, R 1d and R 1g The atoms bonded to it together form 4 to 9-membered heterocycles; and R 1a and R 1e Each time a substituent appears, it is independently selected from the S1 group; the 4 to 9-membered heterocycles optionally contain 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms, and are optionally substituents of one or more R groups. c1 replace;

[0026] R 2a R 2b R 2c R 2d and R 2e The definition is selected from one of the following groups;

[0027] (ii-1)R 2a and R 2b Forming a ring Cy2, and R 2c R 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0028] (ii-2)R 2b and R 2c Forming a ring Cy2, and R 2a R2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0029] (ii-3)R 2c and R 2d Forming a ring Cy2, and R 2a R 2b and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0030] (ii-4)R 2a and R 2e Forming a ring Cy2, and R 2b R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0031] (ii-5)R 2a for And R 2b R 2c R 2d and R 2e Each substituent is independently selected from group S1 when it appears; where “*Ph” indicates the linking site with the benzene ring in formula (I-2) or formula (I-3);

[0032] (ii-6)R 2b for And R 2a R 2c R 2d and R 2e Each substituent is independently selected from group S1 when it appears; where “*Ph” indicates the linking site with the benzene ring in formula (I-2) or formula (I-3);

[0033] U1 is N or CH; U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R) c4 )2 and NR c4 ;

[0034] n2 and n3 are each independently 0, 1, 2 or 3;

[0035] Cy1 and Cy2 are each selected independently each time they appear.

[0036] Among them, A1, A2, A3, and A4 each appear independently as C(R). c4 2. NR c4 O, C(O) or S, at A1 and A2 Each occurrence independently represents a bonding site with a carbon atom on the benzene ring;

[0037] U4, U5, U6, and U7 are each independently CR each time they appear. c4 Or N;

[0038] D2 and D3 each appear independently as a single bond, N, or CR. c4 , This indicates the presence or absence of double bonds at any position within the ring;

[0039] R T Each occurrence is independently CH or N, R t Each occurrence is independently C, N, or CH, R t and R T place Represents the connection site with L;

[0040] The substituents in group S1 are independently selected each time they appear: hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 11 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 aryl and 5 to 12-membered heteroaryl, wherein the C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 11 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 The aryl group and the 5- to 12-membered heteroaryl group are each independently selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, nitro groups, C1-C groups. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C3-C 11 Cycloalkyl, 4- to 12-membered heterocyclic groups, C2-C6 alkenyl, C2-C6 ynyl, C5-C 12 Substituted with aryl and 5 to 12 heteroaryl groups;

[0041] Each occurrence of n1 is independently 0, 1, 2, 3, or 4;

[0042] Each time m11, m21, m31 and m14 appear, they are independently 0, 1, 2, 3, 4 or 5, and m11+m21≤6, m31+m41≤7;

[0043] PTM has the structure shown in equation (P-1):

[0044] Among them, ring A is selected from C5-C 10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms, each independently selected from N, O, and S.

[0045] Ring B is selected from single bonds, C5-C 10 arylene, 5- to 10-membered heteroarylene containing 1 to 4 heteroatoms independently selected from N, O and S, 8- to 14-membered bicyclic heterocyclic group containing 1 to 4 heteroatoms independently selected from N, O and S, and 10- to 16-membered tricyclic heterocyclic group containing 1 to 3 heteroatoms independently selected from N, O and S.

[0046] R aa Each time it appears, it is independently selected from hydrogen, deuterium, oxo group (=O), halogen, hydroxyl group, cyano group, amino group, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 11 cycloalkyl, NHR p1 、N(R p1 2. C2-C6 alkenyl, containing 1-3 4- to 12-membered heterocyclic groups, each independently selected from N, O, and S heteroatoms; C5-C 10 Aryl groups and 5- to 12-membered heteroaryl groups, each independently selected from N, O, and S heteroatoms, wherein the C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, 4- to 12-membered heterocyclic groups, C5-C 10 Aryl and 5 to 12 heteroaryl groups are optionally p' R cc Replaced;

[0047] R bb Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo group, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10Deuterated alkyl, C1-C 10 Haloalkyl, C1-C 10 alkylene-hydroxyl, OR p1 NHR p1 、N(R p1 2. C(O)-O-Cl-C 10 Alkyl, C3-C 11 Cycloalkyl groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms independently selected from N, O, and S, wherein the C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms independently selected from N, O, and S, optionally surrounded by p' R cc Replaced;

[0048] R cc Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 alkylene-hydroxyl, NHR p1 、N(R p1 )2 and C3-C 11 cycloalkyl, wherein the C3-C 11 The cycloalkyl group is optionally surrounded by one, two, or three groups, each independently selected from halogen, hydroxyl, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Substituents of haloalkyl groups;

[0049] L aa Selected from single bonds, C(O), O, NR p1 NR p1 C(O), C(O)NR p1 C1-C 10 alkylene, C2-C6 alkenylene, C2-C6 alkyneene, and C1-C 10 Halogenated alkylene;

[0050] L bb For XL cc Wherein, X is independently selected from single bonds, phenylene, C3-C 11 Cycloalkylene and 4- to 11-membered heterocycloalkylene, wherein the C3-C11 Cycloalkylene and 4 to 11-membered heterocycloalkylene are optionally surrounded by 1, 2, 3 or 4 R's. x Replaced;

[0051] L cc Selected from single bonds, C(O), O, NR p1 NR p1 C(O), C(O)NR p1 C1-C 11 Alkylene, C1-C 10 Alkyl halide, C2-C6 alkenyl halide, and C2-C6 ynyl halide;

[0052] Each time m', n', and p' appear, they are independently selected from 0, 1, 2, and 3;

[0053] R c1 R c2 R c3 R c4 R p1 and R x Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo group, hydroxyl group, nitro group, cyano group, amino group, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, C3-C 11 cycloalkyl, C1-C 10 Alkyl-amino, C(O)-C1-C 10 Alkyl, C(O)-O-C1-C 10 Alkyl, C(O)-NH-C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 aryl and 5 to 12-membered heteroaryl, wherein the C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 11 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 The aryl and 5- to 12-membered heteroaryl groups are each independently and optionally selected from one or more groups selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, C1-C6 alkylene-amino, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 15 Substituted with aryl and 5 to 12 heteroaryl groups;

[0054] In some embodiments, the compound of formula (I) does not contain any of the specific compounds described in PCT / CN2025 / 071930.

[0055] In some embodiments, the CLM is selected from the structures shown in formulas (B-1), (B-2), (B-3), (B-4), (B-5), (B-6), (B-7), (B-8), (B-9), (I-2a1), (I-2a2), (I-2a3), (I-2a4), (I-2b1), (I-2b2), (I-2b3), (I-2b4), (I-2c1), (I-2d1), (I-2d2), and (I-2d3):

[0056] Among them, W1, R W R 1a R 1b R 1c R 1d R 1e R 2a R 2b R 2c R 2d and R 2e Each custom definition is the same as before;

[0057] B1, B2, B3, B6, B7, C1, and C2 each appear independently as a single bond, C(R) c4 2. NR c4 O, C(O) or S;

[0058] In some implementations, B1, B2, B3, B6, B7, C1, and C2 are each independently selected from C(R) each time they appear. c4 )2 and O;

[0059] D2 and D3 are each selected independently from single bonds and CR each time they appear. c4 And N; preferably a single bond, CH or N, more preferably N;

[0060] Each time m1, m2, m3, m4 and m5 appear, they are independently 0, 1, 2, 3, 4 or 5;

[0061] U5 and U6 are each independently designated as CR each time they appear. c4 Or N;

[0062] A5 and A6 are each independently selected from (CH2) each time they appear. 1-3 (CH2) 0-2 O(CH2) 0-2(CH2) 0-2 S(CH2) 0-2 (CH2) 0-2 C(O)(CH2) 0-2 and (CH2) 0- 2NH(CH2) 0-2 ;

[0063] n4 and n5 are each independently selected from 0, 1, 2 and 3 each time they appear;

[0064] R c4 Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl, nitro, cyano, amino, C1-C6 alkyl and C1-C6 alkoxy;

[0065] R T Each occurrence is independently CH or N, R t Each occurrence is independently either C or N;

[0066] In some implementation schemes, B1, B2, B3, and B6 are each independently selected from C(R) each time they appear. c4 )2 and O;

[0067] In some implementations, B7 is selected independently from single bonds and O each time it appears;

[0068] In some implementations, C1 and C2 are each independently represented as C(R) each time they occur. c4 )2;

[0069] In some implementations, D2 and D3 are each independently N each time they occur;

[0070] In some implementations, m1, m2, m3, m4, and m5 are each independently 0, 1, 2, or 3 each time they appear;

[0071] In some implementations, U5 and U6 are each independently CH or N each time they appear;

[0072] R c4 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3 alkyl, and C1-C3 alkoxy; in some embodiments, R c4 For H;

[0073] In some implementations, A5 and A6 are each independently selected from O, CH2, and CH2CH2 each time they appear; in some implementations, A5-A6 are O-CH2 or O-CH2CH2.

[0074] In some implementations, n4 and n5 are each 1 or 2 independently each time they occur, and in some implementations they are 1;

[0075] In some implementations, when the CLM has the structure shown in formula (B-1), formula (B-3), or formula (B-5), R w When the bond is a single bond, W1 is CH, ring B is indazole, triazolidine, imidazopyridine, or pyrazolidine, and X is cyclohexane or piperidine: L cc For C(O) or L containing C3-C 16 Cycloalkylene, 4 to 12-membered heterocyclic alkylene, C5-C 12 A aryl or 5 to 12-membered heteroaryl.

[0076] In some implementations, W1 is independently CH or N each time it appears, preferably N;

[0077] In some implementations, W2 and W3 each occur independently as C(R) c1 )2 or NR c1 CH2 is preferred;

[0078] In some implementation schemes, R W Each occurrence is independently selected from single bonds, C(O), O, NR. c1 NR c1 C(O), C(O)NR c1 C1-C6 alkylene and C1-C6 haloalkylene; in some embodiments, R W Each occurrence is independently selected from single bonds and NR. c1 and NR c1 C(O); In some implementations, R W Each occurrence is independently selected from single bonds, NH, and NHC(O); in some implementations, R W It is a single bond;

[0079] In some implementation schemes, R 1 Each time it appears, it is independently selected from hydrogen and C1-C6 alkyl groups; in some embodiments, R 1 It is hydrogen;

[0080] In some implementations, G is O; Z is O;

[0081] In some implementations, W6 is either N or CH each time it appears;

[0082] In some implementations, W7 is independently CH2, C(O), S(O)2, or NH each time it appears;

[0083] In some embodiments, A1, A2, A3, and A4 are each independently selected from CH2, C(C1-C6 alkyl)2, NH, N(C1-C6 alkyl), O, C(O), and S each time they appear; in some embodiments, A1, A2, A3, and A4 are each independently selected from CH2, C(CH3)2, NH, N(CH3), O, C(O), and S each time they appear; in some embodiments, A1, A2, A3, and A4 are each independently CH2 or O each time they appear.

[0084] In some implementations, U1 is independently N each time it occurs;

[0085] In some embodiments, U2 and U3 are each independently selected from CH2, CH (C1-C6 alkyl), C (C1-C6 alkyl)2, NH and N (C1-C6 alkyl), preferably CH2;

[0086] In some implementations, U4, U5, U6, and U7 are each independently CH or N each time they appear; in some implementations, at least one of U4 and U5 is N, and at least one of U6 and U7 is N;

[0087] In some implementations, D2 and D3 are each independently a single bond, N, CH, or C (C1-C6 alkyl) each time they appear;

[0088] In some embodiments, the S1 group substituents are each independently selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 10 aryl and 5- to 10-membered heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are each independently selected from one or more halogens, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4- to 8-membered heterocyclic, C2-C6 alkenyl, C2-C6 alkynyl, C6-C 10 The substituents are aryl and 5 to 10 heteroaryl groups; in some embodiments, each of the S1 group substituents is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, methyl, ethyl, cyano, methoxy, ethoxy and isopropoxy.

[0089] In some implementations, n1 is independently 0, 1, or 2 each time it appears, preferably 1;

[0090] In some implementations, n2 is independently 0, 1, or 2 each time it appears, preferably 1;

[0091] In some implementations, n3 is independently 0, 1, or 2 each time it appears, preferably 1;

[0092] In some implementations, m11 and m21 each appear independently as 0, 1, 2 or 3, and m11+m21≤4; in some implementations, m11+m21=2 or m11+m21=3;

[0093] In some implementations, m31 and m41 each appear independently as 0, 1, 2 or 3, and m31+m41≤4; in some implementations, m31+m41=2 or m31+m41=3;

[0094] In some embodiments, ring A is selected from C5-C6 aryl, 5-6 membered monocyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, and 9-10 membered bicyclic heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S; in some embodiments, ring A is selected from phenyl, pyridone, oxazolyl, thiazolyl, imidazole, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazole, benzimidazole, pyrazolopyrimidinyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl, pyrimidinylimidazolyl, pyrrolopyrazinyl, pyridopyrimidinyl, and pyridopyrimidone; in some embodiments, ring A is indazole, pyridyl, or pyridone; in some embodiments, the pyridone group is selected from... More preferably

[0095] In some implementations, ring B is selected from single bonds, C5-C 10 The compounds include arylene groups, 5-10 membered heteroarylene groups containing 1-4 heteroatoms independently selected from N, O, and S, 8-10 membered bicyclic heterocyclic groups containing 1-4 heteroatoms independently selected from N, O, and S, and 12-14 membered tricyclic heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, and S; in some embodiments, ring B is selected from phenyl, pyrazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, diazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazole, benzimidazolyl, benzothiazolyl, pyrazolopyrimidinyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl, and pyrimidinimidazolyl. The divalent linker; in some embodiments, ring B is selected from phenyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazole, benzopyrazolyl, benzoimidazolyl, pyrazolopyrimidinyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl, pyrimidinimidazolyl, pyrimidinimidazolyl, and so on. The divalent linker; in some implementations, ring B is Divalent linker;

[0096] In some implementation schemes, R aa Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, NH-C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the 5- to 8-membered heterocyclic groups and the 5- to 10-membered heteroaryl groups are optionally separated by p' R cc Replaced;

[0097] In some implementation schemes, R aa Each of the following groups, when appearing independently, is selected from hydrogen, cyano, C1-C6 haloalkyl, imidazolyl, pyridinyl, morpholinyl, a 7-membered bridged heterocyclic alkyl group containing two heteroatoms independently selected from N and O, and a 9-membered heteroaryl group containing two N atoms, wherein the imidazolyl, pyridinyl, morpholinyl, 7-membered bridged heterocyclic alkyl group, and 9-membered heteroaryl group are optionally separated by p' R cc Replaced;

[0098] In some implementation schemes, R aa Each of the following groups, when appearing independently, is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, methoxy, ethoxy, isopropoxy, C1-C6 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, imidazolyl, pyridyl, morpholinyl, a 7-membered bridged heterocyclic alkyl group containing two heteroatoms independently selected from N and O, and a 9-membered heteroaryl group containing two N atoms, wherein the imidazolyl, pyridyl, morpholinyl, 7-membered bridged heterocyclic alkyl group, and 9-membered heteroaryl group are optionally separated by p' R cc Replaced;

[0099] In some implementation schemes, R aa Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, methoxy, ethoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0100] In some implementation schemes, R aa Each time it appears, it is independently selected from hydrogen, cyano,

[0101] In some implementation schemes, R bb Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl), NH(C1-C6 alkylene-CN), NH(C3-C6 cycloalkyl), C(O)-O-C1-C6 alkyl, O-(C1-C6 alkyl), O-(C3-C6 cycloalkyl), N(C1-C6 alkyl)2, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups containing 1-3 heteroatoms each independently selected from N, O and S heteroatoms, and 5-6 membered heteroaryl groups containing 1-3 heteroatoms each independently selected from N, O and S heteroatoms, wherein the 4-6 membered heterocyclic groups and 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 substituents selected from halogen, C1-C6 alkyl and C1-C6 alkoxy;

[0102] In some implementation schemes, R bb Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -C1-C6 alkylene-hydroxy, NH (C1-C6 alkyl), NH (C1-C6 alkylene-CN), NH (C3-C6 cycloalkyl), -O- (C1-C6 alkyl), -O- (C3-C6 cycloalkyl), N (C1-C6 alkyl)2, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups containing 1-3 heteroatoms each independently selected from N, O, and S heteroatoms, and 5-6 membered heteroaryl groups containing 1-3 heteroatoms each independently selected from N, O, and S heteroatoms, wherein the 4-6 membered heterocyclic groups and 5-6 membered heteroaryl groups are optionally substituted by 1, 2, or 3 substituents selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy;

[0103] In some implementation schemes, R bbEach time it appears, it is independently selected from hydrogen, halogen, hydroxyl, amino, oxo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylene-hydroxy, NH (C1-C3 alkyl), NH (C1-C3 alkylene-CN), NH (C3-C5 cycloalkyl), O- (C1-C3 alkyl), O- (C3-C5 cycloalkyl), N (C1-C3 alkyl)2, C3-C5 cycloalkyl, containing 1-2 4-6 membered heterocyclic groups and pyridyl groups, each independently selected from N and O heteroatoms, wherein the C3-C5 cycloalkyl, 4-6 membered heterocyclic groups and pyridyl groups are optionally substituted by 1 or 2 substituents independently selected from methyl, ethyl, isopropyl, methoxy and ethoxy;

[0104] In some implementation schemes, R bb Each time it appears, it is independently selected from hydrogen, oxo group, F, Cl, Br, cyano, methyl, CH(CH3)2, OCH3, O-CH(CH3)2, CHF2, C(CH3)2OH, NH(CH3), -N(CH3)2, NH-CH(CH3)2, NH-CH(CH3)CN, C(O)-O-CH3,

[0105] In some implementation schemes, R bb Each time it appears, it is independently selected from oxo groups, -CH(CH3)2, -OCH3, -O-CH(CH3)2, -CHF2, -C(CH3)2OH, -NH(CH3), -N(CH3)2, -NH(CH(CH3)CN),

[0106] In some implementation schemes, R cc Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl), and C3-C8 cycloalkyl; in some embodiments, R cc Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, NH(C1-C3 haloalkyl), NH(C1-C3 alkylene-C3-C6 cycloalkyl), and C3-C6 cycloalkyl; in some embodiments, R ccEach time it appears, it is independently selected from cyano, CH3, CH2CH3, CF3, CH(CH3)2, N(CH3)2, N(CH3)(CH2CH3) and NH-CH2-cyclopropyl;

[0107] In some implementations, L aa Each occurrence is independently selected from single bonds, C(O), O, NH, NHC(O), and C(O)NH; in some embodiments, L aa Each occurrence is independently selected from single bonds, NH, C(O)NH, and NHC(O). In some embodiments, L aa Each time it appears, it is independently selected from single bonds, NH, C(O)NH *B and NHC(O) *B ,in," *B "Indicates the connection site with ring B;

[0108] In some implementations, L bb For XL cc In each occurrence, X is independently selected from single bonds, phenylene, C6-C8 cycloalkylene, and 6- to 10-membered heteroalkylene, wherein the C6-C8 cycloalkylene and 6- to 10-membered heteroalkylene are optionally separated by 1, 2, 3, or 4 Rs. x The substitution is preferably made by one or two substituents independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; in some embodiments, X is independently a single bond each time it appears, or is selected from phenyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridaz ... The divalent linker, which is optionally linked by 1, 2, 3 or 4 R x Replaced;

[0109] In some implementations, L cc Each time it appears, it is independently selected from single bond, C(O), O, CH2, NH, NHC(O) and C(O)NH, preferably selected from single bond, C(O), O, NH, NHC(O) and C(O)NH;

[0110] In some implementations, m', n', and p' are each independently selected from 0, 1, and 2 each time they appear;

[0111] In some implementation schemes, R c1 R c2 R c3 and R c4Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C1-C6 alkyl-amino, C(O)-C1-C6 alkyl, C(O)-O-C1-C6 alkyl, C(O)-NH-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 10 aryl and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are each independently and optionally selected from one or more groups selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 10 Substituents of aryl and 5 to 10 heteroaryl groups, or, R c4 Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, and C1-C6 alkoxy; in some embodiments, R c1 R c2 R c3 and R c4 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, oxo, hydroxyl, nitro, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, and trifluoroethyl, or, R c4 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3 alkyl and C1-C3 alkoxy; more preferably, it is H;

[0112] R p1 and R x Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo group, hydroxyl group, nitro group, cyano group, amino group, C1-C. 10 Alkyl, C1-C 10 Alkoxy and C3-C 11 cycloalkyl; in some embodiments, R p1 and R x Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, oxo, hydroxyl, nitro, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, and isopropoxy;

[0113] In some implementation schemes, Selected from

[0114] In some implementation schemes, in some implementation schemes Selected from

[0115] Among them, R aa1 and R aa2 Each of the following groups, when appearing independently, is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, NH-C3-C6 cycloalkyl, C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms independently selected from N, O, and S, wherein the C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups, and 5- to 10-membered heteroaryl groups are optionally separated by p' R cc Replaced; in some implementations, R aa1 and R aa2 Each group, when appearing independently, is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, methyl, ethyl, propyl, methoxy, ethoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; in some embodiments Selected from

[0116] In some implementation schemes, Selected from the following structures:

[0117] Among them, "*L" aa "Indicates L aa The connection site, "*L" bb "Indicates L bb Connection sites;

[0118] In some implementations, L bb For XL cc In this context, X is a single bond or a compound selected from phenyl, cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziroxybutyl, pyrrolidinyl, piperidinyl, piperazineyl, etc. The divalent linker is optionally substituted with one or two substituents independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; in some embodiments, the right-hand linker is associated with L. cc The connection site; L cc Each occurrence is independently selected from single bonds, CH2, and C(O);

[0119] In some implementations, L bb Each occurrence is independently selected from single bonds, C(O), -NH, NHC(O), C(O)NH, In some implementations, the right-hand connection site is the connection site with L.

[0120] In some implementations, the PTM has the structure shown in formula (P-2):

[0121] Among them, ring C and ring E are each independently selected from C6-C. 10 Arylenes and 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms, each independently selected from N, O, and S;

[0122] Ring D is selected from C6-C 10 Aryl groups and 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms, each independently selected from N, O, and S.

[0123] R ee Selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl-amino, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 15 Aryl and 5 to 12 heteroaryl groups;

[0124] R ff and R dd Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, OR p1 C1-C 10 Halogenated alkyl, NHR p1 、N(R p1 2. C3-C 11 Cycloalkyl groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms independently selected from N, O, and S, wherein the C1-C10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms independently selected from N, O, and S, optionally surrounded by p' R cc Replaced;

[0125] R cc Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 alkylene-hydroxyl, NHR p1 、N(R p1 )2 and C3-C 11 cycloalkyl, wherein the C3-C 11 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from halogen, hydroxyl, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Substituents of haloalkyl groups;

[0126] L ff Each occurrence is independently selected from single bonds, C(O), O, and NR. p1 NR p1 C(O), C(O)NR p1 C1-C 10 alkylene, C2-C6 alkenylene, C2-C6 alkyneene, and C1-C 10 Halogenated alkylene;

[0127] L gg For YL cc1 Each time Y appears, it is independently selected from single bonds, C3-C 11 Cycloalkylene and 4- to 11-membered heterocycloalkylene, wherein the C3-C 11 Cycloalkylene and 4 to 11-membered heterocycloalkylene are optionally surrounded by 1, 2, 3 or 4 R's. x Replaced;

[0128] L cc1 Each occurrence is independently selected from single bonds, C(O), O, NR. p1 NR p1 C(O), C(O)NR p1 C1-C 11 Alkylene, C1-C 10Alkyl halide, C2-C6 alkenyl halide, and C2-C6 ynyl halide;

[0129] Each time t', x', y', and p' appear, they are independently selected from 0, 1, 2, and 3;

[0130] R p1 and R x Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo group, hydroxyl group, nitro group, cyano group, amino group, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, C3-C 11 cycloalkyl, C1-C 10 Alkyl-amino, C(O)-C1-C 10 Alkyl, C(O)-O-C1-C 10 Alkyl, C(O)-NH-C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 aryl and 5 to 12-membered heteroaryl, wherein the C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 11 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 The aryl and 5- to 12-membered heteroaryl groups are each independently and optionally selected from one or more groups selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 15 Substituted with aryl and 5 to 12-membered heteroaryl groups;

[0131] In some embodiments, ring D is selected from phenyl, 5-6 membered monocyclic heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and 9-10 membered bicyclic heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S; in some embodiments, ring D is selected from phenyl, 5-6 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S, and 9-10 membered bicyclic heteroaryl groups containing 2-3 heteroatoms selected from N and O; in some embodiments, ring D is selected from phenyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazole, benzimidazolyl, pyrazolopyrimidinyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl, pyrimidinylimidazolyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyridopyrimidinyl, and pyridopyrimidinoneyl.

[0132] In some embodiments, ring E is selected from phenylene and 5-6 membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, O and S; in some embodiments, ring E is selected from phenylene and 5-6 membered heterocyclic aryl groups containing 1-2 heteroatoms selected from N and O; in some embodiments, ring E is selected from phenyl, oxazolyl, thiazolyl, imidazolyl and pyridinyl.

[0133] In some embodiments, the ring C is selected from phenyl and 5-6 membered monocyclic heteroaryl groups containing 1-3 heteroatoms selected from N, O and S, preferably selected from phenyl, diazolyl, triazolyl and thiadiazolyl;

[0134] In some implementation schemes, R ff Each of the following is independently selected from NH (C1-C6 alkyl), N (C1-C6 alkyl)2, NH- (C3-C6 cycloalkyl), C1-C6 alkoxy and O- (C3-C6 cycloalkyl), preferably selected from NH-CH(CH3)2, NH-CH3, NH-cyclopropyl, O-CH3, O-CH(CH3)2 and O-cyclopropyl;

[0135] In some implementations, L ff Each occurrence is independently selected from single bonds, C(O), O, NH, NHC(O), and C(O)NH; in some embodiments, L ff Selected from single bonds;

[0136] In some implementations, L gg For YL cc1 Each time Y appears, it is independently selected from single bonds, C6-C8 cycloalkyl groups and 6- to 10-membered heteroalkyl groups, wherein the C6-C8 cycloalkyl groups and 6- to 10-membered heteroalkyl groups are optionally substituted by one or two substituents independently selected from halogens, C1-C6 alkyl groups and C1-C6 alkoxy groups;

[0137] In some implementations, L cc1 Each time it appears, it is independently selected from single bond, C(O), O, NH, NHC(O), and C(O)NH;

[0138] In some implementations, x', y', and t' are each independently selected from 0, 1, and 2 each time they appear;

[0139] In some implementation schemes, Selected from Among them, R ee1 and R ee2Each of the following groups, when appearing independently, is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, containing 1-3 5- to 8-membered heterocyclic groups selected from N, O, and S heteroatoms, and containing 1-4 5- to 10-membered heteroaryl groups selected from N, O, and S heteroatoms; in some embodiments, R ee1 and R ee2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, and cyano groups;

[0140] In some implementation schemes, Selected from Preferred Among them, "*L" ff "Indicates L ff Connection sites;

[0141] In some implementation schemes, Selected from

[0142] In some implementations, L gg For YL cc1 In each occurrence of Y, it is independently a single bond or selected from cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziridine, pyrrolidinyl, piperidinyl, piperazineyl, etc. The divalent linker is optionally substituted with one or two substituents independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; in some embodiments, the right-hand linker is associated with L. cc1 The connection site; L cc1 Each occurrence is independently selected from single bonds and C(O); in some implementations, L gg Each occurrence is independently selected from single bonds, C(O), C(O)NH, In some implementations, the right-hand connection site is the connection site with L.

[0143] In some embodiments, the PTM is selected from the structures shown in Equations A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11a, A-11b, and A-12:

[0144] In equation A-1, X and L cc and R bb Each occurrence is defined as described above;

[0145] Ring A a Each time it appears, it is selected independently.

[0146] In some implementation schemes, ring A a Each time it appears, it is selected independently.

[0147] Preferred selection Wherein, “*Ab” represents the connection site with the ring Ab;

[0148] R aa Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; in some embodiments, R aa Each time it appears, it is independently either hydrogen or methyl;

[0149] Ring A b Each time it appears, it is independently selected from hydrogen, In some implementation schemes, ring A b Each time it appears, it is independently selected from hydrogen,

[0150] p' is independently 1, 2, or 3 each time it appears; R cc Each occurrence is defined as described above;

[0151] In some implementation schemes, R bb Each time it appears, it is independently selected from hydrogen and C1-C6 haloalkyl, more preferably C1-C6 alkyl with 1, 2 or 3 fluorine substitutions, more preferably fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl, more preferably difluoromethyl;

[0152] In some implementation schemes, R cc Each occurrence is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C3-C6 cycloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl), and C3-C6 cycloalkyl, wherein the NH(C3-C6 cycloalkyl) and C3-C6 cycloalkyl are optionally substituted by one or two substituents selected from C1-C6 alkyl and C1-C6 fluoroalkyl; in some embodiments, R ccEach time it appears, it is independently selected from hydrogen, cyano, CH3, CH2CH3, CF3, CH(CH3)2, N(CH3)2, N(CH3)(CH2CH3), NH-CH2-CF3, NH-CH2-cyclopropyl,

[0153] In some implementations, X is independently selected from single bonds each time it appears. It may optionally be substituted with one or two independent substituents selected from halogens, C1-C6 alkyl groups and C1-C6 alkoxy groups;

[0154] In some implementations, L cc Each occurrence is independently selected from single bonds, methylene groups, and C(O);

[0155] In equation A-2, X and L cc R bb Both n and n' are defined as previously stated;

[0156] Q1 is selected from CH and N; W 81 Selected from C(O) and CH2; W 82 Selected from C(O) and CH2;

[0157] Ring A c Each time it appears, it is selected independently. In some implementation schemes, ring A c Each time it appears independently *A d "Indicates and ring A" d Connection sites;

[0158] R aa Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; in some embodiments, R aa It is hydrogen;

[0159] Ring A d Each time it appears, it is selected independently. In some implementation schemes, ring A d Each time it appears independently

[0160] p' is 1, 2, or 3 each time it appears;

[0161] R ccEach time it appears, it is independently selected from hydrogen, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C 1-4 alkylene-C3-C6 cycloalkyl) and C3-C8 cycloalkyl; in some embodiments, R cc Each time it appears, it is independently selected from hydrogen and C1-C6 alkyl groups; in some embodiments, R cc Each time it appears, it is independently selected from hydrogen and methyl;

[0162] In some implementations, X is independently selected from single bonds each time it appears. It is optionally substituted with one or two substituents independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; in some embodiments, X is...

[0163] In some implementations, L cc Each occurrence is independently selected from single bonds, methylene groups, and C(O);

[0164] In some implementation schemes, R bb Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy and C1-C6 alkylene-hydroxyl, preferably C1-C6 alkoxy or C1-C6 alkylene-hydroxyl, more preferably -OCH3, -C(CH3)2OH or -N(CH3)2;

[0165] In some implementations, n' is 0 or 1;

[0166] In equation A-3, X and L cc R bb Both n and n' are defined as previously stated;

[0167] Q1 is selected from CH and N;

[0168] Ring A e Selected from In some implementation schemes, ring A e for

[0169] R aa Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups and C1-C 10Haloalkoxy; in some embodiments, R aa Each time it appears, it is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl; in some embodiments, R aa Each time it appears, it is either hydrogen or CF3 independently;

[0170] In some implementation schemes, R bb Each occurrence is independently selected from hydrogen, hydroxyl, halogen, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, 4-6 membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, and 5-6 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, wherein the 4-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by 1, 2, or 3 substituents selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy; in some embodiments, R bb Each occurrence is independently selected from C1-C6 alkoxy, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, In some implementation schemes, R bb Each time it appears, it is independently selected from OCH3, C(CH3)2OH, N(CH3)2, In some implementation schemes, R cc Each time it appears, it is independently selected from hydrogen and C1-C6 alkyl groups;

[0171] Each time X appears, it is selected independently from a single key. It is optionally substituted with one or two substituents independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; in some embodiments, X is independently substituted each time it appears.

[0172] In some implementations, L cc Each occurrence is independently selected from single bonds, methylene groups, and C(O);

[0173] In some implementations, n' is independently 0 or 1 each time it appears;

[0174] In equation A-4, X and L cc Each is as defined above;

[0175] Q1 is selected from CH and N; in some implementations, Q1 is N;

[0176] Q2 is selected from CH2 and O;

[0177] Each time q1 and q2 appear, they are independently selected from 0, 1, 2, and 3;

[0178] R bb1 and R bb2 Each time it appears, it is independently selected from hydrogen, halogen, amino, hydroxyl, oxo, C1-C3 alkyl, C1-C3 alkoxy and C1-C3 haloalkyl;

[0179] R bb3 Each occurrence is independently selected from hydrogen, halogen, amino, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylene-hydroxy, 4-6 membered heterocyclic groups containing 1-2 heteroatoms independently selected from N and O, and pyridyl, wherein the 4-6 membered heterocyclic group and pyridyl group are optionally substituted by 1 or 2 substituents independently selected from methyl, ethyl, isopropyl, methoxy, and ethoxy; in some embodiments, R bb3 Each time it appears, it is selected independently.

[0180] Ring A f Each time it appears, it is selected independently.

[0181] R cc Each time it appears, it is independently selected from hydrogen, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C 1-4 alkylene-C3-C6 cycloalkyl) and C3-C8 cycloalkyl; in some embodiments, R cc Each time it appears, it is independently selected from hydrogen and C1-C6 haloalkyl; in some embodiments, R cc Each time it appears, it is independently selected from hydrogen and CF3;

[0182] In some implementations, X is independently selected from single bonds each time it appears. It is optionally substituted with one or two substituents independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; in some embodiments, X is a single bond; in some embodiments...

[0183] L cc Each occurrence is independently selected from single bonds, methylene groups, and C(O);

[0184] R bb1 Each time it appears, it is independently selected as hydrogen;

[0185] R bb2 Each time it appears, it is independently a hydrogen or oxo group;

[0186] In equation A-5, X and L cc Each is as defined above;

[0187] R bb1 R bb2 and R bb3 Each of the following is independently selected from hydrogen, amino, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, C(O)-O-C1-C6 alkyl, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2; in some embodiments, R bb1 and R bb2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylene-hydroxy, C(O)-O-C1-C3 alkyl, NH (C1-C3 alkyl), and N (C1-C3 alkyl)2; in some embodiments, R bb3 For hydrogen; in some implementations, R bb1 and R bb2 Each time it appears, it is independently hydrogen, fluorine, C(O)OCH3, OCH3, C(CH3)2OH or N(CH3)2;

[0188] In some implementation schemes, R bb1 R bb2 and R bb3 Each of these elements, when appearing independently, is selected from hydrogen, amino, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, NH (C1-C6 alkyl), and N (C1-C6 alkyl)2; in some embodiments, R bb1 and R bb2 Each of these elements, when present, is independently selected from hydrogen, fluorine, chlorine, bromine, C1-C3 haloalkyl, C1-C3 alkylene-hydroxy, NH (C1-C3 alkyl), and N (C1-C3 alkyl)2; in some embodiments, R bb3 For hydrogen; in some implementations, R bb1 and R bb2 Each time it appears, it is independently fluorine, OCH3, C(CH3)2OH, or N(CH3)2;

[0189] Ring A a Each time it appears, it is selected independently.

[0190] In some implementation schemes, ring A a Each time it appears, it is selected independently.

[0191] Preferred selection *A b "Indicates and ring A" b Connection sites;

[0192] R aa Each occurrence is as defined above; in some implementations, R aa Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C 10 Haloalkoxy groups and 5- or 6-membered heterocyclic groups; in some embodiments, R aa Each time it appears, it is independently hydrogen, cyano, methyl, difluoromethyl, trifluoromethyl, or morpholino; in some embodiments, R aa Each time it appears, it is independently hydrogen, cyano, or trifluoromethyl;

[0193] Ring A b Each time it appears, it is independently selected from H.

[0194] p' is 1, 2, or 3 each time it appears;

[0195] R cc Each time it appears, it is independently selected from hydrogen, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl), and C3-C8 cycloalkyl; in some embodiments, R cc Each time it appears, it is independently hydrogen, cyano, CH3, CH2CH3, CF3, CH(CH3)2, N(CH3)2, N(CH3)(CH2CH3) or NH-CH2-cyclopropyl;

[0196] In some implementations, X is independently selected from single bonds each time it appears. It may optionally be substituted with one or two independent substituents selected from halogens, C1-C6 alkyl groups and C1-C6 alkoxy groups;

[0197] In some implementations, L cc Selected from single bonds, methylene groups, and C(O);

[0198] In equation A-6, R ff Y and L cc1 Each is as defined above;

[0199] Ring A L Each time it appears, it is selected independently. In some implementation schemes, ring A L Each time it appears, it is selected independently. The preferred right-side connection site is the connection site with Y; R dd As defined above;

[0200] Ring A k Each time it appears, it is selected independently. Among them, R ee1 and R ee2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl; in some embodiments, R ee1 and R ee2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, and cyano groups;

[0201] In some implementation schemes, R dd Each time it appears, it is independently selected from hydrogen, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl), and C3-C8 cycloalkyl; in some embodiments, R dd Each time it appears, it is independently selected from hydrogen, F, Cl, Br, CH3, CH2CH3, CF3 and CH(CH3)2;

[0202] In some implementation schemes, R ff Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, O-C3-C6 cycloalkyl, NH-C1-C6 alkyl, NH-C3-C6 cycloalkyl, and C3-C6 cycloalkyl; in some embodiments, R ff Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, O-C3-C5 cycloalkyl, NH-C1-C3 alkyl, NH-C3-C5 cycloalkyl and C3-C5 cycloalkyl, more preferably NH-CH(CH3)2, NH-CH3, NH-cyclopropyl, O-CH3, O-CH(CH3)2 or O-cyclopropyl;

[0203] In equation A-7, X and L ccEach is as defined above;

[0204] Ring A L1 Each time it appears, it is selected independently. Preferred selection Where "*X" represents the connection site with X; R bb Each occurrence is independent of the definition given above;

[0205] Ring A k1 Each time it appears, it is selected independently.

[0206] R aa1 and R aa2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, C(O)NH2, cyano, R cc Each occurrence of p' is independently defined as described above;

[0207] R aa1 and R aa2 Each time it appears, it is independently selected from hydrogen, cyano,

[0208] In some implementation schemes, R bb Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, OCH3, O-CH(CH3)2, CHF2, C(CH3)2OH, NH(CH3), N(CH3)2, CH(CH3)2, NH-CH(CH3)2, NH-CH(CH3)CN,

[0209] In some implementation schemes, R aa1 and R aa2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, and

[0210] In some implementation schemes, R cc Each time it appears, it is independently selected from hydrogen and methyl;

[0211] In formula A-8, X and L cc and R bb Each is as defined above;

[0212] Ring A a1 Each time it appears, it is selected independently. Preferred selection Among them, "*A" b1 "Indicates and ring A" b1The connection site; where R aa2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, OCH3, O-CH(CH3)2, CHF2, C(CH3)2OH, NH(CH3), N(CH3)2, NH-CH(CH3)2, CH(CH3)2.

[0213] Ring A b1 Each occurrence is independently selected from hydrogen, C1-C6 alkyl,

[0214] p' is 1, 2, or 3 each time it appears;

[0215] R cc Each occurrence is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl), and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by one or two substituents selected from C1-C6 alkyl and C1-C6 fluoroalkyl; in some embodiments, R cc Each time it appears, it is independently selected from hydrogen, cyano, -CH3, -CH2CH3, -CF3, -CH(CH3)2 and -N(CH3)2;

[0216] In some implementation schemes, ring A b1 Each time it appears, it is independently selected from hydrogen, methyl,

[0217] In formula A-9, X and L cc and R bb Each is as defined above;

[0218] Ring A a Selected from Among them, R aa Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy; in some embodiments, R aa Each time it appears, it is independently either hydrogen or methyl;

[0219] Ring A b Each time it appears, it is independently selected from hydrogen, p' is independently 1, 2, or 3 each time it appears; R ccEach occurrence is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl), and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by one or two substituents selected from C1-C6 alkyl and C1-C6 fluoroalkyl; in some embodiments, R cc Each time it appears, it is independently selected from hydrogen, cyano, CH3, CH2CH3, CF3, CH(CH3)2, N(CH3)2, N(CH3)(CH2CH3), NH-CH2-cyclopropyl,

[0220] In formula A-10, X and L cc Each is as defined above;

[0221] R bb1 R bb2 and R bb3 Each time it appears, it is independently selected from hydrogen, amino, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2;

[0222] Ring A a Each time it appears, it is selected independently. Preferred selection Among them, "*A" b "Indicates and ring A" b Connection site; R aa As defined above;

[0223] Ring A b Each time it appears, it is independently selected from H. p' is 1, 2, or 3; R cc Each time it appears, it is independently selected from hydrogen, hydroxyl, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl) and C3-C8 cycloalkyl;

[0224] In some implementation schemes, R aa Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C(O)NH2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C10 Haloalkoxy and C3-C6 cycloalkyl, preferably hydrogen, methyl, C(O)NH2, cyano, methyl or cyclopropyl;

[0225] In some implementation schemes, R bb1 and R bb2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 alkylene-hydroxy, NH (C1-C3 alkyl), and N (C1-C3 alkyl)2; in some embodiments, R bb1 and R bb2 Each time it appears, it is independently fluorine, OCH(CH3)2, OCH3, C(CH3)2OH or N(CH3)2;

[0226] In some implementation schemes, R bb3 It is hydrogen;

[0227] In some implementation schemes, R cc Each time it appears, it is independently hydrogen, cyano, CH3, CH2CH3, CF3, CH(CH3)2, N(CH3)2, NHCH2CF3, N(CH3)(CH2CH3) or NH-CH2-cyclopropyl;

[0228] In equations A-11a and A-11b, X and L cc Each is as defined above;

[0229] Q7 and Q8 each appear independently from N or CR. aa ;

[0230] Q9 is selected from O or S;

[0231] Ring A j1 Each occurrence is independently selected from Preferred selection Among them, "*A" j2 "Indicates and ring A" j2 Connection sites;

[0232] Ring A j2 Each occurrence is independently selected from

[0233] R bb and R cc Each is as defined above;

[0234] In some implementation schemes, R aaEach time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6. 10 Halogenated alkoxy groups;

[0235] In some implementation schemes, R bb Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, OCH3, O-CH(CH3)2, CHF2, C(CH3)2OH, NH(CH3), N(CH3)2, NH-CH(CH3)2, CH(CH3)2 and NH-CH(CH3)CN;

[0236] In some implementation schemes, R cc Each occurrence is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl), and C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is optionally substituted by one or two substituents selected from C1-C6 alkyl and C1-C6 fluoroalkyl; in some embodiments, R cc Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, cyano, CH3, CH2CH3, CF3, CH(CH3)2 and N(CH3)2;

[0237] In some implementations, the PTM has the structure shown in Equation A-1:

[0238] In equation A-12, X and L cc Each is as defined above;

[0239] Ring A j4 Selected from It is further divided into 1, 2, 3 or 4 Rs j4 The right-hand connection site is the connection site with X;

[0240] Q j1 Q j2 and Q j3 Each occurrence is independently selected from N and CR. j4 ;

[0241] R j4Each time it appears, it is independently selected from hydrogen, amino, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C3-C6 cycloalkyl, O-C3-C6 cycloalkyl and 3-6 membered heterocyclic groups;

[0242] Ring A j3 Selected from

[0243] p' is selected from 1, 2, 3, and 4;

[0244] R j3 Selected from amino, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, 5-12 membered spirocyclic, C1-C6 alkylene-C3-C8 cycloalkyl, and C1-C6 alkylene-3-8 membered heterocyclic; wherein the C3-C8 cycloalkyl, 3-8 membered heterocyclic, 6-10 membered aryl, 5-10 membered heteroaryl, and 5-12 membered spirocyclic are each independently and optionally surrounded by 1, 2, 3, 4, 5, or 6 R groups. j8 replace;

[0245] Q j5 Selected from N and CR j5 ;

[0246] Q j6 Selected from N and CR j6 ;

[0247] Q j7 Selected from N and CR j7 ;

[0248] R j5 R j6 and R j7 Each group is independently selected from hydrogen, amino, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C3-C6 cycloalkyl and 3-6 membered heterocyclic groups, preferably selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy and trifluoromethyl;

[0249] Or, R j5 and R j6 or R j6 and R j7A group of carbon atoms bonded to it forms a 3-8 member heterocycle or C3-C8 carbon ring containing 1, 2, or 3 heteroatoms selected from N, O, and S; the 3-8 member heterocycle or C3-C8 carbon ring containing 1, 2, or 3 heteroatoms selected from N, O, and S can optionally be bonded by 1, 2, 3, 4, or 5 R atoms. j8 replace;

[0250] R j8 Each time it appears, it is independently selected from hydrogen, amino, hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C3-C6 cycloalkyl and 3-6 membered heterocyclic groups, preferably selected from fluorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and trifluoroethyl;

[0251] In some implementation schemes, R j4 Each of the following is independently selected from hydrogen, fluorine, chlorine, bromine, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylene-hydroxy, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C3-C6 cycloalkyl, O-C3-C6 cycloalkyl, and 3-6 heterocyclic alkyl containing 1, 2, or 3 heteroatoms selected from N, O, and S; in some embodiments, R j4 Each time it appears, it is independently hydrogen, fluorine, OCH(CH3)2, OCH3, C(CH3)2OH, N(CH3)2,

[0252] In some implementation schemes, ring A j4 Selected from Its right-hand connection point is the connection point with X;

[0253] In some implementation schemes, R j3 Selected from amino, hydroxyl, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-7 membered heteroaryl, 5-11 membered spirocyclic, C1-C6 alkylene-C3-C6 cycloalkyl, and C1-C6 alkylene-3-6 membered heterocyclic; wherein the C3-C6 cycloalkyl, 3-6 membered heterocyclic, phenyl, 5-7 membered heteroaryl, and 5-11 membered spirocyclic may optionally be surrounded by 1, 2, 3, 4, 5, or 6 R groups. j8 Replace; in some implementations, R j3Selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F, Cl, Br, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl (preferably difluoromethyl, trifluoromethyl, CH2CF3 or CH(CH3)CF3), C1-C3 haloalkoxy, CH2-cyclopropyl, The cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups... It can be optionally divided into 1, 2, 3 or 4 Rs j8 The substitution is preferably optional, consisting of one, two, or three substituents independently selected from fluorine, methyl, ethyl, isopropyl, and methoxy;

[0254] In some implementation schemes, ring A j3 Selected from

[0255] Each time X appears, it is selected independently from a single key. It may optionally be substituted with one or two independent substituents selected from halogens, C1-C6 alkyl groups and C1-C6 alkoxy groups;

[0256] L cc Selected from single bonds, methylene groups, and C(O).

[0257] In some implementations, the PTM is selected from the following structures:

[0258] Among them, R aa R bb R cc R ff R ee R ee1 R ee2 L bb L gg R j3 R j4 R j8 Each occurrence is defined as described above;

[0259] Q1, Q2, Q3, Q4, Q7, and Q8 are each independently N or CH each time they appear; in some implementations, they are N.

[0260] Q5 and Q6 are each independently selected from NH, O, and S each time they appear; in some implementations, they are O or S.

[0261] Q9 is selected independently from O and S each time it appears; in some implementations, it is S;

[0262] Each time q1 and q2 appear, they are independently selected from 0, 1, 2, and 3;

[0263] Alternatively, the PTM may be selected from the following structures:

[0264] Among them, R aa R bb R cc and L cc Each time it appears, it is defined independently in different regions as described above;

[0265] Q 10 Each occurrence is independently either N or CH; in some implementations, it is CH.

[0266] Each time q1 and q2 appear, they are independently selected from 1 and 2 respectively;

[0267] In some implementation schemes, R aa Each time it appears, it is independently selected from hydrogen, cyano, Each time p' appears, it is defined independently in each context as above;

[0268] In some implementation schemes, R bb Each time it appears, it is independently selected from hydrogen, oxo group (=O), OCH3, OCH(CH3)2, CHF2, COOCH3, C(CH3)2OH, OCH(CH3)2, NH-CH(CH3)2, NH(CH3), N(CH3)2.

[0269] In some implementation schemes, R cc Each time it appears, it is independently selected from hydrogen, hydroxyl, fluorine, cyano, CH3, CH2CH3, CH(CH3)2, OCH3, CHF2, C(CH2)OH, NHCH2-CF3, CF3, CONH2, NH-CH2-cyclopropyl, NH-CH(CH3)2, N(CH3)2, and cyclopropyl;

[0270] In some implementations, L cc Each time it appears, it is independently selected from single bond, NH, C(O) and C(O)NH.

[0271] In some implementations, the PTM shown is selected from the following structures: The PTM is selected from the following structures:

[0272] In some implementation schemes, wherein, for In some embodiments, the CLM is selected from the structures shown in formulas (B-1a), (B-2a), (B-3a), and (B-4a):

[0273] Among them, R 1b R 1c R 1d and R 1e Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, amino, C. 1-3 Alkyl and C 1-3 Alkoxy;

[0274] B2 is selected independently from C(R) each time it appears. c4 2. NR c4 and O;

[0275] B1 and B3 are each selected independently from C(R) each time they appear. c4 2. O and C(O);

[0276] U5 and U6, one is N and the other is CR. c4 ;

[0277] B6 is selected from C(R) c4 )2 and O;

[0278] C1 and C2 are each selected independently from C(R) each time they appear. c4 )2;

[0279] m1, m2, m3, m4 and m5 are each independently selected from 0, 1, 2 and 3; in some implementations, m1+m2+m3=0, m1+m2+m3=1 or m1+m2+m3=2; in some implementations, m4+m5=2, m4+m5=3 or m4+m5=4;

[0280] R c4Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3 alkyl and C1-C3 alkoxy; more preferably, it is H;

[0281] R T Each time it appears, it is independently selected as N;

[0282] In some implementation schemes, R 1b R 1c R 1d and R 1e Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, and methoxy;

[0283] In some implementations, B2 is independently set to 0 each time it occurs;

[0284] In some implementations, B1 and B3 are each independently selected from CH2, NH, C(C) each time they appear. 1-3 Alkyl)2 and N(C) 1-3 Alkyl group, preferably CH2;

[0285] In some implementations, B6 is independently selected from CH2 and O each time it appears; in some implementations

[0286] In some implementations, C1 and C2 are each independently selected from CH2 and C(C) each time they appear. 1-3 Alkyl group 2, preferably CH2;

[0287] In some implementations, one of U5 and U6 is N and the other is CH; in other implementations, U5 is CH and U6 is N.

[0288] In some implementations, m1 is 0, m2 is 1 or 2, and m3 is 0;

[0289] m4 is 1, m5 is 2.

[0290] In some implementations, the CLM is selected from the following structures:

[0291] In some implementations, L is a single bond or -(A L ) q -; among which, q are A's L They may be the same as or different from each other, and each time they appear, they are independently selected from C1-C. 10 Alkylene, C2-C 10 alkenyl, C2-C 10 Ethyne group, CR L1 R L2,O,S,C(O),S(O),S(O)2,NR L1 C3-C 16 Cycloalkylene, 4 to 12-membered heterocyclic alkylene, C5-C 12 arylene and 5 to 12-membered heteroarylene, wherein the C3-C 16 Cycloalkylene, 4 to 12-membered heterocyclic alkylene, C5-C 12 The aryl and 5- to 12-membered heteroaryl groups are optionally surrounded by 1-6 R groups. L1 and / or R L2 replace;

[0292] R L1 and R L2 Each time it appears, it is independently selected from hydrogen, halogen, cyano, hydroxyl, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 12 cycloalkyl, C2-C 10 alkenyl, C2-C 10 Haloalkenyl, C2-C 10 alkynyl group, C2-C 10 Halogenated alkynyl group, C5-C 12 aryl, 5- to 12-membered heteroaryl and 4- to 12-membered heterocyclic groups;

[0293] q is an integer greater than or equal to 1 and less than or equal to 15;

[0294] In some implementation schemes, R L1 and R L2 Each time it appears, it is independently selected from H, halogen, cyano, hydroxyl, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 12 cycloalkyl, C2-C 10 alkenyl, C2-C 10 Haloalkenyl, C2-C 10 alkynyl group, C2-C 10 Halogenated alkynyl group, C5-C 12 Aryl groups, 5- to 12-membered heteroaryl groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, and 4- to 12-membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S; in some embodiments, R L1 and R L2Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C5-C8 aryl, 5- to 8-membered heteroaryl, and 4- to 7-membered heterocyclic groups; in some embodiments, R L1 and R L2 Each time it appears, it is independently selected from fluorine, chlorine, bromine, cyano, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; in some embodiments, R L1 and R L2 Each time it appears, it is independently selected from hydrogen, fluorine, cyano, hydroxyl, methyl, and methoxy.

[0295] In some implementation schemes, A L They are either the same as or different from each other, and each time they appear, they are independently selected from C2-C. 10 alkenyl, C2-C 10 Ethyne group, CR L1 R L2 ,O,S,C(O),S(O),S(O)2,NR L1 C3-C 16 Cycloalkylene groups, containing 1, 2, 3, or 4 4- to 12-membered heterocyclic groups, each independently selected from N, O, and S heteroatoms, C5-C 12 arylene and 5 to 12 heteroarylene groups containing 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S, wherein the C3-C 16 Cycloalkylene, 4 to 12-membered heterocyclic alkylene, C5-C 12 The aryl and 5- to 12-membered heteroaryl groups are optionally surrounded by 1-6 R groups. L1 and / or R L2 replace;

[0296] In some implementation schemes, A L Selected from one or more of the following groups, and the two connection sites of the following structures are interchangeable: covalent bond, -O-, -(CH2). k -, -C(O)-, -NH-, -N(CH3)-,

[0297] In some implementations, k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0298] In some implementations, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0299] In some implementations, the L is selected from the following structures: single bond, -(CH2). j -、 -NH-(CH2) j -、-(CH2) j -NH-, -NH-(CH2) j -NH-、

[0300] Where j and k are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0301] p and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;

[0302] In some implementations, L is selected from single bonds, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, and -(CH2) 10 -、-(CH2) 11-NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-, -C(O)-CH2-, -C(O)-NH-C H2-, -C(O)-NH-(CH2)2-, -C(O)-NH-(CH2)3-, -C(O)-NH-(CH2)4-, -C(O)-NH-(CH2)5-, -C(O)-NH-(CH2)6-, -C(O)-NH-(CH2)7-, -C(O)-NH-(CH2)8-, -CH2-NH-,-(CH2)2-NH-,-(CH2)3-NH-,-(CH2)4-NH-,-(CH2)5-NH-,-(CH2)6-NH-,-(CH2)7-NH-,-(CH2)8-NH-,-NH-CH2-NH-,-NH-(CH2)2-NH-,-NH-(CH2)3-NH-,-NH-(CH2)4-NH-,-NH-(CH2)5-NH-,-NH-(CH2)6-NH-,-NH-(CH2)7-NH-,-NH-(CH2)8-NH-,-C(O)-NH-CH2-NH-,-C(O)-NH-(CH2)2-NH- -C(O)-NH-(CH2)3-NH-, -C(O)-NH-(CH2)4-NH-, -C(O)-NH-(CH2)5-NH-, -C(O)-NH-(CH2)6-NH-, -C(O)-NH-(CH2)7-NH-, -C(O)-NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(C H2-CH2-O)3-CH2-CH2-、-C(O)-NH-(CH2-CH2-O)-CH2-CH2-、-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-、-C(O)-NH-(CH2-CH2-O)3-CH2-CH2-、-(CH2-CH2-O)-CH2-CH2-NH-、-(CH2-CH2-O)2-CH2-CH2-NH-、-(CH2-CH2-O)3-CH2-CH2-NH-、-NH-(CH2-CH2-O)-CH2-CH2-NH-、-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)2-CH2- CH2-NH-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-, -CH2-CH2-(O-CH2-CH2)-, -CH2-CH2-(O-CH2-CH2)2-, - CH2-CH2-(O-CH2-CH2)3-, -NH-CH2-CH2-(O-CH2-CH2)-, -NH-CH2-CH2-(O-CH2-CH2)2-, -NH-CH2-CH2-(O- CH2-CH2)3-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-, -C(O)-NH-CH2-CH2 -(O-CH2-CH2)3-, -CH2-CH2-(O-CH2-CH2)-NH-, -CH2-CH2-(O-CH2-CH2)2-NH-, -CH2-CH2-(O-CH2-CH2)3- NH-, -NH-CH2-CH2-(O-CH2-CH2)-NH-, -NH-CH2-CH2-(O-CH2-CH2)2-NH-, -NH-CH2-CH2-(O-CH2-CH2)3-NH -, -C(O)-NH-CH2-CH2-(O-CH2-CH2)-NH-, -C(O)-NH-CH2-CH2-(O-CH2-CH2)2-NH-, -C(O)-NH-CH2-CH2-(O -CH2-CH2)3-NH-, -(CH2)4-O-, -(CH2)5-O-, -(CH2)6-O-, -(CH2)7-O-, -(CH2)8-O-, -(CH2)9-O-, -(CH2), 10 -O-、-(CH2) 11 -O-、

[0303] In some implementations, L is selected from single bonds, -CH2CH2-, p is 0, 1, or 2, y is 0, 1, or 2, j is 0, 1, or 2, and k is 0, 1, or 2; in some implementations, p is 0, y is 1, j is 0, and k is 0.

[0304] In some implementations, L is selected from single bonds, -CH2-, -CH2CH2-,

[0305] In another aspect of this disclosure, compounds or pharmaceutically acceptable salts thereof are provided, said compounds being selected from the structures shown in formulas (III-1), (III-2), (III-3), and (III-4):

[0306] Among them, p1, p2, p3 and p4 are each independently selected from 0, 1 or 2 each time they appear;

[0307] Each time q1 and q2 appear, they are independently selected from 0, 1, or 2;

[0308] X1, X2, X3, and X4 are each independently selected from N and CR each time they appear. L3 ;R L3 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy and C3-C6 cycloalkyl;

[0309] R bb1 and R bb2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2;

[0310] R aa1 R aa2 R aa3 and R aa4 Each of the following groups, when present in any instance, is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and 5- to 10-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the 5- to 10-membered heterocyclic alkyl groups are optionally substituted by 1, 2, or 3 substituents independently selected from hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy.

[0311] CLM has a structure selected from the formulas (B-1), (B-2), (B-3), and (B-4):

[0312] Each time W1 appears, it is independently selected from N, CH and C (C1-C6 alkyl);

[0313] R W Each time it appears, it is independently selected from single bond, C(O), O, NH, NHC(O), and C(O)NH;

[0314] R 1a R 1b R 1c R 1d and R 1e Each time it appears, it is independently selected from H, F, Cl, Br, amino, C. 1-6 Alkyl and C 1-6 Alkoxy;

[0315] B1, B2, B3, B6, C1, and C2 are each independently selected from C(R) each time they appear. c4 2. NR c4 , O and C(O); where R c4 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, oxo, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, and C1-C6 alkoxy.

[0316] Each of m1, m2, m3, m4, and m5 is independently 0, 1, 2, 3, or 4 each time it appears; and m1 + m2 + m3 ≤ 4; m4 + m5 ≤ 4;

[0317] U5 and U6 each appear independently as CH or N;

[0318] R T Each occurrence is independently either CH or N;

[0319] In some implementations, when R in equation (III-3) aa3 It is trifluoromethyl, R bb2 It is hydrogen, and CLM has the structure of formula (B-1), where R 1e When it is hydrogen, R bb1 It is not -C(CH3)2OH, -OCH3 or -O-CH(CH3)2.

[0320] In another aspect of this disclosure, compounds or pharmaceutically acceptable salts thereof are provided, said compounds being selected from the structures shown in formulas (III-5), (III-6), and (III-7):

[0321] Among them, p1, p2, p3 and p4 are each independently selected from 0, 1 or 2 each time they appear;

[0322] Each time q1 and q2 appear, they are independently selected from 0, 1, or 2;

[0323] X1, X2, X3, and X4 are each independently selected from N and CR each time they appear. L3 ;R L3 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy and C3-C6 cycloalkyl;

[0324] R bb1 and R bb2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, amino, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, NH(C1-C6 alkyl) and N(C1-C6 alkyl)2;

[0325] R aa1 Each of the following groups, when present, is independently selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, and 5- to 10-membered heterocyclic alkyl groups containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the 5- to 10-membered heterocyclic alkyl groups are optionally substituted by 1, 2, or 3 substituents independently selected from hydroxyl, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy.

[0326] R aa5 Each time it appears, it is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-hydroxy, NH(C1-C6 alkyl), N(C1-C6 alkyl)2 and O-C3-C6 cycloalkyl;

[0327] R cc1 and R cc2 Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NH(C1-C6 haloalkyl), NH(C1-C4 alkylene-C3-C6 cycloalkyl) and C3-C8 cycloalkyl;

[0328] CLM is defined as in Equations (III-1), (III-2), (III-3) and (III-4) above.

[0329] In some implementations, p1, p2, p3, and p4 are each independently set to 1 each time they occur;

[0330] In some implementations, q1 is 0 or 1; q2 is 0, 1, or 2; in other implementations, q1 is 0; q2 is 1.

[0331] In some implementations, X1, X2, X3, and X4 are each independently selected from N and CH each time they appear; at least one of X1, X2, X3, and X4 is N; in some implementations, X1 is CH; X2 is CH; X3 is N; and X4 is CH.

[0332] In some implementation schemes, R bb1 Each occurrence is independently selected from hydrogen, C1-C6 alkoxy, C1-C6 alkylene-hydroxy, NH (C1-C6 alkyl), and N (C1-C6 alkyl)2; in some embodiments, R bb1 Each occurrence is independently selected from -N(CH3)2, -NH(CH3), -C(CH3)2OH, -OCH3, and -O-CH(CH3)2; in some embodiments, R bb1 It is -N(CH3)2;

[0333] In some implementation schemes, R bb2 Each occurrence is independently selected from hydrogen, fluorine, chlorine, and bromine, preferably hydrogen or fluorine; in some embodiments

[0334] In some implementation schemes, R aa1 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, C1-C6 alkyl, C1-C6 haloalkyl, morpholino, piperidinyl, The morpholino group, piperidinyl group, Optionally substituted with one, two, or three substituents independently selected from hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy groups; in some embodiments, R aa1 Each time it appears, it is independently selected from hydrogen, cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, In some implementation schemes, R aa1 Each time it appears, it is independently hydrogen or

[0335] In some implementation schemes, R aa2 Each occurrence is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, C1-C6 alkyl, and C1-C6 haloalkyl, preferably R. aa2 Each time it appears, it is independently either hydrogen or cyano;

[0336] In some implementation schemes, R aa3Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, nitro, C1-C6 alkyl, and C1-C6 haloalkyl, preferably selected from hydrogen, fluorine, chlorine, bromine, cyano, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl, more preferably selected from hydrogen, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl; more preferably R aa3 Each time it appears, it is independently cyano, difluoromethyl, or trifluoromethyl;

[0337] In some implementation schemes, R aa4 Each time it appears, it is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, and C3-C6 cycloalkyl. In some embodiments, R aa4 Each occurrence is independently selected from C1-C6 haloalkyl and C3-C6 cycloalkyl; or, R aa4 Each time it appears, it is independently methyl, ethyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl, more preferably fluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl, more preferably methyl or cyclopropyl;

[0338] In some implementation schemes, R aa5 Each time it appears, it is independently selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl, isopropyl, -OCH3, -O-CH(CH3)2, -CHF2, -C(CH3)2OH, -NH(CH3), -N(CH3)2, -NH-CH(CH3)2, and Preferably -O-CH(CH3)2;

[0339] In some implementation schemes, R cc1 and R cc2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, NH(C1-C3 alkyl), N(C1-C3 alkyl)2, NH(C1-C3 haloalkyl), NH(C1-C3 alkylene-C3-C6 cycloalkyl), and C3-C6 cycloalkyl; in some embodiments, R cc1 and R cc2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, cyano, CH3, CH2CH3, CF3, CH(CH3)2, N(CH3)2, N(CH3)(CH2CH3), NH-CH2-cyclopropyl; in some embodiments, R cc1 It is fluorine, chlorine or bromine, R cc2 It is cyano;

[0340] In some implementations, W1 is independently CH or N each time it appears, more preferably N;

[0341] In some implementation schemes, R W Each occurrence is independently selected from single bonds, NH, and NHC(O); in some implementations, R W It is a single bond;

[0342] In some implementation schemes, R 1b R 1c R 1d and R 1e Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, and C. 1-3 Alkyl and C 1-3 Alkyl groups, preferably hydrogen, fluorine, chlorine, or methoxy groups; in some embodiments, R 1b R 1c and R 1d Each time it appears, it is independently hydrogen, R 1e Each time it appears, it is independently hydrogen, fluorine, chlorine, or methoxy;

[0343] In some implementations, B2 is independently set to 0 each time it occurs;

[0344] In some implementations, B1 and B3 are each independently selected from CH2, NH, C(C) each time they appear. 1-3 Alkyl)2 and N(C) 1-3 Alkyl group, preferably CH2;

[0345] In some implementations, B6 is selected independently from CH2 and O each time it appears;

[0346] In some implementations, C1 and C2 are each independently selected from CH2 and C(C) each time they appear. 1-3 Alkyl group 2, preferably CH2;

[0347] In some implementations, one of U5 and U6 is N and the other is CH; in other implementations, U5 is CH and U6 is N.

[0348] In some implementations, m1 is 0, m2 is 1 or 2, and m3 is 0;

[0349] In some implementation schemes, m4 is 1 and m5 is 2;

[0350] In some implementation schemes, R T Each occurrence is independently N.

[0351] In another aspect of this disclosure, compounds of formula (I') or pharmaceutically acceptable salts thereof are provided.

[0352] PTM-L-CLM formula (I')

[0353] Where L is the key or linker sub-part connecting CLM and PTM, which is -(A L ) q -; q A's L They may be the same as or different from each other, and each is independently selected from covalent bonds, C2-C 10 alkenyl, C2-C 10 Ethyne group, CR L1 R L2 O, S, S(O), S(O)2, NR L1 C(O), SiR L1 R L2 P(O)R L1 P(O)OR L1 ,C(=NCN),C(=CNO2),C3-C 11 Cycloalkylene, 4 to 12-membered heterocyclic alkylene, C5-C 12 aryl, 5- to 12-membered heteroaryl, C6-C 16 Subspirocyclic groups and 6- to 16-membered subheterocyclic groups, wherein the C3-C 11 Cycloalkylene, 4 to 12-membered heterocyclic alkylene, C5-C 12 aryl, 5- to 12-membered heteroaryl, C6-C 16 Subspirocyclic and 6- to 16-membered subheterocyclic groups are optionally divided by 1-6 R L1 In some implementation schemes, R L2 replace;

[0354] R L1 and R L2 Each time it appears, it is independently selected from H, halogen, C1-C. 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy groups, C2-C 10 alkenyl, C2-C 10 Haloalkenyl, C2-C 10 alkynyl group, C2-C 10 Halogenated alkynyl group, -SR L3 -NR L3 R L4 C3-C 12 cycloalkyl, C5-C 12 aryl, 5- to 12-membered heteroaryl, 4- to 12-membered heterocyclic, -OR L3 -S(O)2-R L3 -P(O)R L3 R L4 -Si(OH)3, -SiR L3 R L4 RL5 -C(O)R L5 , -CN, -NO2, -SF5, -S(O)2NR L3 R L4 -C(O)NR L3 R L4 -N(R) L3 )C(O)NR L4 R L3 and -N(R) L3 )S(O)2NR L3 R L4 ;

[0355] R L3 R L4 and R L5 Each time it appears, it is independently selected from H, OH, halogen, C1-C. 10 Alkyl, C1-C 10 Halogenated alkyl, alkoxy, C1-C 10 Halogenated alkoxy groups, C2-C 10 alkenyl, C2-C 10 Haloalkenyl, C2-C6 ynyl, C2-C6 haloalkynyl, C3-C 12 cycloalkyl, halogenated C3-C 12 Cycloalkyl, 4- to 12-membered heterocyclic groups, 4- to 12-membered halocyclic groups, C6-C 12 Aryl, halogenated C6-C 12 Aryl, 5- to 12-membered heteroaryl and halogenated 5- to 12-membered heteroaryl;

[0356] q is an integer greater than or equal to 1 and less than or equal to 15;

[0357] CLM is selected from the structures shown in Equations (I-1), (I-2), (I-3), and (I-4):

[0358] In this case, G and Z are each independently selected from O and S each time they appear;

[0359] W1 is CR c1 Or N; W2 and W3 each appear independently as C(R) c1 2. NR c1 , O or S;

[0360] R W Each occurrence is independently selected from single bonds, C(O), O, S, S(O)2, NR. c1 NR c1Combinations of one or more of C(O), C1-C6 alkylene, C2-C6 alkenylene, C2-C6 ynynylene, C1-C6 haloalkylene and C1-C6 heteroalkylene;

[0361] W4 and W5 are each independently selected from N and C. Indicates either a single or double key; and At least one of them is a double bond;

[0362] W6 is N or CR c1 ;

[0363] W7, W8, and W9 each appear independently as CR. c2 R c3 C(O), S(O)2 or NR c2 And at least one of W8 and W9 is C(O);

[0364] R 1 Each time it appears, it is independently selected from hydrogen and C1-C. 10 alkyl;

[0365] R 1a R 1b R 1c R 1d and R 1e The definition is selected from one of the following groups;

[0366] (i-1)R 1a and R 1b The carbon atoms bonded to it together form a ring Cy1, and R 1c R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0367] (i-2)R 1b and R 1c The carbon atoms bonded to it together form a ring Cy1, and R 1a R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0368] (i-3)R 1c and R 1d The carbon atoms bonded to it together form a ring Cy1, and R 1a R 1b and R 1e Each substituent is independently selected from group S1 when it appears; and

[0369] (i-4)R 1d and R 1eThe carbon atoms bonded to it together form a ring Cy1, and R 1a R 1b and R 1c Each time it appears, it is independently selected from the substituents of group S1;

[0370] (i-5)R 1c for Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc. c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0371] R 1b and R 1f The atoms bonded to it together form 4 to 9-membered heterocycles, R 1d and R 1g The atoms bonded to it together form 4 to 9-membered heterocycles; and R 1a Each time a substituent appears, it is independently selected from the S1 group; the 4 to 9-membered heterocycles optionally contain 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms, and are optionally substituents of one or more R groups. c1 replace;

[0372] (i-6)R W For NR c1 At that time, R c1 and R 1a The atoms connected to it together form the Cy4 ring, and R 1b R 1c R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0373] R 2a R 2b R 2c R 2d and R 2e The definition is selected from one of the following groups;

[0374] (ii-1)R 2a and R 2b The carbon atoms bonded to it together form a ring Cy2, and R 2c R 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0375] (ii-2)R 2b and R 2c The carbon atoms bonded to it together form a ring Cy2, and R 2aR 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0376] (ii-3)R 2c and R 2d The carbon atoms bonded to it together form a ring Cy2, and R 2a R 2b and R 2e Each substituent is independently selected from group S1 when it appears; and

[0377] (ii-4)R 2a and R 2e The atoms connected to it together form a ring Cy2, and R 2b R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0378] (ii-5)R 2a for And R 2b R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0379] Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc. c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0380] (ii-6)R 2b for And R 2a R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0381] Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc. c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0382] (ii-7) When W6 is CR c1 At that time, R 2e and R c1 The carbon atoms bonded to it together form a cyclone Cy3, and R 2b R 2b R 2cand R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0383] Cy1 and Cy2 are each independently selected from

[0384] Cy3 is

[0385] Each occurrence of A1, A2, A3, A4, A5, and A6 is independently C(R). c4 2. NR c4 O, C(O) or S, at A1 and A2 Each occurrence independently represents a bonding site with a carbon atom on the benzene ring;

[0386] U4 and U5 are each independently designated as CR each time they appear. c4 Or N;

[0387] Each of D1, D2, D3, and D4 appears independently as a single bond, N, or CR. c4 , This indicates the presence or absence of double bonds at any position within the ring;

[0388] R T Each occurrence is independently CH or N, R t Each occurrence is independently C or N, R t and R T place Represents the connection site with CLM or L;

[0389] R 2f Each time it appears, it is independently selected from the substituents of group S1; q2 is 0, 1, 2, 3 or 4;

[0390] The substituents in group S1 are selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C1-C 10 Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 11 Cycloalkyl, 4 to 12-membered heterocyclic groups, C5-C 12 aryl and 5 to 12-membered heteroaryl, wherein the C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C1-C 10Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 11 Cycloalkyl, 4 to 12-membered heterocyclic groups, C5-C 12 The aryl group and the 5 to 12 heteroaryl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, nitro groups, C1-C groups. 10 Alkyl, C1-C 10 Heteroalkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C3-C 11 Cycloalkyl, 4- to 12-membered heterocyclic groups, C2-C6 alkenyl, C2-C6 ynyl, C5-C 12 Substituted with aryl and 5 to 12-membered heteroaryl groups;

[0391] Each time n1, n2, and n3 appear, they are independently 0, 1, 2, 3, or 4;

[0392] Each of m1, m2, m3, m4, m5, m6, m7, m8, m9, and m10 is independently 0, 1, 2, 3, 4, or 5 when it appears.

[0393] PTM has the following structure:

[0394] Ring A is selected from C5-C 10 Aryl, 5- to 10-membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, and 7- to 12-membered heterofused aryl containing 1-6 heteroatoms selected from N, O, and S;

[0395] Cycle B is selected from 5 to 10-membered cycloalkyl subgroups, 8 to 14-membered bicyclic subgroups containing 1 to 4 heteroatoms selected from N, O, and S, and 10 to 16-membered tricyclic subgroups containing 1 to 3 heteroatoms selected from N, O, and S.

[0396] R aa Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C6 alkenyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy, amino, 4- to 12-membered heterocyclic, 6- to 14-membered heterobridged cyclic, 5- to 12-membered heteroaryl, and 8- to 18-membered heterofused aryl, wherein the C1-C 10 Alkyl, C1-C 10Deuterated alkyl, C2-C6 alkenyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, 4- to 12-membered heterocyclic, 6- to 14-membered heterobridged cyclic, 5- to 12-membered heteroaryl, and 8- to 18-membered heterofused aryl are optionally p'-R cc Replaced;

[0397] R bb Each time it appears, it is independently selected from hydrogen, deuterium, hydroxyl, halogen, amino, C1-C. 10 Alkyl, amino, hydroxyl -C1-C 10 Alkyl-, oxo- (=O), C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, and 6- to 10-membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, O, and S, wherein the C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy, 4- to 12-membered heterocyclic groups and 6- to 10-membered groups optionally surrounded by p' R cc Replaced;

[0398] R cc Each time it appears, it is independently selected from hydrogen, hydroxyl, halogen, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Alkoxy, hydroxy-C1-C 10 Alkyl-, halogenated C1-C 10 Alkyl and C3-C 11 cycloalkyl;

[0399] L aa Independently selected from single bonds, C(O), O, -NR p1 -、-NR p1 C(O)-、-C(O)NR p1 -、C1-C 10 alkylene, C2-C6 alkenylene, C2-C6 alkyneene, and C1-C 10 Halogenated alkylene;

[0400] L bb For XL cc X is independently selected from single bonds, C3-C 11 Cycloalkylene and 6- to 10-membered heterocycloalkylene, L cc Independently selected from single bonds, C(O), O, -NRp1 -、-NR p1 C(O)-、-C(O)NR p1 -、C1-C 11 alkylene, C2-C6 alkenylene, C2-C6 alkyneene, and C1-C 10 Halogenated alkylene;

[0401] Each time m', p', and n' appear, they are independently selected from 0, 1, 2, and 3;

[0402] R c1 R c2 R c3 R c4 and R p1 Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, oxo group, hydroxyl group, nitro group, cyano group, amino group, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C1-C 10 Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C 10 Alkoxy, C3-C 11 Cycloalkyl, 4- to 12-membered heterocyclic groups, -C1-C 10 Alkyl-amino, C1-C 10 Alkyl acyl-, C1-C 10 Alkyl-oxy-acyl-, C1-C 10 Alkyl-NH-acyl-, C5-C 12 aryl and 5 to 12-membered heteroaryl, wherein the C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C 10 Alkoxy, C3-C 12 Cycloalkyl, 4 to 12-membered heterocyclic groups, C5-C 12 The aryl and 5- to 12-membered heteroaryl groups are each independently and optionally separated by one or more groups selected from F, Cl, Br, I, cyano, amino, nitro, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4- to 8-membered heterocyclic, -C1-C6 alkylamino, C6-C 15 It is substituted by aryl and 5 to 12 heteroaryl substituents.

[0403] In another aspect of this disclosure, a compound of formula (Ⅰ”) or a pharmaceutically acceptable salt thereof is provided.

[0404] PTM-L-CLM Formula (Ⅰ”)

[0405] Where L is the key or linker sub-part connecting CLM and PTM, and its structure is -(A L ) q -;

[0406] A L Each occurrence may be identical or different from the others, and each is independently selected from covalent bonds, C 2-10 imidene group, C 2-10 Ethyne group, CR L1 R L2 O, S, S(O), S(O)2, NR L1 C(O), SiR L1 R L2 P(O)R L1 P(O)OR L1 C (=NCN), C (=CNO2), C 3-11 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 5-12 aryl, 5-12 methyl aryl, C 6-16 Subspirocyclic and 6-16 quinary subheterocyclic, wherein the C 2-10 imidene group, C 2-10 Ethyne group, C 3-11 Cycloalkylene, 4-12 membered heterocyclic alkylene, C 5-12 aryl, 5-12 methyl aryl, C 6-16 Subspirocyclic and 6-16 quinary subheterocyclic, optionally surrounded by 1-6 R... L1 and / or R L2 replace;

[0407] R L1 and R L2 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, nitro, amino, C. 1-10 Alkyl, Halogenated C 1-10 Alkyl, C 2-10 alkenyl, halogenated C 2-10 alkenyl, C 2-10 alkynyl group, C 2-10 Halogenated alkynyl group, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-12 Aryl and 5-12 heteroaryl groups;

[0408] q is selected from integers greater than or equal to 1 and less than or equal to 15;

[0409] CLM is selected from the structures shown in Equations (I-1), (I-2), (I-3), (I-4), and (I-5):

[0410] In this case, G is independently selected from O and S each time it appears;

[0411] W1 is selected independently from CR each time it appears. c1 and N;

[0412] W2 and W3 are each selected independently from C(R) each time they appear. c1 2. NR c1 O and S;

[0413] R W Each occurrence is independently selected from single bonds, C(O), O, S, S(O)2, NR. c1 NR c1 C(O), C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Ethyne group, C 1-6 Halogenated alkylene and C 1-6 A combination of one or more heteroalkyl groups;

[0414] R 2f Each occurrence is independently selected from single bonds, O, and C. 1-6 Alkylene;

[0415] W4 and W5 are each independently selected from N and C. Indicates either a single or double key; and Only one of them is a double bond; when When it is a double bond, W4 is selected from C, and W5 is selected from N; when When it is a double bond, W4 is selected from N and W5 is selected from C;

[0416] W6 is selected from N and CR c1 ;

[0417] W7, W8, and W9 are each selected independently from CR each time they appear. c2 R c3 C(O), S(O)2 and NR c2 And at least one of W8 and W9 is selected from C(O);

[0418] R 1 Each time it appears, it is independently selected from hydrogen and C. 1-10 alkyl;

[0419] R 1a R 1b R 1c R 1d and R 1e The definition is selected from one of the following groups;

[0420] (i-1)R1a and R 1b The carbon atoms bonded to it together form a ring Cy1, and R 1c R 1d and R 1e Each time it appears, the substituents are independently selected from group S1;

[0421] (i-2)R 1b and R 1c The carbon atoms bonded to it together form a ring Cy1, and R 1a R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0422] (i-3)R 1c and R 1d The carbon atoms bonded to it together form a ring Cy1, and R 1a R 1b and R 1e Each substituent is independently selected from group S1 when it appears; and

[0423] (i-4)R 1d and R 1e The carbon atoms bonded to it together form a ring Cy1, and R 1a R 1b and R 1c Each time it appears, the substituents are independently selected from group S1;

[0424] (i-5)R 1c for Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc. c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0425] R 1b and R 1f The atoms bonded to it together form 4-9 membered heterocycles, R 1d and R 1g The atoms bonded to it together form 4-9 membered heterocycles; and R 1a Each time a substituent appears, it is independently selected from the S1 group; the 4-9 membered heterocycles optionally contain 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms, and are optionally substituents of one or more R groups. c1 replace;

[0426] (i-6)R W For NR c1 At that time, R c1 and R1a The atoms connected to it together form the Cy4 ring, and R 1b R 1c R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0427] R 2a R 2b R 2c R 2d and R 2e The definition is selected from one of the following groups;

[0428] (ii-1)R 2a and R 2b The carbon atoms bonded to it together form a ring Cy2, and R 2c R 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0429] (ii-2)R 2b and R 2c The carbon atoms bonded to it together form a ring Cy2, and R 2a R 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0430] (ii-3)R 2c and R 2d The carbon atoms bonded to it together form a ring Cy2, and R 2a R 2b and R 2e Each substituent is independently selected from group S1 when it appears; and

[0431] (ii-4)R 2a and R 2e The atoms connected to it together form a ring Cy2, and R 2b R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0432] (ii-5)R 2a for And R 2b R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0433] Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc.c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0434] (ii-6)R 2b for And R 2a R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0435] Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc. c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0436] (ii-7) When W6 is CR c1 At that time, R 2e and R c1 The carbon atoms bonded to it together form a cyclone Cy3, and R 2b R 2b R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0437] Cy1 and Cy2 are each independently selected

[0438] Cy3 is selected from

[0439] Cy4 is selected from *R c1 "Indicates and NR" c1 Connection sites;

[0440] A1, A2, A3, A4, A5, and A6 are each independently selected from C(R) each time they appear. c4 2. NR c4 O, C(O) and S; each of A1 and / or U4, U5, U6 and U7 is independently CR each time it appears. c4 Or N;

[0441] Each of D1, D2, D3, and D4 appears independently as a single bond, N, or CR. c4 , This indicates the presence or absence of double bonds at any position within the ring;

[0442] R T Each occurrence is independently CH or N, Rt Each occurrence is independently C or N, R t and R T place Represents the connection site with L or PTM;

[0443] The substituents in group S1 are selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, amino, C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 3-11 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-12 aryl and 5-12 heteroaryl, wherein the C 1-10 Alkyl, C 1-10 Deuterated alkyl, C 1-10 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 3-11 Cycloalkyl, 4-12 membered heterocyclic groups, C 5-12 The aryl group and the 5-12 heteroaryl group are each independently and optionally selected from one or more groups chosen from halogen, hydroxyl, cyano, amino, nitro, C 1-10 Alkyl, Halogenated C 1-10 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-10 Heteroalkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkoxy, C 3-11 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-12 Substituents of aryl and 5-12 heteroaryl groups;

[0444] R c1 R c2 R c3 and R c4 Each time it appears, it is independently selected from H, deuterium, halogen, oxo group (=O), hydroxyl group, nitro group, cyano group, amino group, and C. 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-10 Alkoxy, C 3-11Cycloalkyl, 4-12 membered heterocyclic groups, -NH-C 1-10 Alkyl, -N(C) 1-10 Alkyl)2、-C(O)-C 1-10 Alkyl, -C(O)-OC 1-10 Alkyl, -C(O)-NH-C 1-10 Alkyl, C 5-12 aryl and 5-12 heteroaryl, wherein the C 1-10 Alkyl, deuterated C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-10 Alkoxy, C 3-11 Cycloalkyl, 3-12 membered heterocyclic groups, C 5-12 The aryl group and the 5-12 heteroaryl group are each independently and optionally bonded by one or more groups selected from halogen, cyano, amino, nitro, C 1-6 Alkyl, C 1- Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, hydroxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 5-12 Substituents of aryl and 5-12 heteroaryl groups;

[0445] Each time q0 and n1 appear, they are independently 0, 1, 2, 3, or 4;

[0446] Each of m1, m2, m3, m4, m5, m6, m7, m8, m9, and m10 is independently 0, 1, 2, 3, 4, or 5 when it appears.

[0447] PTM is selected from the structures shown in Equations A, B, and C below:

[0448] Ring A a Ring B a and ring C a Selected from 5-10-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S; 5-10-membered heterocyclic alkyl groups containing 1-4 heteroatoms selected from N, O, and S; 5-10-membered bridged heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S; and 7-12-membered fused heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, optionally separated by 0-5 R... aa replace;

[0449] Ring Ab Selected from C 5-10 aryl groups, 5-10-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, and 7-12-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, optionally surrounded by 0-5 R groups. aa replace;

[0450] Ring A c and Ring B b Selected from 5-10-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, and 8-14-membered diheterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, optionally surrounded by 0-5 R groups. aa replace;

[0451] Ring A d and Ring B c Selected from C 5-10 Cycloalkylene groups, 5-10 membered heterocyclic alkylene groups containing 1-4 heteroatoms selected from N, O, and S, and 5-13 membered spirocyclic alkylene groups containing 1-4 heteroatoms selected from N, O, and S, optionally surrounded by 0-5 R groups. aa replace;

[0452] Ring C b Selected from 10-16 membered subtricyclic heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, and 8-14 membered subbicyclic heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, optionally separated by 0-5 R groups. aa replace;

[0453] Ring C c Selected from 3-10-membered heterocyclic alkyl groups containing 1-4 heteroatoms selected from N, O, and S, and 5-10-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, optionally surrounded by 0-5 R groups. aa replace;

[0454] Ring C d Does not exist or selected from C 5-10 Cycloalkylene groups and 5-10 membered heterocyclic alkylene groups containing 1-4 heteroatoms selected from N, O, and S, optionally surrounded by 0-5 R atoms. aa replace;

[0455] L a1 L a2 L a3 L a4 L b1 L b2 L b3 L c1 L c2 L c3 and L c4 Each is independently selected from single bonds, C(O), O, NR p1 NRp1 C(O), C(O)NR p1 C 1-6 Alkylene, C 2-6 imidene group, C 2-6 Alkyne and halogenated C 1-6 Alkylene;

[0456] R aa Each of these groups is independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, oxo (=O), -NH-C. 1-6 Alkyl, -NH-halogenated C 1-6 Alkyl, -NH-C 1-6 Alkylene-C 3-8 cycloalkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 alkylene -OH, -C(C 1-6 alkyl)2-OH and halocarbon 1- 6-alkyl;

[0457] R p1 Each time it appears, it is independently selected from H, deuterium, halogen, oxo group (=O), hydroxyl group, nitro group, cyano group, amino group, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-11 Cycloalkyl, 3-11 membered heterocyclic groups, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)-C 1-6 Alkyl, -C(O)-OC 1-6 Alkyl, -C(O)-NH-C 1-6 Alkyl, C 5-10 Aryl and 5-10 heteroaryl groups;

[0458] This represents the connection point with L or CLM.

[0459] In some implementation schemes, A L Each occurrence may be identical or different from the others, and each is independently selected from covalent bonds, C 2-6 imidene group, C 2-6 Ethyne group, CR L1 R L2 O, S, S(O), S(O)2, NR L1 C(O), SiR L1 RL2 P(O)R L1 P(O)OR L1 C (=NCN), C (=CNO2), C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 5-8 aryl, 5-8 quinone heteroaryl, C 6-12 Subspirocyclic and 6-12 quinone subheterocyclic, wherein the C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, C 5-8 aryl, 5-8 quinone heteroaryl, C 6-12 Subspirocyclic and 6-12 quinary subheterocyclic, optionally surrounded by 1-4 R... L1 and / or R L2 replace;

[0460] R L1 and R L2 Each occurrence is independently selected from H, F, Cl, Br, I, -CN, -NO2, -SF5, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocyclic groups, C 5-8 Aryl and 5-8 quinone heteroaryl; in some embodiments, R L1 and R L2 Each occurrence is independently selected from H, F, Cl, Br, -CN, -OH, C. 1-6 Alkyl and C 1-6 Alkoxy; in some embodiments, R L1 and R L2 Each time it appears, it is independently selected from H, F, -CN, -OH, methyl, and methoxy;

[0461] In some implementations, q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0462] In some implementations, G is selected from O;

[0463] In some implementations, W1 is selected from CH and N;

[0464] In some implementations, W2 and W3 are each independently selected from C(R) each time they appear. c1 )2 and NR c1 ;

[0465] In some implementation schemes, R W Each occurrence is independently selected from single bonds, C(O), O, and NR. c1 NR c1 C(O), C 1-6 Alkylene and C 1-6 Halogenated alkylene; in some embodiments, R W Each occurrence is independently selected from single bonds and NR. c1 and NR c1 C(O);

[0466] In some implementations, W7, W8, and W9 are each independently selected from CR each time they appear. c2 R c3 And C(O), and at least one of W8 and W9 is selected from C(O);

[0467] In some implementation schemes, R 1 Each time it appears, it is independently selected from hydrogen and C. 1-6 alkyl;

[0468] In some implementations, A1, A2, A3, A4, A5, and A6 are each independently selected from CH2, C(C) each time they appear. 1-6 Alkyl)2, NH, N(C) 1-6 Alkyl), O, C(O) and S; in some embodiments, A1, A2, A3, A4, A5 and A6 are each independently selected from CH2, C(C) and S when they appear. 1-3 Alkyl)2, NH, N(C) 1-3 Alkyl groups), O, and C(O);

[0469] In some implementations, D1, D2, D3, and D4 are each independently selected from single bonds, N, CH, and C (C) each time they appear. 1-6 alkyl);

[0470] In some embodiments, the S1 group substituents are selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, amino, C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Heteroalkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, halogenated C 1- 6-alkyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, nitro groups, C-groups, and C-groups. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 3-6 cycloalkyl, 4-8 membered heterocyclic, C 2-6 alkenyl, C 2-6 alkynyl group, C 6-10 Substituents of aryl and 5-10 heteroaryl groups;

[0471] In some implementation schemes, R c1 R c2 R c3 and R c4 Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, oxo group (=O), hydroxyl group, nitro group, cyano group, amino group, C. 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, -NH-C 1-6 Alkyl, -N(C) 1-6 Alkyl)2、-C(O)-C 1-6 Alkyl, -C(O)-OC 1-6 Alkyl, -C(O)-NH-C 1-6 Alkyl, C 5-10 aryl and 5-10 heteroaryl, wherein the C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 5-10 The aryl group and the 5-12 heteroaryl group are each independently and optionally bonded by one or more groups selected from F, Cl, Br, I, hydroxyl, cyano, amino, nitro, C. 1-6 Alkyl, C 1-3 Heteroalkyl, C 2-3alkenyl, C 2-3 alkynyl group, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 cycloalkyl, 4-6 membered heterocyclic groups, -NH-C 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 5-8 Substituents of aryl and 5-8 heteroaryl groups;

[0472] In some implementations, q0, n1, n2, and n3 are each independently 0, 1, or 2 each time they appear;

[0473] In some implementations, m1, m2, m3, m4, m5, m6, m7, m8, m9, and m10 are each independently 0, 1, 2, or 3 each time they appear;

[0474] In some implementation schemes, ring A a Ring B a and ring C a Selected from 5-8-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S; 5-8-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, and S; 5-8-membered bridged heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S; and 7-10-membered fused heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, optionally separated by 0-4 R... aa replace;

[0475] In some implementation schemes, ring A b Selected from C 5-8 arylene, 5-8-membered heteroarylene containing 1-3 heteroatoms selected from N, O, and S, and 7-10-membered heteroarylene containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-4 R atoms. aa replace;

[0476] In some implementation schemes, ring A c and Ring B b Selected from 5-8-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and 9-12-membered diheterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-4 R groups. aa replace;

[0477] Ring A d and Ring B c Selected from C 5-8 Cycloalkylene groups, 5-8 membered heterocyclic alkylene groups containing 1-3 heteroatoms selected from N, O, and S, and 6-12 membered spirocyclic alkylene groups containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-4 R groups. aa replace;

[0478] In some implementation schemes, ring C b Selected from 12-15 membered tricyclic sub-heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, and 9-12 membered dicyclic sub-heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-4 R groups. aa replace;

[0479] In some implementation schemes, ring C c Selected from 5-8 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O, and S, and 5-8 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-4 R groups. aa replace;

[0480] In some implementation schemes, ring C d Does not exist or selected from C 5-8 Cycloalkylene groups and 5-8 membered heteroalkylene groups containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-4 R atoms. aa replace;

[0481] In some implementations, L a1 L a2 L a3 L a4 L b1 L b2 L b3 L c1 L c2 L c3 and L c4 Each is independently selected from single bonds, C(O), O, NR p1 NR p1 C(O), C(O)NR p1 C 1-3 Alkylene, C 2-4 imidene group, C 2-4 etyne and C 1-3 Halogenated alkylene;

[0482] In some implementation schemes, R aa Each time it appears, it is independently selected from hydrogen, deuterium, hydroxyl, halogen, cyano, oxo (=O), -NH-C 1-3 Alkyl, -NH-halogenated C 1-3 Alkyl, -NH-C 1-3 Alkylene-C 3-6 cycloalkyl, -N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Alkoxy, -C 1-3 alkylene -OH, -C(C 1-3 alkyl)2-OH and halocarbon1-3 alkyl.

[0483] In some implementation schemes, ring A a Ring B a and ring C a Selected from 5-6-membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S; 5-6-membered heterocyclic alkyl groups containing 1-2 heteroatoms selected from N, O, and S; 6-8-membered bridged heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S; and 8-9-membered fused heteroaryl groups containing 2-3 heteroatoms selected from N, O, and S, optionally separated by 0-2 R groups. aa Replacement; in some implementations, ring A a Ring B a and ring C a Selected from 5-6-membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S, 6-membered heterocyclic alkyl groups containing 2 heteroatoms selected from N, O, and S, 7-membered bridged heterocyclic groups containing 2 heteroatoms selected from N, O, and S, and 9-membered fused heteroaryl groups containing 2-3 heteroatoms selected from N, O, and S, optionally separated by 0-2 R groups. aa Replacement; in some implementations, ring A a Ring B a and ring C a Selected from

[0484] In some implementation schemes, ring A b Selected from C 5-6 arylene, 5-6 membered heteroarylene containing 1-3 heteroatoms selected from N, O, and S, and 8-9 membered heteroarylene containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-3 R aa Replacement; in some implementations, ring A b Selected from phenylene, 5-6 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and 9 membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-2 R groups. aa Replacement; in some implementations, ring A b Selected from

[0485] In some implementation schemes, ring A c and Ring B b Selected from 5-6-membered heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and 9-11-membered diheterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, optionally surrounded by 0-3 R groups. aa Substitution; Ring A c and Ring B bSelected from 5-6 membered heteroaryl groups containing 2-3 heteroatoms selected from N, O, and S, and 9 membered diheterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, optionally surrounded by 0-2 R groups. aa Replacement; in some implementations, ring A c and Ring B b Selected from

[0486] In some implementation schemes, ring A d and Ring B c Selected from C 5-6 Cycloalkylene groups, 5-6 membered heterocyclic alkylene groups containing 1-3 heteroatoms selected from N, O, and S, and 7-11 membered spirocyclic alkylene groups containing 1-3 heteroatoms selected from N, O, and S, optionally surrounded by 0-3 R groups. aa Replacement; in some implementations, ring A d and Ring B c Selected from C6 cycloalkyl groups, 6-membered heterocyclic alkyl groups containing 1-2 heteroatoms selected from N, O, and S, and 7-, 9-, or 11-membered heterospirocyclic groups containing 1-2 heteroatoms selected from N, O, and S, optionally surrounded by 0-2 R groups. aa Replacement; in some implementations, ring A d and Ring B c Selected from

[0487] In some implementation schemes, ring C b Selected from 12-14 membered subtricyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, and 9-11 membered subbicyclic heterocyclic groups containing 1-2 heteroatoms selected from N, O, and S, optionally separated by 0-3 R groups. aa Replacement; in some implementations, ring C b Selected from 12- or 14-membered subtricyclic heterocyclic groups containing two heteroatoms selected from N, O, or S, and 9-membered subbicyclic heterocyclic groups containing one to two heteroatoms selected from N, O, or S, optionally surrounded by 0 to 3 R groups. aa Replacement; in some implementations, ring C b Selected from

[0488] In some implementation schemes, ring C c Selected from 5-6-membered heterocyclic alkyl groups containing 1-2 heteroatoms selected from N, O, and S, and optionally surrounded by 0-3 R groups. aa Replacement; in some implementations, ring C cSelected from 6-membered heterocyclic alkyl groups containing 1-2 heteroatoms selected from N, O, and S, and 6-membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S, optionally separated by 0-2 R groups. aa Replacement; in some implementations, ring C c Selected from

[0489] In some implementation schemes, ring C d Does not exist or selected from C 5-6 Cycloalkylene groups and 5-6 membered heteroalkylene groups containing 1-2 heteroatoms selected from N, O, and S, optionally surrounded by 0-3 R atoms. aa Replacement; in some implementations, ring C d It is absent or selected from C6 cycloalkylene groups and contains 1-2 6-membered heteroalkylene groups selected from N, O, and S heteroatoms, optionally surrounded by 0-2 R atoms. aa Replacement; in some implementations, ring C d Not present or selected

[0490] In some implementations, L a1 L a2 L a3 L a4 L b1 L b2 L b3 L c1 L c2 L c3 and L c4 Each is independently selected from single bonds, C(O), O, -NH-, C(O)NH, C(O)N(C 1-3 alkyl) and C 1-3 Alkylene; in some embodiments, L a1 L a2 L a3 L a4 L b1 L b2 L b3 L c1 L c2 L c3 and L c4 Each is independently selected from single bonds, C(O), O, NH, and C(O)NH; in some embodiments, L a1 L a3 and L c3 Selected from single bond, L a2 L b1 L b2 and L c1 Each is independently selected from single bonds and C(O)NH,La4 L b3 L c2 and L c4 Each is independently selected from single bonds and C(O);

[0491] In some implementation schemes, R aa Each time it appears, it is independently selected from hydrogen, deuterium, F, Cl, Br, I, -CN, oxo group (=O), -NH-CH2-CF3, -NH-CH2-C3 cycloalkyl, -NH-CH3, -N(CH3)2, -N(CH3)(CH2CH3), -CH3, -CH2CH3, -C(CH3)2, -CHF2, -CF3, -OCH3, -CH2-OH and -C(CH3)2-OH;

[0492] In some implementation schemes, R p1 Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, oxo group (=O), hydroxyl group, nitro group, cyano group, amino group, C. 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Heteroalkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, -NH-C 1-3 Alkyl, -N(C) 1-3 Alkyl)2、-C(O)-C 1-3 Alkyl, -C(O)-OC 1-3 Alkyl, -C(O)-NH-C 1-3 Alkyl, C 5-8 Aryl and 5-8 quinone heteroaryl groups;

[0493] Represents the connection site.

[0494] In some implementations, the PTM is selected from the following structures:

[0495] in,

[0496] Ring A a Selected from

[0497] Ring A b Selected from

[0498] Ring A d Selected from

[0499] Ring B a Selected from

[0500] Ring C a Selected from

[0501] Ring C c Selected from

[0502] Q1 is selected from CH and N;

[0503] Q2 is selected from CH2 and O;

[0504] q1 and q2 are each independently selected from 0, 1, 2, and 3;

[0505] L a4 L b3 L c2 and L c4 Each is independently selected from single bonds and C(O); and

[0506] When PTM is selected from formula A-1, the compound is not...

[0507] In another aspect of this disclosure, compounds of formula (Ⅰ”’) or pharmaceutically acceptable salts thereof are provided.

[0508] PTM-L-CLM (Ⅰ”')

[0509] Where L is the key or connector sub-part that connects CLM and PTM;

[0510] CLM is selected from the structures shown in Equations (I-1), (I-2), and (I-3):

[0511] In this case, G and Z are each independently selected from O and S each time they appear;

[0512] W1 is CR c1 Or N;

[0513] W2 and W3 are each selected independently from C(R) each time they appear. c1 2. NR c1 O and S;

[0514] R W Each occurrence is independently selected from single bonds, C(O), O, S, S(O)2, NR. c1 NR c1 Combinations of one or more of C(O), C1-C6 alkylene, C1-C6 haloalkylene, C2-C6 alkenylene, C2-C6 ynynylene and C1-C6 heteroalkylene;

[0515] W4 and W5 are each independently selected from N and C. Indicates either a single or double key; and At least one of them is a double bond;

[0516] W6 is N or CR c1 ;

[0517] W7 is CR c2 R c3 C(O), S(O)2 or NR c2 ;

[0518] R 1 Each time it appears, it is independently selected from hydrogen and C1-C. 10 alkyl;

[0519] R 1a R 1b R 1c R 1d and R 1e The definition is selected from one of the following groups;

[0520] (i-1)R 1a and R 1b The carbon atoms bonded to it together form a ring Cy1, and R 1c R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0521] (i-2)R 1b and R 1c The carbon atoms bonded to it together form a ring Cy1, and R 1a R 1d and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0522] (i-3)R 1c and R 1d The carbon atoms bonded to it together form a ring Cy1, and R 1a R 1b and R 1e Each time it appears, it is independently selected from the substituents of group S1;

[0523] (i-4)R 1d and R 1e The carbon atoms bonded to it together form a ring Cy1, and R 1a R 1b and R 1c Each time it appears, it is independently selected from the substituents of group S1;

[0524] (i-5)R 1c for Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc. c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0525] R 1b and R 1f The atoms bonded to it together form 4 to 9-membered heterocycles, R 1d and R 1g The atoms bonded to it together form 4 to 9-membered heterocycles; and R 1a and R 1e Each time a substituent appears, it is independently selected from the S1 group; the 4 to 9-membered heterocycles optionally contain 1, 2, or 3 heteroatoms selected from N, O, and S as ring atoms, and are optionally substituents of one or more R groups. c1 replace;

[0526] R 2a R 2b R 2c R 2d and R 2e The definition is selected from one of the following groups;

[0527] (ii-1)R 2a and R 2b The carbon atoms bonded to it together form a ring Cy2, and R 2c R 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0528] (ii-2)R 2b and R 2c The carbon atoms bonded to it together form a ring Cy2, and R 2a R 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0529] (ii-3)R 2c and R 2d The carbon atoms bonded to it together form a ring Cy2, and R 2a R 2b and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0530] (ii-4)R 2a and R 2e The atoms connected to it together form a ring Cy2, and R2b R 2c and R 2d Each time it appears, it is independently selected from the substituents of group S1;

[0531] (ii-5)R 2a for And R 2b R 2c R 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0532] Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc. c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0533] (ii-6)R 2b for And R 2a R 2c R 2d and R 2e Each time it appears, it is independently selected from the substituents of group S1;

[0534] Wherein, "*Ph" indicates the linkage site with the benzene ring, U1 is N or CH, and U2 and U3 are each independently selected from O, S, S(O)2, C(O), C(R)2, etc. c4 )2 and NR c4 n2 and n3 are each independently 0, 1, 2 or 3;

[0535] Cy1 and Cy2 are each independently selected

[0536] Each occurrence of A1, A2, A3, and A4 is independently C(R). c4 2. NR c4 O, C(O) or S, at A1 and A2 Each occurrence independently represents a bonding site with a carbon atom on the benzene ring;

[0537] U4, U5, U6, and U7 are each independently CR each time they appear. c4 Or N;

[0538] Each of D1, D2, D3, and D4 appears independently as a single bond, N, or CR. c4 , This indicates the presence or absence of double bonds at any position within the ring;

[0539] RT Each occurrence is independently CH or N, R t Each occurrence is independently C or N, R t and R T place Represents the connection site with L;

[0540] The substituents in group S1 are selected from: hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Deuterated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 11 Cycloalkyl, 4 to 12-membered heterocyclic groups, C5-C 12 aryl and 5 to 12-membered heteroaryl, wherein the C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 11 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 The aryl group and the 5 to 12 heteroaryl group are each independently and optionally selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, nitro groups, C1-C groups. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C3-C 11 Cycloalkyl, 4- to 12-membered heterocyclic groups, C2-C6 alkenyl, C2-C6 ynyl, C5-C 12 Substituted with aryl and 5 to 12-membered heteroaryl groups;

[0541] Each time n1, n2, and n3 appear, they are independently 0, 1, 2, 3, or 4;

[0542] Each of m1, m2, m3, m4, m5, m6, m7, m8, m9, and m10 is independently 0, 1, 2, 3, 4, or 5 when it appears.

[0543] PTM has the following structure:

[0544] Ring A is selected from C5-C 10 Aryl, containing 1-4 5- to 10-membered heteroaryl groups selected from N, O, and S heteroatoms;

[0545] Ring B is selected from single bonds, C5-C 10 Aryl, 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, 8- to 14-membered bicyclic heterocyclic groups containing 1-4 heteroatoms selected from N, O, and S, and 10- to 16-membered tricyclic heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S;

[0546] R aa Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, C1-C 10 Haloalkyl, C1-C 10 Halogenated alkoxy groups, C3-C 11 cycloalkyl, NHR p1 、N(R p1 2. C2-C6 alkenyl, containing 1-3 4- to 12-membered heterocyclic groups selected from N, O, and S heteroatoms, C5-C 10 Aryl groups and 5- to 12-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C1-C 10 Alkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, C1-C 10 Haloalkoxy, 4- to 12-membered heterocyclic groups, C5-C 10 Aryl groups and heteroaryl groups containing 5 to 12 members are optionally p' R cc Replaced;

[0547] R bb Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, oxo group, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, C1-C 10 Halogenated alkyl, hydroxy-C1-C 10 Alkyl-, NHR p1 、N(R p1 2. C3-C 11 Cycloalkyl groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S, wherein the C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyl, C1-C 10Alkoxy groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms selected from N, O, and S are optionally surrounded by p' R cc Replaced;

[0548] R cc Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl, hydroxy-C1-C 10 Alkyl-, NHR p1 、N(R p1 )2 and C3-C 11 cycloalkyl, wherein the C3-C 11 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from halogen, hydroxyl, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Substituents of haloalkyl groups;

[0549] L aa Independently selected from single bonds, C(O), O, -NR p1 -、-NR p1 C(O)-、-C(O)NR p1 -、C1-C 10 alkylene, C2-C6 alkenylene, C2-C6 alkyneene, and C1-C 10 Halogenated alkylene;

[0550] L bb For XL cc X is independently selected from single bonds, C3-C 11 Cycloalkylene and 4- to 11-membered heterocycloalkylene, wherein the C3-C 11 Cycloalkylene and 4 to 11-membered heterocycloalkylene are optionally surrounded by 1, 2, 3 or 4 R's. x Replaced;

[0551] L cc Independently selected from single bonds, C(O), O, -NR p1 -、-NR p1 C(O)-、-C(O)NR p1 -、C1-C 11 Alkylene, C1-C 10 Alkyl halide, C2-C6 alkenyl halide, and C2-C6 ynyl halide;

[0552] Each time m', n', and p' appear, they are independently selected from 0, 1, 2, and 3;

[0553] R c1 R c2 R c3 R c4 R p1 and R x Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo group, hydroxyl group, nitro group, cyano group, amino group, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, C3-C 11 cycloalkyl, amino-C1-C 10 Alkyl-, C1-C 10 alkyl-acyl-, C1-C 10 Alkyl-oxy-acyl-, C1-C 10 Alkyl-NH-acyl-, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 12-membered heterocyclic groups, C5-C 12 aryl and 5 to 12-membered heteroaryl, wherein the C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 11 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 The aryl and 5- to 12-membered heteroaryl groups are each independently and optionally selected from one or more groups selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, amino-C1-C6 alkyl-, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 15 It is substituted by aryl and 5 to 12 heteroaryl substituents.

[0554] According to the compound described above or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compound shown in claim 15.

[0555] Another aspect of this disclosure provides a ligand-drug conjugate that uses the aforementioned compound as the toxic portion of the drug.

[0556] In another aspect of this disclosure, a pharmaceutical composition is provided, the pharmaceutical composition comprising a therapeutically effective amount of the compound described above or a pharmaceutically acceptable salt thereof or a ligand-drug conjugate described above, and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

[0557] Another aspect of this disclosure provides the use of the compounds described above, or pharmaceutically acceptable salts thereof, the pharmaceutical compositions described above, or the ligand-drug conjugates described above, in the preparation of medicaments for the prevention or treatment of diseases or conditions mediated by IRAK4.

[0558] Another aspect of this disclosure provides a method for preventing or treating diseases or conditions mediated by IRAK4, comprising administering to a subject in need a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, the aforementioned ligand-drug conjugate, or the aforementioned pharmaceutical composition.

[0559] Another aspect of this disclosure provides the aforementioned compounds or pharmaceutically acceptable salts thereof, the aforementioned pharmaceutical compositions, or the aforementioned ligand-drug conjugates for the prevention or treatment of diseases or conditions mediated by IRAK4.

[0560] In some embodiments, the IRAK4-mediated diseases or conditions include immune diseases, inflammatory diseases, and cancer; in some embodiments, the IRAK4-mediated diseases or conditions include rheumatoid arthritis, atopic dermatitis, hidradenitis suppurativa, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, and gout.

[0561] Another aspect of this disclosure provides the use of the foregoing compounds or pharmaceutically acceptable salts thereof for the preparation of ligand-drug conjugates.

[0562] In some implementations, the ligand is an antibody or its antigen-binding fragment.

[0563] In another aspect of this disclosure, compounds or salts thereof represented by the following formulas (II-1a), (II-1b), (II-1c), (II-2a1), (II-2a2), (II-2a3), (II-2a4), (II-2b1), (II-2b2), (II-2b3), (II-2b4), (II-2d1), (II-2d2), (II-2d3), (II-3a), (II-3b), or (II-3c) are provided:

[0564] in,

[0565] R 1 W1, R W R 1a R 1d and R 1e Each customization is the same as described in any of the preceding implementation schemes;

[0566] n4 and n5 are each independently selected from 0, 1, 2 and 3 each time they appear;

[0567] R lev It is a leaving group;

[0568] R L It is protected by hydrogen, amino groups (e.g., Boc), or -Lz-Cys;

[0569] A5, A6, A7, and A8 are each independently selected from single bonds and (CH2) each time they appear. 1-3 (CH2) 0-2 O(CH2) 0-2 (CH2) 0-2 S(CH2) 0-2 (CH2) 0- 2C(O)(CH2) 0-2 and (CH2) 0-2 NH(CH2) 0-2 ;

[0570] L z Each occurrence is independently selected from single bonds, C(O), O, NH, NHC(O), C 1-3 Alkylene and C 1-3 Alkyl halide, preferably methylene;

[0571] Each occurrence of Cys is independently selected from C3-C. 16 cycloalkyl groups and 4 to 12-membered heterocyclic groups, wherein the C3-C 16 Cycloalkyl groups and 4 to 12-membered heterocyclic groups are optionally surrounded by 1 to 6 R groups. L1 replace;

[0572] R L1 Selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C5-C8 aryl, 5- to 8-membered heteroaryl, and 4- to 7-membered heterocyclic groups; in some embodiments, R L1 It is selected from fluorine, chlorine, bromine, cyano, hydroxyl, C1-C6 alkyl and C1-C6 alkoxy; more preferably selected from hydrogen, fluorine, cyano, hydroxyl, methyl and methoxy;

[0573] In some implementation schemes, R 1 It is hydrogen;

[0574] In some implementations, W1 is CR c1 Or N; in some implementations, W1 is CH or N;

[0575] In some implementation schemes, R W Each occurrence is independently selected from single bonds, C(O), and NR. c1 and NHC(O);

[0576] In some implementations, A5, A6, A7, and A8 are each independently selected from single bond, O, CH2, and CH2CH2 each time they appear; in some implementations, A5-A6 are O-CH2 or O-CH2CH2; and A7-A8 are single bond, O-CH2, or O-CH2CH2.

[0577] In some implementations, n4 and n5 are each independently 1 or 2 each time they occur;

[0578] In some embodiments, the leaving group is selected from: chlorine, bromine, iodine, hydroxyl, aldehyde, amino, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromobenzene)sulfonyloxy, (4-nitrobenzene)sulfonyloxy, (2-nitrobenzene)sulfonyloxy, (4-isopropylbenzene)sulfonyloxy, (2,4,6-triisopropylbenzene)sulfonyloxy, (2,4,6-trimethylbenzene)sulfonyloxy, (4-tert-butylbenzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxybenzene)sulfonyloxy.

[0579] Among them, R 1 W1, R W R 2b R 2c R 2d and R 2e Each definition is the same as above;

[0580] A5 and A6 are each independently selected from (CH2) each time they appear. 1-3 (CH2) 0-2 O(CH2) 0-2 (CH2) 0-2 S(CH2) 0-2 (CH2) 0-2 C(O)(CH2) 0-2 and (CH2) 0- 2NH(CH2) 0-2 ;

[0581] n4 and n5 are each independently selected from 0, 1, 2 and 3 each time they appear;

[0582] R L Protected by hydrogen, amino groups (e.g., Boc), or -Lz-Cys; L zEach occurrence is independently selected from single bonds, C(O), O, NH, NHC(O), C 1-3 Alkylene and C 1-3 Alkyl halide, preferably methylene;

[0583] Each occurrence of Cys is independently selected from C3-C. 16 cycloalkyl groups and 4 to 12-membered heterocyclic groups, wherein the C3-C 16 Cycloalkyl groups and 4 to 12-membered heterocyclic groups are optionally surrounded by 1 to 6 R groups. L1 replace;

[0584] R L1 Selected from hydrogen, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C5-C8 aryl, 5- to 8-membered heteroaryl, and 4- to 7-membered heterocyclic groups; in some embodiments, R L1 It is selected from fluorine, chlorine, bromine, cyano, hydroxyl, C1-C6 alkyl and C1-C6 alkoxy; more preferably selected from hydrogen, fluorine, cyano, hydroxyl, methyl and methoxy;

[0585] In some implementation schemes, R 1 It is hydrogen;

[0586] In some implementations, W1 is CR c1 Or N; In some implementations, W1 is CH or N, and in some implementations, W1 is CH;

[0587] In some implementation schemes, R W Selected from single bonds, C(O), NR c1 and NHC(O); in some implementations, R W It is a single bond;

[0588] In some implementations, A5 and A6 are each independently selected from O, CH2, and CH2CH2 each time they appear; in some implementations, A5-A6 are O-CH2 or O-CH2CH2.

[0589] In some implementations, n4 and n5 are each independently 1 or 2 each time they appear, preferably 1;

[0590] In some implementation schemes, R 2e It is methyl;

[0591] Among them, R 1 W1, R W R 1a R1d and R 1e Each definition is the same as above;

[0592] Each occurrence of B1, B2, B3, and B6 is independently C(R). c4 2. NR c4 O, C(O) or S; in some implementations, B1, B2, B3 and B6 are each independently selected from C(R) each time they appear. c4 )2 and O;

[0593] D2 and D3 are each selected independently from single bonds and CR each time they appear. c4 And N; preferably a single bond, CH or N, more preferably N;

[0594] Each time m1 and m2 appear, they are independently 0, 1, 2, 3, 4 or 5;

[0595] Each time U5 appears, it is independently designated as CR. c4 Or N;

[0596] R T Each occurrence is independently CH or N, R t Each occurrence is independently either C or N;

[0597] R c4 Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, -C1-C6 alkyl-amino, -C(O)-C1-C6 alkyl, -C(O)-O-C1-C6 alkyl, -C(O)-NH-C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4 to 8 membered heterocyclic groups, C6-C 10 aryl and 5- to 10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic, C6-C 10 The aryl and 5- to 10-membered heteroaryl groups are each independently and optionally selected from one or more groups selected from fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, C3-C6 cycloalkyl, 4- to 8-membered heterocyclic, -C1-C6 alkyl-amino, C6-C 10 The aryl group is substituted with substituents of 5 to 10 heteroaryl groups; in some embodiments, R c4Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo, hydroxyl, nitro, cyano, amino, C1-C6 alkyl, and C1-C6 alkoxy; in some embodiments, R c4 Each of the following is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, C1-C3 alkyl and C1-C3 alkoxy groups; more preferably hydrogen.

[0598] In some embodiments, the compound is selected from the following compounds:

[0599] Among them, R lev The leaving group is selected from: chlorine, bromine, iodine, hydroxyl, aldehyde, amino, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy, (4-bromobenzene)sulfonyloxy, (4-nitrobenzene)sulfonyloxy, (2-nitrobenzene)sulfonyloxy, (4-isopropylbenzene)sulfonyloxy, (2,4,6-triisopropylbenzene)sulfonyloxy, (2,4,6-trimethylbenzene)sulfonyloxy, (4-tert-butylbenzene)sulfonyloxy, benzenesulfonyloxy, and (4-methoxybenzene)sulfonyloxy.

[0600] In another aspect of this disclosure, a compound of formula B or a pharmaceutically acceptable salt thereof is provided.

[0601] Among them, L gga As a leaving group, in some embodiments, L gga Selected from Br, Cl, I, methanesulfonates, toluenesulfonates, trifluoromethanesulfonates, and OH;

[0602] Ring C and ring E are each independently selected from C6-C. 10 arylene, and 5- to 10-membered heteroarylene containing 1 to 4 heteroatoms, each independently selected from N, O, and S;

[0603] Ring D is selected from C6-C 10 Aryl groups, and 5- to 10-membered heteroaryl groups containing 1 to 4 heteroatoms, each independently selected from N, O, and S.

[0604] R ee Selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl-amino, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 15Aryl and 5 to 12 heteroaryl groups;

[0605] R ff and R dd Each time it appears, it is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, O-C1-C 10 Alkyl, OR p1 C1-C 10 Halogenated alkyl, NHR p1 、N(R p1 2. C3-C 11 Cycloalkyl groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms independently selected from N, O, and S, wherein the C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Deuterated alkyl, C1-C 10 Alkoxy groups, 4- to 12-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O, and S, and 5- to 10-membered heteroaryl groups containing 1-4 heteroatoms independently selected from N, O, and S, optionally surrounded by p' R cc Replaced;

[0606] R cc Each time it appears, it is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl, -C1-C 10 alkylene-hydroxyl, NHR p1 、N(R p1 )2 and C3-C 11 cycloalkyl, wherein the C3-C 11 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from halogen, hydroxyl, cyano, C1-C. 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Substituents of haloalkyl groups;

[0607] L ff Each occurrence is independently selected from single bonds, C(O), O, and -NR. p1 -、-NR p1 C(O)-、-C(O)NR p1 -、C1-C 10alkylene, C2-C6 alkenylene, C2-C6 alkyneene, and C1-C 10 Halogenated alkylene;

[0608] L gg For YL cc1 Each time Y appears, it is independently selected from single bonds, C3-C 11 Cycloalkylene and 4- to 11-membered heterocycloalkylene, wherein the C3-C 11 Cycloalkylene and 4 to 11-membered heterocycloalkylene are optionally surrounded by 1, 2, 3 or 4 R's. x Replaced;

[0609] L cc1 Each occurrence is independently selected from single bonds, C(O), O, and -NR. p1 -、-NR p1 C(O)-、-C(O)NR p1 -、C1-C 11 Alkylene, C1-C 10 Alkyl halide, C2-C6 alkenyl halide, and C2-C6 ynyl halide;

[0610] Each time t', x', y', and p' appear, they are independently selected from 0, 1, 2, and 3;

[0611] R p1 and R x Each time it appears, it is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, oxo group, hydroxyl group, nitro group, cyano group, amino group, C1-C. 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Deuterated alkyl, C3-C 11 cycloalkyl, -C1-C 10 Alkyl-amino, -C(O)-C1-C 10 Alkyl, -C(O)-O-C1-C 10 Alkyl, -C(O)-NH-C1-C 10 Alkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12 aryl and 5 to 12-membered heteroaryl, wherein the C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 11 Cycloalkyl, C2-C6 alkenyl, C2-C6 ynyl, 4- to 12-membered heterocyclic groups, C5-C 12The aryl and 5- to 12-membered heteroaryl groups are each independently and optionally selected from one or more groups selected from fluorine, chlorine, bromine, iodine, cyano, amino, hydroxyl, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylene-hydroxy, C3-C6 cycloalkyl, C1-C6 alkyl-amino, C2-C6 alkenyl, C2-C6 alkynyl, 4- to 8-membered heterocyclic groups, C6-C 15 Substituted with aryl and 5 to 12 heteroaryl groups;

[0612] In some embodiments, ring D is selected from phenyl, 5-6 membered monocyclic heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S, and 9-10 membered bicyclic heteroaryl groups containing 1-3 heteroatoms selected from N, O, and S; in some embodiments, ring D is selected from phenyl, 5-6 membered heteroaryl groups containing 1-2 heteroatoms selected from N, O, and S, and 9-10 membered bicyclic heteroaryl groups containing 2-3 heteroatoms selected from N and O; in some embodiments, ring D is selected from phenyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazole, benzimidazolyl, pyrazolopyrimidinyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl, pyrimidinylimidazolyl, pyrrolopyrazinyl, pyridopyrimidinyl, and pyridopyrimidinoneyl.

[0613] In some embodiments, ring E is selected from phenylene and 5-6 membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, O, and S; in some embodiments, ring E is selected from phenylene and 5-6 membered heterocyclic aryl groups containing 1-2 heteroatoms selected from N and O; in some embodiments, ring E is selected from phenyl, oxazolyl, thiazolyl, imidazolyl, and pyridinyl.

[0614] In some embodiments, the ring C is selected from phenyl and contains 1-3 5-6 membered monocyclic heteroaryl groups selected from N, O, and S heteroatoms; in some embodiments, the ring C is selected from phenyl and contains 1-3 5-6 membered heteroaryl groups selected from N, O, and S heteroatoms.

[0615] In some implementations, L ff Each occurrence is independently selected from single bonds, C(O), O, -NH-, -NHC(O)-, and -C(O)NH-; in some embodiments, L ff Selected from single bonds;

[0616] In some implementations, L gg For YL cc1 Each time Y appears, it is independently selected from single bonds, C6-C8 cycloalkyl groups and 6- to 10-membered heteroalkyl groups, wherein the C6-C8 cycloalkyl groups and 6- to 10-membered heteroalkyl groups are optionally substituted by one or two substituents independently selected from halogens, C1-C6 alkyl groups and C1-C6 alkoxy groups;

[0617] In some implementations, L cc1 Each occurrence is independently selected from single bonds, C(O), O, -NH-, -NHC(O)-, and -C(O)NH-;

[0618] In some implementations, x', y', and t' are each independently selected from 0, 1, and 2 each time they appear;

[0619] In some implementation schemes, Selected from R ee1 and R ee2 Each time it appears, it is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl, containing 1-3 5- to 8-membered heterocyclic groups selected from N, O, and S heteroatoms, and containing 1-4 5- to 10-membered heteroaryl groups selected from N, O, and S heteroatoms;

[0620] In some implementation schemes, Selected from R ff Each occurrence is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, O-C3-C6 cycloalkyl, NH-C1-C6 alkyl, NH-C3-C6 cycloalkyl, C3-C6 cycloalkyl, containing 1-3 5- to 8-membered heterocyclic groups selected from N, O, and S heteroatoms, and containing 1-4 5- to 10-membered heteroaryl groups selected from N, O, and S heteroatoms, wherein the C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups, and 5- to 10-membered heteroaryl groups are optionally surrounded by p' R cc Replaced;

[0621] In some implementation schemes, Selected from Among them, R dd Each of the following groups, when appearing independently, is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, containing 1-3 5- to 8-membered heterocyclic groups selected from N, O, and S heteroatoms, and containing 1-4 5- to 10-membered heteroaryl groups selected from N, O, and S heteroatoms, wherein the C3-C6 cycloalkyl, 5- to 8-membered heterocyclic groups, and 5- to 10-membered heteroaryl groups are optionally separated by p' R cc Replaced;

[0622] In some implementations, L gg For YL cc1 In each occurrence of Y, it is independently a single bond or selected from cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziridine, pyrrolidinyl, piperidinyl, piperazineyl, etc. The divalent linker, optionally substituted by one or two independent substituents selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; L cc1 Each occurrence is independently selected from single bonds and C(O); in some implementations, L gg Each occurrence is independently selected from single bonds, -C(O), -C(O)NH-,

[0623] Another aspect of this disclosure provides compounds selected from those shown in the following formula or pharmaceutically acceptable salts thereof:

[0624] Among them, R ee R ee1 R ee2 L gg R ff Each occurrence is defined as described above;

[0625] Q1, Q2, Q3, Q4, Q7, and Q8 each appear independently as N or CH; N is preferred.

[0626] Q9 is selected independently from O and S each time it appears; S is preferred.

[0627] Each time q1 and q2 appear, they are independently selected from 0, 1, 2, and 3;

[0628] L gga As a leaving group, in some embodiments, L gga Selected from non-existent, OH, Br, Cl, I, methanesulfonate, toluenesulfonate and trifluoromethanesulfonate;

[0629] In some implementations, L gg For YL cc1In each occurrence of Y, it is independently selected from single bonds, C6-C8 cycloalkyl groups, and 6- to 10-membered heteroalkyl groups, wherein the C6-C8 cycloalkyl groups and 6- to 10-membered heteroalkyl groups are optionally substituted by one or two substituents independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; in some embodiments, each occurrence of Y is independently a single bond or selected from cyclobutyl, cyclopentyl, cyclohexyl, oxecyclobutyl, oxecyclopentyl, oxecyclohexyl, aziridine, pyrrolidinyl, piperidinyl, piperazine, ... The divalent linker is optionally substituted with one or two substituents independently selected from halogens, C1-C6 alkyl groups, and C1-C6 alkoxy groups; in some embodiments, the right-hand linker is associated with L. cc1 Connection sites;

[0630] In some implementations, L cc1 Each occurrence is independently selected from single bonds, C(O), O, NH, NHC(O), and C(O)NH; L is preferred. cc1 Selected from single bonds and C(O);

[0631] In some implementations, L gg Each occurrence is independently selected from single bonds, -C(O), -C(O)NH-, In some implementations, its right-side connection site is associated with L gga Connection sites;

[0632] In some embodiments, the compound is selected from:

[0633] Q 10 Each occurrence is independently either N or CH; CH is preferred.

[0634] R bb Each time it appears, it is independently selected from hydrogen, oxo group (=O), OCH3, OCH(CH3)2, CHF2, COOCH3, C(CH3)2OH, OCH(CH3)2, NH-CH(CH3)2, NH(CH3), N(CH3)2.

[0635] In some implementation schemes, R cc Each time it appears, it is independently selected from hydrogen, hydroxyl, fluorine, cyano, CH3, CH2CH3, CH(CH3)2, OCH3, CHF2, C(CH2)OH, NHCH2-CF3, CF3, CONH2, NH-CH2-cyclopropyl, NH-CH(CH3)2, N(CH3)2, and cyclopropyl;

[0636] In some implementations, L cc Each is independently selected from single bonds, NH, C(O) and C(O)NH.

[0637] In some embodiments, the compound is selected from:

[0638] L gga As defined above.

[0639] In another aspect of this disclosure, a protein degrading agent is provided, comprising the aforementioned compound covalently linked to other portions, wherein L gga He has left;

[0640] In some embodiments, the protein degrading agent is a targeted protein degradation chimera comprising a covalently linked IRAK4 protein-binding moiety, a linker, and an E3 ubiquitin ligand; the IRAK4 protein ligand is the compound described above, wherein L gga He has left;

[0641] In some embodiments, the E3 ubiquitin ligase ligand is the compound described above, wherein R lev They have already left.

[0642] In another aspect of this disclosure, the use of the compounds described above or salts thereof in the preparation of E3 ubiquitin ligands is provided, in some embodiments, wherein the E3 ubiquitin ligand is a cerebellar protein E3 ubiquitin ligand ligand.

[0643] Another aspect of this disclosure provides the use of the foregoing compounds or pharmaceutically acceptable salts thereof or the foregoing protein degraders in the preparation of medicaments for the prevention or treatment of IRAK4-mediated diseases or conditions; in some embodiments, the IRAK4-mediated diseases or conditions include immune diseases, inflammatory diseases, and cancer; in some embodiments, the IRAK4-mediated diseases or conditions include rheumatoid arthritis, atopic dermatitis, hidradenitis suppurativa, systemic lupus erythematosus (SLE), inflammatory bowel disease, psoriasis, and gout.

[0644] Another aspect of this disclosure provides the use of the foregoing compounds or salts thereof, or pharmaceutically acceptable salts thereof, in the preparation of protein degrading agents; in some embodiments, the protein degrading agent is a targeted protein degradation chimera. Attached Figure Description

[0645] Figure 1 shows the inhibition of inflammatory factors IL-6 and IL-17 by compounds 190, 187, 206, 188 and 9 in mouse serum (one-way ANOVA, n=4, **p<0.01, ***p<0.001, ****p<0.0001, ns=no significance vs. Vehicle group).

[0646] Figure 2 shows the degradation of IRAK4 in mouse spleens of compounds 190, 187, 206, 188, and 9.

[0647] Figure 3 shows the inhibition of inflammatory factors IL-6 and IL-17 by compounds 198, 220 and 215 in mouse serum (one-way ANOVA, n=4, **p<0.01, ***p<0.001, ****p<0.0001, ns=no significance vs. Vehicle group).

[0648] Figure 4 shows the degradation of IRAK4 in mouse spleen and skin by compounds 198, 220 and 215. Detailed Implementation

[0649] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0650] I. Terms and Definitions

[0651] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are all widely used terms and routine procedures in the respective fields. To better understand this invention, definitions and explanations of related terms are provided below.

[0652] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0653] As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” “containing,” and their grammatical equivalents, including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0654] In this specification and the claims reported herein, the phrase “and / or” is interpreted as meaning “any one or both” of the elements, that is, the elements may exist together in some cases or the elements may exist separately in other cases.

[0655] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0656] The term "heteroatom" is selected from nitrogen, oxygen, or sulfur. Nitrogen may optionally be substituted; sulfur may also optionally be substituted, for example, by oxidation, thus forming S(O). t3 (where t3 is an integer from 0 to 2).

[0657] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms or 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, and the substituent is preferably independently selected from RS group groups.

[0658] The term "heteroalkyl" refers to an alkyl group in which one or more (e.g., 1, 2, 3, 4 or 5) -CH2- atoms are substituted with heteroatoms selected from N, O and S, or where one or more -CH- atoms are substituted with N atoms; wherein the alkyl group is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable connection point, the substituent preferably being one or more RS group groups.

[0659] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described herein. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, isopropoxy, butoxy, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, and -O-cyclohexyl. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more RS group groups.

[0660] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl is preferably an alkyl group having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon double bond. 2-8 "Alkenyl" is preferred; more preferably, C is preferred. 2-6 Alkenyl (i.e., alkenyl groups having 2 to 6 carbon atoms and 1 to 2 carbon-carbon double bonds). More preferably, C 2-4 Alkenyl (i.e., alkenyl groups having 2 to 4 carbon atoms and 1 to 2 carbon-carbon double bonds). Specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, pentenyl, hexenyl, butadienyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more RS group groups.

[0661] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in its molecule, wherein the alkyl group is defined as described above. The alkynyl group is preferably a "C" group having 2 to 8 carbon atoms and at least one (e.g., 1 to 2) carbon-carbon triple bond. 2-8 "Alkyne group". Preferably C 2-6 Alkynyl (i.e., alkynyl group having 2 to 6 carbon atoms and 1 to 2 carbon-carbon triple bonds). More preferably C 2-4 Alkynyl (i.e., an alkynyl group having 2 to 4 carbon atoms and 1 to 2 carbon-carbon triple bonds). Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more RS group groups.

[0662] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and even more preferably 4 to 7 or 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl. The cycloalkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more RS group groups.

[0663] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms (e.g., 1, 2, 3, 4, 5, or 6) are selected from nitrogen, oxygen, or S(O). mThe heterocyclic group comprises (where m is an integer from 0 to 2) heteroatoms, excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. The ring carbon atoms of the heterocyclic group may optionally be substituted with 1, 2, or 3 oxo groups to form cyclic ketones, cyclic lactones, or cyclic lactam structures.Specific examples of heterocyclic groups include, but are not limited to, aziridine, ethylene oxide, aziridine, aziridine-2-one, oxazolidinyl, oxazolidinyl-2-one ... 1,1-dioxide of 3-lineone, thiomorpholine, thiomorpholine-1,1-dioxide, tetrahydropyran, 1,2-dihydroazacyclobutadiene, 1,2-dihydrooxocyclobutadiene, 2,5-dihydro-1H-pyrrole, 2,5-dihydrofuran, 2,3-dihydrofuran, 2,3-dihydro-1H-pyrrole, 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, 3,6-dihydro-2H-pyran, 1,2,3,6-tetrahydropyridine, 1,3-oxazine, hexahydropyrimidine, 1,4-dioxane, tetrahydropyrimidine-2(1H)-one, 1,4-dioxane-2-one, 5,6-dihydro-2H-pyran-2-one, 5 6-Dihydropyrimidin-4(3H)-one, 3,4-Dihydropyridin-2(1H)-one, 5,6-Dihydropyridin-2(1H)-one, 5,6-Dihydropyrimidin-4(1H)-one, pyrimidin-4(3H)-one, pyrimidin-4(1H)-one, 4,5-Dihydro-1H-imidazolium, 2,3-Dihydro-1H-imidazolium, 2,3-Dihydrooxazole, 1,3-Dioxacyclopentene, 2,3-Dihydrothiophene, 2,5-Dihydrothiophene, 3,4-Dihydro-2H-1,4-oxazine, 3,4-Dihydro-2H-1,4-thiazine 1,1-dioxide, 1,2,3,4-Tetrahydropyrazine, 1,3-Dihydro-2H-pyrrole-2- Ketones, 1,5-dihydro-2H-pyrrole-2-one, 1H-pyrrole-2,5-dione, furan-2(3H)-one, furan-2(5H)-one, 1,3-dioxacyclopenten-2-one, oxazol-2(3H)-one, 1,3-dihydro-2H-imidazol-2-one, furan-2,5-dione, 3,6-dihydropyridin-2(1H)-one, pyridin-2,6-(1H,3H)-dione, 5,6-dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran-2-one, 3,4-dihydro-2H-1,3-oxazine, 3,6-dihydro-2H-1,3-oxazine, 1,2,3,4-tetrahydropyrimidine, etc. The heterocyclic group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably one or more RS group groups.

[0664] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring. The aryl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably one or more RS group groups.

[0665] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyridoneyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0666] In this invention, the 5- to 10-membered heteroaryl group can be a monocyclic heteroaryl (e.g., a 5- or 6-membered monocyclic heteroaryl), a fused bicyclic heteroaryl (e.g., an 8- to 10-membered bicyclic heteroaryl), or a fused tricyclic heteroaryl. The term "5- or 6-membered monocyclic heteroaryl" refers to a group having 5 or 6 ring atoms, wherein 1, 2, or 3 ring atoms are selected from nitrogen, oxygen, or S (=O). m Monocyclic heteroaryl groups with heteroatoms (where m' is an integer from 0 to 2). Specific examples of monocyclic heteroaryl groups include, but are not limited to, thiophene, furan, thiazole, isothiazole, imidazole, oxazole, pyrrole, pyrazole, triazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,5-triazole, 1,3,4-triazole, tetrazolium, isoxazole, oxadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, etc.

[0667] The term "8- to 10-membered bicyclic heteroaryl" refers to a compound with 8 to 10 ring atoms, of which 1, 2, 3, 4, or 5 ring atoms are selected from nitrogen, oxygen, or S (=O). mThe fused bicyclic heteroaryl group is a heteroatom of '(m' is an integer from 0 to 2). The fused bicyclic heteroaryl group can be a bicyclic group (preferably a 9- or 10-membered bicyclic heteroaryl ring) formed by fusion of a monoaryl ring (such as phenyl) and a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring), or a bicyclic group formed by fusion of a monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring) and another monocyclic heteroaryl ring (preferably a 5- or 6-membered monocyclic heteroaryl ring).

[0668] Any two ring atoms attached to the aforementioned monocyclic heteroaryl ring, including CC, NC, and NN, can be fused with cycloalkyl, heterocyclic, aryl, or heteroaryl groups, such as monocyclic cycloalkyl rings, monocyclic heterocyclic rings, monoaryl rings, and 5- or 6-membered monocyclic heteroaryl rings, as defined in this invention, to form fused polycyclic rings. The two ring atoms attached to the monocyclic heteroaryl ring forming the fused ring with other rings are preferably CC, and non-limitingly include the following forms:

[0669] The above groups are passed through The marked ring atoms are connected to other parts of the molecule.

[0670] Non-limiting examples of 8- to 10-membered bicyclic heteroaryl groups include: benzo[d]isoxazole, 1H-indole, isoindole, 1H-benzo[d]imidazol, benzo[d]isothiazol, 1H-benzo[d][1,2,3]triazole, benzo[d]oxazole, benzo[d]thiazol, indazole, benzofuran, benzo[b]thiophene, quinoline, isoquinoline, quinazoline, quinoxaline, cyclophosphine, pyrido[3,2-d]pyrimidine, pyrido[2,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[4,3-d]pyrimidine, 1,8-naphthoidine, 1,7-naphthoidine, 1,6-naphthoidine, 1,5-naphthoidine, pyrazolo[1,5-a]pyrimidine, imidazo[1,2-b]pyridazine, etc.

[0671] Specific examples of bicyclic heteroaryl groups include, but are not limited to: These groups can be attached to the rest of the molecule via any suitable ring atom. The ring attached to the parent structure can be a monocyclic heteroaryl ring or a benzene ring.

[0672] The term "subspirocyclic group" refers to the free radical formed by losing a hydrogen atom from a "spirocyclic group". A "spirocyclic group" refers to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing a single carbon atom (called a spiro atom). Based on the number of shared spiro atoms between rings, spirocyclic groups are classified into monospirocyclic, bispirocyclic, and polyspirocyclic groups. The terms "5- to 20-membered spirocyclic group" or "C..." 5-20"Spirocyclic group" refers to a polycyclic hydrocarbon group having 5 to 20 ring carbon atoms, wherein the monocyclic ring sharing the spiro atom is a 3- to 8-membered monocyclic ring. Specific examples of spirocyclic groups include, but are not limited to: These spiroheterocyclic groups can be attached to the rest of the molecule via any suitable ring atom. The heteroaryl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more RS group groups.

[0673] Each RS group is independently selected from hydrogen, deuterium, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups each time it appears.

[0674] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0675] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0676] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0677] The term "amino" refers to -NH2.

[0678] The term "cyano" refers to -CN.

[0679] The term "covalent bond" includes single, double, and triple bonds, with single bonds being preferred. In this text, the wavy line on a group, regardless of its form, indicates a connection to other parts of the molecule. If no wavy line is marked on a group, it means that any position within that group could potentially connect to other positions in the molecule.

[0680] Unless otherwise defined, when a group described in this invention is substituted by a substituent, it means that all identical groups appearing in this invention can be substituted by the substituent. This means that the group can be substituted whether it exists alone or in combination with other groups. For example, R is -C. 1-6 Alkyl, C 6-10 Aryl, C 3-6 Monocyclic cycloalkyl, -C(O)C 1-6 Alkyl, -C 1-4 Alkyl-C 6-10 Aryl or -S(O)2-C 3-6 Monocyclic cycloalkyl, wherein the C 1-6 Alkyl, C 6-10 Aryl, C 3-6 The monocyclic cycloalkyl group is optionally substituted, and the description also includes -C(O)C 1-6Alkyl, -C 1-4 Alkyl-C 6-10 Aryl and -S(O)2-C 3-6 C in monocyclic cycloalkyl 1-6 Alkyl, C 6-10 Aryl and C 3-6 The monocyclic cycloalkyl group may optionally be substituted.

[0681] Unless otherwise defined, the phrase "...same or different" in this invention means that when there are more than one identical substituent group in the general formula, the substituent group can be the same or different.

[0682] Unless otherwise defined, the phrase "substituents selected independently of each other" in this invention means that when one or more hydrogen atoms on a group are replaced by substituents, the types of substituents may be the same or different, and the selected substituents are of independent types.

[0683] The present invention refers to compounds of formula (I), and also includes their tautomers, stereoisomers, mixtures of stereoisomers, solvates or derivatives, etc.

[0684] In It refers to the point where chemical bonds are joined. Including possible Configuration, as long as it is chemically permissible.

[0685] When the ring appears Furthermore, if the connection location is uncertain, it indicates that the connection site is located at... Any atom on the monocyclic ring, as long as its valence allows.

[0686] The terms “optional” or “optionally” mean that the event or situation described below may, but does not have to, occur, and the description includes the circumstances in which the event or situation occurs or does not occur. For example, “optionally substituted cyclopropyl” means that the cyclopropyl group may, but does not have to, be substituted, and the description includes both cases where the cyclopropyl group is substituted and cases where the cyclopropyl group is not substituted.

[0687] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions without much effort (through experiment or theory). When any variable (e.g., R...) 1 When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is surrounded by 0-2 R... 1 If replaced, the group may optionally be replaced by at most two R groups.1 Replaced, and R in each case 1 Each has its own independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce stable compounds.

[0688] The term "leaving group" should mean a charged or uncharged atom or group that detaches during a substitution or replacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, methanesulfonates, toluenesulfonates, trifluoromethanesulfonates, etc.

[0689] The "compounds" of this invention also include tautomer forms. A tautomer form arises from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton. The terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature that can rapidly interconvert. It refers to one of two or more structural isomers that exist in equilibrium and readily transform from one isomer form to another. This transformation results in the formal migration of a hydrogen atom, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer groups in solution. In solutions where tautomerization is possible, chemical equilibrium of the tautomers will be reached. The exact proportions of the tautomers depend on several factors, including temperature, solvent, and pH conditions. The concept of tautomers that can interconvert through tautomerization is called tautomerism.

[0690] When this specification describes compounds that are readily tautomerizable, but only one of the tautomers is described, it should be understood that all tautomers are included as part of the chemical meaning described. It should be understood that the compounds disclosed herein can be described as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included, and the naming of the compound does not exclude any tautomeric form.

[0691] The term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. The compounds containing asymmetric carbon atoms of the present invention can be isolated in optically active pure form or in the form of a mixture of two or more isomers. The optically active pure form can be resolved from a mixture of two or more isomers, or synthesized using chiral starting materials or chiral reagents.

[0692] Depending on their structure, the compounds of the present invention can exist in different stereoisomeric forms. These forms include configurational isomers or optical conformational isomers (enantiomers and / or diastereomers, including those with inhibited transisomers). Therefore, the present invention includes enantiomers, diastereomers, and mixtures thereof. Pure stereoisomers can be isolated from those mixtures of enantiomers and / or diastereomers using methods known in the art, preferably chromatography, especially high-performance liquid chromatography (HPLC) using achiral or chiral phases. The present invention further includes all mixtures of the above-described stereoisomers, regardless of proportions, including racemic mixtures.

[0693] According to their structure, the compounds of the present invention can exist in various stable isotopic forms. These forms include those in which one or more hydrogen atoms are replaced by deuterium atoms, those in which one or more nitrogen atoms are replaced by 15N atoms, or those in which one or more carbon, fluorine, chlorine, bromine, sulfur, or oxygen are replaced by stable isotopes of their respective original atoms.

[0694] Unless otherwise stated, the structures described herein are also intended to include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or configurational isomers) of the structures; for example, R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E configurational isomers. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or configurational isomers), are within the scope of the present invention. Unless otherwise stated, all tautomers of the compounds of the present invention are within the scope of the present invention. Furthermore, unless otherwise stated, the structures described herein are also intended to include compounds differing only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention (including hydrogen replaced by deuterium or tritium, or carbon replaced by 13C or 14C enriched carbon) are within the scope of the present invention. Such compounds can be used, for example, as analytical tools, probes in bioanalysis, or therapeutic agents according to the present invention.

[0695] The term "solvent" as used in this invention refers to a complex formed by the compounds of this invention with a solvent. These complexes either react in the solvent or precipitate or crystallize from the solvent. For example, a complex formed with water is called a "hydrate". Solvents of the compounds represented by formula (I) of this invention are within the scope of this invention.

[0696] This invention includes prodrugs of the above-mentioned compounds. The prodrugs include known amino and carboxyl protecting groups, and are released from the parent compound by hydrolysis under physiological conditions or via an enzymatic reaction. Specific methods for preparing the prodrugs can be found in (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DMB Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).

[0697] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting those proteins for degradation. For example, cerebellar proteins are E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-binding enzymes, that cause ubiquitin to attach to a lysine residue on a target protein and subsequently target a specific protein substrate for degradation via the proteasome. Therefore, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin-binding enzymes, are the cause of ubiquitin transfer to the target protein. Generally, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin, a third ubiquitin to a second ubiquitin, and so on. Polyubiquitinated proteins are used for degradation via the proteasome. However, there are some ubiquitination events limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule via a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but may instead be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Complicating matters further, different lysine residues on ubiquitin can be targeted by E3 to prepare chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to prepare polyubiquitin, and it is recognized by the proteasome.

[0698] The term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of this disclosure with an acid or base that is suitable for use as a medicine, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0699] The term "therapeutic effective amount" refers to the amount of the compound of the present invention that will elicit a biological or medical response in an individual, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing or delaying disease progression, or preventing disease.

[0700] The term "pharmaceutically acceptable carrier" refers to a non-toxic, inert, solid, semi-solid substance or liquid filling agent, diluent, encapsulation material or excipient or any type of excipient that is compatible with patients, preferably mammals, more preferably humans, and is suitable for delivering an active agent to a target site without terminating the activity of the agent.

[0701] As used in this article, "patient" or "subject" refers to an animal, preferably a mammal, and more preferably a human. The term "mammal" refers to warm-blooded vertebrate mammals, including animals such as cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, rats, pigs, and humans.

[0702] As used in this article, the term "disease" is a state of health in an animal in which the animal is unable to maintain homeostasis and the animal's health continues to deteriorate if the disease does not improve.

[0703] As used herein, “treatment” means to reduce, slow the progression of, attenuate, prevent, or maintain an existing disease or condition (e.g., cancer). Treatment also includes curing, preventing the development of, or reducing to some extent one or more symptoms of a disease or condition. As used herein, the term “treatment” or “treatment” is defined as the administration or application of a therapeutic agent, namely a compound of this disclosure (alone or in combination with another pharmaceutical agent), or the administration or application of a therapeutic agent to an isolated tissue or cell from a patient who suffers from a disease or condition considered herein, a sign or symptom of a disease or condition considered herein, or has the potential to develop a disease or condition considered herein, with the aim of curing, resolving, alleviating, reducing, altering, remedying, improving, ameliorating, or influencing the disease or condition considered herein, a sign or symptom of a disease or condition considered herein, or the possibility of developing a disease or condition considered herein. Such treatments can be specifically tailored or modified based on knowledge obtained from the field of pharmacogenomics. As used herein, the term “treatment” for a disease refers to reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a subject.

[0704] II. Examples

[0705] The following examples pertain to the intermediate compounds and final products identified in the specification and synthetic regimens. The preparation of the compounds of the present invention is described in detail using the following examples, but the described chemical reactions are disclosed in accordance with their general applicability to the preparation of the compounds of the present invention. Sometimes, the reactions may not be applicable to every compound within the scope of the present invention as described. Compounds in which this may occur are readily identifiable to those skilled in the art. In these cases, the reactions can be successfully carried out with conventional modifications known to those skilled in the art. In all preparation methods, all starting materials are known or can be readily prepared using known starting materials.

[0706] The starting materials, chemical reagents, and solvents used in this invention are all commercially available and were purchased from companies such as Anaiji Chemical, Shanghai Bide Pharmaceutical, Beijing Innocare, Jiangsu Aikon, and Sinopharm Group.

[0707] The structures of all compounds synthesized in this invention were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0708] Nuclear magnetic resonance (NMR) measurements were performed using a Bruke AVANCE-400 / 600 NMR spectrometer. The deuterated solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0709] Mass spectrometry (MS) measurements were performed using Waters Acquity Plus device implementation.

[0710] High-performance liquid chromatography (HPLC) preparation was carried out using a Waters 2489 system.

[0711] The medium-pressure rapid preparative chromatograph is a COMBIFLASH NEXTGEN 300+.

[0712] The thin-layer chromatography silica gel plates used are Silica gel 60 thin-layer chromatography silica gel plates (aluminum plates, containing fluorescence).

[0713] The silica gel (100-200 mesh, 200-300 mesh) used in the silica gel column chromatography was purchased from Inokai.

[0714] The reaction process in the examples was detected using thin-layer chromatography (TLC). The systems used to monitor the developing solvent and the eluent used to purify the compounds by column chromatography included: petroleum ether / ethyl acetate system and dichloromethane / methanol system.

[0715] Preparation Example

[0716] I. Synthesis of PTM intermediates

[0717] 1) Synthesis of intermediate A-1

[0718] Step 1: tert-butyl (4-bromopyridin-2-yl)carbamate (intermediate A-1a)

[0719] To a solution of 2-amino-4-bromopyridine (10 g, 57.8 mmol) in 100 mL of dichloromethane, di-tert-butyl dicarbonate (13.25 g, 60.7 mmol), 4-dimethylaminopyridine (706.1 mg, 5.78 mmol), and triethylamine (17.55 g, 173.40 mmol) were added, and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, the solvent was evaporated, and the solution was purified by column chromatography to give a white solid intermediate A-1a (10.9 g, 69.05%).

[0720] 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),8.14(d,J=5.4Hz,1H),8.04(d,J=1.7Hz,1H),7.27(dd,J=5.3,1.8Hz,1H),1.47(s,9H).

[0721] LC-MS(ESI):[M+H- t Bu] + =217.15.

[0722] Step 2: Tert-butyl(4-bromopyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (intermediate A-1b)

[0723] To a solution of intermediate A-1a (4.43 g, 16.22 mmol) in N,N-dimethylformamide (50 mL), 2,2,2-trifluoroethyltrifluoromethanesulfonate (4.52 g, 19.46 mmol) and cesium carbonate (10.57 g, 32.44 mmol) were added, and the mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was quenched with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated solution was then subjected to column chromatography to give intermediate A-1b (4.22 g, 73.26%), a pale yellow oily liquid.

[0724] 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=5.3Hz,1H),7.93(d,J=1.6Hz,1H),7.50(dd,J=5.4,1.7Hz,1H),4.81(q,J=9.1Hz,2H),1.47(s,9H).

[0725] LC-MS(ESI):[M+H- t Bu] + =301.08.

[0726] Step 3: 2-(2-(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxylic acid ester (intermediate A-1c)

[0727] Under a nitrogen atmosphere, ethyl 4-oxazolamide (953.67 mg, 6.76 mmol), tris(o-methylphenyl)phosphine (342.81 mg, 1.13 mmol), palladium acetate (126.43 mg, 0.564 mmol), and cesium carbonate (3.67 g, 11.26 mmol) were added to a 20 mL solution of intermediate A-1b (2.0 g, 5.63 mmol) in N,N-dimethylformamide. The mixture was then heated to 80 °C and reacted overnight. After the reaction was complete, the reaction solution was quenched with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration followed by column chromatography yielded a pale yellow oily liquid intermediate A-1c (1.90 g, 81.23%).

[0728] 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 8.60 (d, J = 5.2Hz, 1H), 8.28 (t, J = 1.1Hz, 1H), 7.75 (dd, J = 5 .1,1.4Hz,1H),4.89(q,J=9.0Hz,2H),4.33(q,J=7.1Hz,2H),1.50(s,9H),1.32(t,J=7.1Hz,3H).

[0729] LC-MS(ESI):[M+H- t Bu] + =360.39.

[0730] Step 4: 2-(2-(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazol-4-carboxylic acid (intermediate A-1)

[0731] Sodium hydroxide (433 mg, 10.83 mmol) was added to a 10 mL (5 / 1) methanol-water mixture of intermediate A-1c (900 mg, 2.17 mmol) and reacted at 60 °C for 1 hour. After the reaction was complete, the solvent was evaporated, and the pH was adjusted to 2-3 with 1 N HCl. A pale yellow solid precipitated out. The precipitate was filtered to obtain the pale yellow solid intermediate A-1, which was used directly in the next reaction.

[0732] 1 H NMR (400MHz, DMSO-d6) δ9.00(s,1H),8.60(dd,J=5.2,0.8Hz,1H),8.27(t,J=1.1Hz,1H),7.74(dd,J=5.2,1.4Hz,1H),4.89(q,J=9.1Hz,2H),1.50(s,9H).

[0733] LC-MS(ESI):[M+H- t Bu] + =332.29.

[0734] 2) Synthesis of intermediate A-4

[0735] Step 1: 4-Bromo-N,N-dimethylpyridin-2-amine (Intermediate A-4a)

[0736] 4-Bromopyridin-2-amine (2 g, 11.56 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and sodium hydride (1.39 g, 34.68 mmol) was added. After stirring for 0.5 hours, iodomethane (3.61 g, 25.43 mmol) was added, and the reaction was carried out overnight at 25 °C. After the reaction was completed, the solvent was evaporated, and the product was purified by column chromatography to give a yellow oily intermediate A-4a (2.0 g, 86.05%).

[0737] 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=5.3Hz,1H),6.80(d,J=1.6Hz,1H),6.73(dd,J=5.3,1.6Hz,1H),3.00(s,6H).

[0738] LC-MS(ESI):[M+H] + =201.25.

[0739] Step 2: Ethyl 2-(2-(dimethylamino)pyridin-4-yl)oxazol-4-carboxylate (intermediate A-4b)

[0740] To a solution of 20 mL of 4-bromo-N,N-dimethylpyridin-2-amine (2.0 g, 9.95 mmol) in DMF, Pd(dppf)Cl2 (727.83 mg, 0.995 mmol), cesium carbonate (6.48 g, 19.89 mmol), and ethyl 4-oxazolyl carboxylate (1.68 g, 11.94 mmol) were added sequentially, and the reaction was carried out at 60 °C for 12 hours. After the reaction was completed, the solvent was evaporated, and the solution was purified by column chromatography to obtain a yellow oily intermediate A-4b (1.6 g, 61.56%).

[0741] 1 H NMR(400MHz, DMSO-d6)δ8.94(d,J=1.7Hz,1H),8.25–8.18(m,1H),7.07–7.02( m,1H),7.03–6.98(m,1H),4.34–4.28(m,2H),3.07(s,6H),1.34–1.28(m,3H).

[0742] LC-MS(ESI):[M+H] + =262.57.

[0743] Step 3: 2-(2-(dimethylamino)pyridin-4-yl)oxazol-4-carboxylic acid (intermediate A-4)

[0744] Sodium hydroxide (918.48 mg, 22.96 mmol) was added to a solution of ethyl 2-(2-(dimethylamino)pyridin-4-yl)oxazol-4-carboxylate (2.0 g, 7.65 mmol) in methanol:tetrahydrofuran:water = 1:1:1 (18 mL), and the mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 4–5 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrate was then used to give a white solid intermediate A-4 (1.5 g, 84.02%).

[0745] 1 H NMR (400MHz, DMSO-d6) δ11.9(br,1H),9.04(s,1H),8.19(d,J=6.2Hz,1H),7.42(s,1H),7.26(dd,J=6.2,1.3Hz,1H),3.24(s,6H).

[0746] LC-MS(ESI):[M+H] + =234.32.

[0747] 3) Synthesis of intermediate A-6

[0748] Step 1: Methyl 2-(2-methylpyridin-4-yl)-2H-1,2,3-triazole-4-carboxylic acid ester (intermediate A-6a)

[0749] 4-Fluoro-2-methylpyridine (0.50 g, 4.50 mmol) was dissolved in DMSO (5 mL), and methyl 2H-1,2,3-triazol-4-carboxylate (857.9 mg, 6.75 mmol) was added. The mixture was reacted overnight at 120 °C. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, filtered and concentrated, and purified by column chromatography (EA:PE = 0-50%) to obtain a yellow solid intermediate A-6a (394.2 mg, 40%).

[0750] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.66(d,J=5.5Hz,1H),7.94(d,J=2.0Hz,1H),7.85(dd,J=5.5,1.8Hz,1H),3.93(s,3H),2.60(s,3H).

[0751] LC-MS(ESI):[M+H] + =219.26.

[0752] Step 2: 2-(2-methylpyridin-4-yl)-2H-1,2,3-triazole-4-carboxylic acid (intermediate A-6)

[0753] Sodium hydroxide (73.3 mg, 1.83 mmol) was added to a methanol:water solution (0.1 g, 0.458 mmol) in a methanol:water ratio of 5:1 (6 mL), and the mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 4–5 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrate was then used to obtain a white solid intermediate A-6 (80.0 mg, 85.5%).

[0754] LC-MS(ESI):[M+H] + =205.25.

[0755] 4) Synthesis of intermediate A-12

[0756] Step 1: 1-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (intermediate A-12)

[0757] tert-butyl(4-bromopyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (1.0 g, 2.82 mmol, 1.0 eq) was dissolved in DMF (10 mL), followed by the addition of methyl 1H-pyrazole-3-carboxylic acid ester (532.65 mg, 4.22 mmol, 1.5 eq) and cesium carbonate (4.59 g, 14.08 mmol, 5.0 eq). The mixture was then subjected to nitrogen purging and the temperature was raised to 90 °C for 12 hours. After the reaction was complete, the mixture was quenched with water, extracted three times with EA, and the organic phase was washed three times with saturated brine. The organic phase was concentrated and purified by normal phase chromatography (EA:PE = 0-60%) to obtain hydrolysis product A-12 (505 mg, 46.42%).

[0758] LC-MS(ESI):[M+H] + =287.19.

[0759] 5) Synthesis of intermediate A-13

[0760] Step 1: Ethyl 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)thiazolyl-4-carboxylate (Intermediate A-13a)

[0761] To a DMF (22 mL) solution of intermediate A-1a (2.26 g, 6.36 mmol), ethyl thiazole-4-carboxylate (1.2 g, 7.64 mmol), tris(o-methylphenyl)phosphine (387.4 mg, 1.27 mmol), palladium acetate (143.9 mg, 0.636 mmol), and cesium carbonate (4.15 g, 12.73 mmol) were added, and the mixture was reacted overnight at 80 °C under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, concentrated by filtration, and purified by column chromatography (EA:PE = 0-25%) to obtain a white solid intermediate A-13a (1.67 g, 64%).

[0762] 1 H NMR(400MHz, DMSO-d6)δ8.74(s,1H),8.56(dd,J=5.2,0.8Hz,1H),8.24–8.21(m,1H),7.76(dd,J= 5.2,1.6Hz,1H),4.88(q,J=9.1Hz,2H),4.35(q,J=7.1Hz,2H),1.51(s,9H),1.33(t,J=7.1Hz,3H).

[0763] LC-MS(ESI):[M+H- t Bu] + =376.29.

[0764] Step 2: 2-(2-(tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)thiazolyl-4-carboxylic acid (intermediate A-13)

[0765] Sodium hydroxide (769.5 g, 19.24 mmol) was added to a tetrahydrofuran:water solution (4:1, 15 mL) of intermediate A-13a (1.66 g, 3.85 mmol), and the reaction was carried out at 60 °C for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 with 2N hydrochloric acid, extracted three times with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, a white solid intermediate A-13b (1.88 g, 100%) was obtained.

[0766] LC-MS(ESI):[M+H- t Bu] + =348.19.

[0767] 6) Synthesis of intermediate B-6

[0768] Step 1: 5-((2R,5R)-2,5-dimethylmorpholino)pyrazoline[1,5-a]pyrimidine-3-carboxylic acid ester (intermediate B-6a)

[0769] Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.00 g, 4.43 mmol) was dissolved in ACN (10 mL), and 2R,5R-dimethylmorpholine hydrochloride (1.01 g, 6.65 mmol) and N,N-diisopropylethylamine (2.86 g, 22.16 mmol) were added. The reaction was carried out overnight at 60 °C. After the reaction was completed, the solution was concentrated and purified by column chromatography (MeOH:DCM = 0-3%) to give a white solid intermediate B-6a (1.50 g, 100%).

[0770] 1 H NMR(400MHz,DMSO-d6)δ8.75(d,J=7.9Hz,1H),8.21(s,1H),6.83(d,J=7.9Hz,1H),4 .73(d,J=125.9Hz,1H),4.18(qd,J=7.1,2.2Hz,2H),3.76(dd,J=11.6,1.1Hz,1H),3. 67(dd,J=11.6,3.2Hz,1H),3.53(dqd,J=12.2,6.0,2.7Hz,1H),3.35–3.32(m,1H),3. 30–2.62(m,1H),1.28(t,J=7.1Hz,3H),1.21(d,J=6.8Hz,3H),1.19(d,J=6.1Hz,3H).

[0771] LC-MS(ESI):[M+H] + =305.38.

[0772] Step 2: 5-((2R,5R)-2,5-dimethylmorpholine)pyrazoline[1,5-a]pyrimidine-3-carboxylic acid (intermediate B-6)

[0773] Sodium hydroxide (735.9 mg, 18.40 mmol) was added to a methanol:water solution (4:1, 15 mL) of intermediate B-6a (1.40 g, 4.60 mmol), and the reaction was carried out at 60 °C for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 3-4 with 2N hydrochloric acid, and the solution was concentrated to obtain a white solid intermediate B-6 (1.24 g, 97%).

[0774] LC-MS(ESI):[M+H] + =277.25.

[0775] 7) Synthesis of intermediate B-7

[0776] Step 1: Ethyl 5-((2S,5S)-2,5-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (intermediate B-7a)

[0777] Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.31 g, 5.81 mmol) was dissolved in 13 mL of ACN, and (2S,5S)-2,5-dimethylmorpholine hydrochloride (1 g, 8.71 mmol) was added. The reaction was carried out overnight at 60 °C. After the reaction was completed, the product was purified by column chromatography (EA:PE = 0-50%) to give a yellow solid intermediate B-7a (1.8 g, 101.87%).

[0778] LC-MS(ESI):[M+H] + =305.38.

[0779] Step 2: 5-((2S,5S)-2,5-dimethylmorpholino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (intermediate B-7)

[0780] Sodium hydroxide (709.65 mg, 17.74 mmol) was added to a methanol:water solution (1.8 g, 5.91 mmol) in a methanol:water ratio of 5:1 (10 mL), and the mixture was reacted at 60 °C for 1 hour. After the reaction was complete, the pH of the reaction solution was adjusted to 4-5 with 2N hydrochloric acid, and the solution was concentrated to obtain a white solid intermediate B-7 (1.63 g, 100%).

[0781] LC-MS(ESI):[M+H] + =277.27.

[0782] 8) Synthesis of intermediate C-1

[0783] Step 1: Ethyl pyridinecarboxylate 6-(1-methyl-1H-pyrazole-3-yl)pyridinecarboxylate (intermediate C-1a)

[0784] 1-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole (2.0 g, 9.61 mmol) and ethyl 6-bromopyridinecarboxylate (2.21 g, 9.61 mmol) were dissolved in Dioxane / H₂O (10 v / 1 v, 20 mL), and Pd(dppf)Cl₂ (784.91 mg, 0.961 mmol) and K₂CO₃ (3.99 g, 28.84 mmol) were added. The reaction mixture was reacted overnight at 90 °C. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, filtered and concentrated, and purified by column chromatography (MeOH:DCM = 0-10%) to obtain a yellow solid intermediate C-1a (1.94 g, 87.27%).

[0785] 1 H NMR(400MHz, DMSO-d6)δ8.11(dd,J=7.9,1.2Hz,1H),8.03–7.97(m,1H),7.93(dd,J=7.7,1.3Hz,1H), 7.81(d,J=2.2Hz,1H),6.83(d,J=2.2Hz,1H),4.37(q,J=7.1Hz,2H),3.94(s,3H),1.39–1.32(m,3H).

[0786] LC-MS(ESI):[M+H] + =232.46.

[0787] Step 2: 6-(1-methyl-1H-pyrazol-3-yl)pyridinecarboxylic acid (intermediate C-1)

[0788] Sodium hydroxide (1.61 g, 40.22 mmol) was added to a methanol:water solution (5:1, 20 mL) of intermediate C-1a (1.55 g, 6.70 mmol), and the reaction was carried out at 60 °C for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 4–5 with 2N hydrochloric acid, extracted three times with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrate yielded a yellow oily intermediate C-1 (1.2 g, 88.11%).

[0789] 1 H NMR (400MHz, DMSO-d6) δ13.11(s,1H),8.10(dd,J=7.7,1.3Hz,1H),7.99(t,J=7.7Hz,1H) ,7.93(dd,J=7.7,1.3Hz,1H),7.81(d,J=2.2Hz,1H),6.94(d,J=2.2Hz,1H),3.93(s,3H).

[0790] LC-MS(ESI):[M+H] + =204.35.

[0791] 9) Synthesis of intermediates D-7 and D-8

[0792] Step 1: Tert-butyl 3-iodo-1-oxa-8-azaepoxy[4.5]decane-8-carboxylic acid ester (intermediate D-7a)

[0793] N-tert-butoxycarbonyl-1-oxa-8-azaspiro[4.5]decane-3-ol (3 g, 11.66 mmol) was dissolved in toluene (30 mL). Imidazole (1.59 g, 23.32 mmol), triphenylphosphine (4.59 g, 17.49 mmol), and iodine (4.44 g, 17.49 mmol) were slowly added under ice bath conditions. The reaction was first carried out at room temperature for 1 hour, and then at 60 °C for 1 hour. After the reaction was completed, the reaction solution was diluted with water, extracted three times with EA, and concentrated by filtration to obtain a yellow oily intermediate D-7a (4.28 g, 100%), which was used directly in the next step without purification.

[0794] Step 2: Tert-butyl 3-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-1-oxa-8-aza[4.5]decane-8-carboxylic acid ester (intermediate D-7b)

[0795] Intermediate D-7a (4.05 g, 11.04 mmol) and potassium carbonate (5.08 g, 36.79 mmol) were added to a solution of 3-(difluoromethyl)-4-nitro-1H-pyrazole (1.20 g, 7.36 mmol) in DMSO (12 mL), and the mixture was reacted overnight at 120 °C. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, concentrated by filtration, and purified by column chromatography (EA:PE = 0-40%) to obtain a yellow oily intermediate D-7b (878 mg, 29.6%).

[0796] 1 H NMR(400MHz, DMSO-d6)δ9.09(d,J=1.1Hz,1H),7.32(t,J=52.9Hz,1H),5.24–5.15(m,1H),4.18–4.12(m,1H),4.10–4.06(m,1H),3.51–3.42( m,2H),3.27–3.16(m,2H),2.38(dd,J=13.6,8.3Hz,1H),2.27(dd,J=13.6,5.4Hz,1H),1.65–1.60(m,2H),1.40(d,J=5.6Hz,2H),1.39(s,9H).

[0797] LC-MS(ESI):[M+H-Boc] + =303.28.

[0798] Step 3: Tert-butyl(S)-3-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate and tert-butyl(R)-3-(3-(difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (intermediates D-7b-P1 and D-7b-P2)

[0799] D-7b is split using SFC to obtain intermediates D-7b-P1 and D-7b-P2.

[0800] Step 4: Tert-butyl(S)-3-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)-1-oxa-8-aza[4.5]decane-8-carboxylic acid ester (intermediate D-7)

[0801] Pd / C (50 mg) was added to 5 mL of an EA solution of intermediate D-7b-P1 (190 mg, 0.472 mmol), and the reaction was carried out overnight at room temperature under a hydrogen atmosphere. After the reaction was completed, the solution was filtered and concentrated to obtain a pale yellow solid intermediate D-7 (198 mg, 100%).

[0802] 1 H NMR(600MHz, DMSO-d6)δ7.19(s,1H),6.88(td,J=54.1,1.8Hz,1H),4.91(t,J=7.0Hz ,1H),4.11(s,2H),4.08–4.04(m,1H),3.91(dd,J=9.4,5.0Hz,1H),3.44(dt,J=13.8 ,4.7Hz,2H),2.28(dd,J=13.3,8.5Hz,1H),2.08(dd,J=13.3,5.8Hz,1H),1.59(ddt, J=22.2,9.3,4.1Hz,3H),1.50(ddd,J=13.3,9.5,4.1Hz,1H),1.39(d,J=1.9Hz,9H).

[0803] LC-MS(ESI):[M+H- t Bu] + =317.28.

[0804] tert-Butyl(R)-3-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)-1-oxa-8-azaspirol[4.5]decane-8-carboxylic acid ester (intermediate D-8)

[0805] Pd / C (50 mg) was added to 5 mL of an EA solution of intermediate D-7b-P2 (200 mg, 0.497 mmol), and the reaction was carried out overnight at room temperature under a hydrogen atmosphere. After the reaction was completed, the solution was filtered and concentrated to give a pale yellow solid intermediate D-8 (233 mg, 100%).

[0806] 1 H NMR (600MHz, DMSO-d6) δ7.19 (s, 1H), 6.89 (t, J = 54.1Hz, 1H), 4.91 (q, J = 6.5, 6.0Hz,1H),4.12(s,2H),4.06(dd,J=9.5,6.5Hz,1H),3.91(dd,J=9.5,5.1Hz ,1H),3.44(dt,J=13.7,4.8Hz,2H),2.28(dd,J=13.3,8.4Hz,1H),2.11–2.06 (m,1H),1.65–1.55(m,3H),1.50(ddd,J=13.4,9.5,4.2Hz,1H),1.39(s,9H).

[0807] LC-MS(ESI):[M+H- t Bu] + =317.28.

[0808] 10) Synthesis of intermediate E-5

[0809] Step 1: ((1r,4r)-4-(6-amino-5-isopropoxybenzo[d]thiazolyl-2-yl)cyclohexyl)methanol (intermediate E-5)

[0810] Intermediate E-4 (300 mg, 0.86 mmol) was dissolved in THF (3 mL), and LiAlH4 (3.01 mL, 1 M, 3.01 mmol) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was quenched with water, extracted three times with DCM, and concentrated by filtration to obtain a yellow oily intermediate E-6 (326 mg, 100%).

[0811] LC-MS(ESI):[M+H] + =321.38.

[0812] 11) Synthesis of intermediate E-10

[0813] Step 1: tert-butyl-4-(2,4-difluorobenzyl)-4-hydroxypiperidine-1-carboxylate (intermediate E-10a)

[0814] Magnesium (609.91 mg, 25.09 mmol, 1.0 eq) was added to a three-necked flask, purged with nitrogen, and then ether (30 mL) and iodine (127.38 mg, 501.88 μmol, 0.02 eq) were added. The mixture was heated to 35 °C, and 1-(bromomethyl)-2,4-difluorobenzene (5.0 g, 25.09 mmol, 1.0 eq) was added. After reacting for two hours, the reaction solution was slowly added dropwise at -75 °C to a solution of 4-oxopiperidinium-1-carboxylate tert-butyl ester (7.79 g, 37.64 mmol, 1.5 eq) in ether (30 mL). The reaction was allowed to proceed for 1 hour. The mixture was then quenched with water, extracted with EA, concentrated with silica gel, and purified by column chromatography (EA:PE = 0-30%) to obtain a yellow oily liquid intermediate E-10a (4.8 g, 58.43%).

[0815] 1 H NMR(400MHz,DMSO-d6)δ7.39–7.29(m,1H),7.18–7.08(m,1H),7.04–6.94(m,1H),4 .49(s,1H),3.65(d,J=10.7Hz,2H),3.00(s,2H),2.68(s,2H),1.45–1.28(m,13H).

[0816] LC-MS(ESI):[M+H] + =327.37.

[0817] Step 2: tert-butyl-6-fluoro-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (intermediate E-10b)

[0818] Potassium tert-butoxide (1.59 g, 14.20 mmol, 2.5 eq) was added to a solution of intermediate E-10a (1.86 g, 5.68 mmol, 1.0 eq) in tetrahydrofuran (20 mL), and the mixture was reacted at 65 °C for 3 hours. After the reaction was complete, the solvent was evaporated, and the mixture was purified by column chromatography (EA:PE = 0-30%) to obtain a yellow oily intermediate E-10b (970 mg, 55.55%).

[0819] LC-MS(ESI):[M+H] + =307.37.

[0820] Step 3: 6-Fluoro-3H-spiro[benzofuran-2,4'-piperidine] (intermediate E-10c)

[0821] Intermediate E-10b (900 mg, 1.0 eq) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (5 mL). The mixture was reacted at room temperature for 2 hours. After the reaction was complete, the solvent was evaporated, and the mixture was purified by column chromatography (EA:PE = 0-30%) to obtain a yellow oily intermediate E-10c (348 mg, 57.35%).

[0822] 1 H NMR (400MHz, DMSO-d6) δ7.18(dd,J=8.0,6.1Hz,1H),6.74–6.56(m,2H),5.25(s,1H),3.10–2.88(m,6H),1.85(tdt,J=13.4,8.3,4.6Hz,4H).

[0823] LC-MS(ESI):[M+H] + =207.11.

[0824] Step 4: 6-Fluoro-5-nitro-3H-spiro[benzofuran-2,4'-piperidine] (Intermediate E-10d)

[0825] Intermediate E-10c (348 mg, 1.68 mmol, 1.0 eq) was added to dichloromethane (10 mL), cooled to -15 °C, and then concentrated sulfuric acid (6 mL) and concentrated nitric acid (3 mL) were added, respectively, and the reaction was carried out for 2 h. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to quench the reaction, followed by extraction with EA, concentration of the organic phase, and column chromatography to obtain colorless oily liquid intermediate E-10d (300 mg, 70.83%).

[0826] LC-MS(ESI):[M+H] + =252.25.

[0827] Step 5: tert-butyl-6-fluoro-5-nitro-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (intermediate E-10e)

[0828] To a solution of intermediate E-10d (100 mg, 396.44 μmol, 1.0 eq) in dichloromethane (5 mL), DIEA (361.05 mg, 1.19 mmol, 3.0 eq) and di-tert-butyl dicarbonate (311.48 mg, 475.73 μmol, 1.2 eq) were added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated, and the solution was purified by column chromatography (EA:PE = 0-30%) to obtain a yellow oily intermediate E-10e (220 mg, 57.35%).

[0829] LC-MS(ESI):[M+H] + =352.25.

[0830] Step 6: tert-butyl-6-morpholino-5-nitro-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (intermediate E-10f)

[0831] A solution of intermediate E-10e (140 mg, 397.32 μmol, 1.0 eq) in acetonitrile (15 mL) was added with morpholine (64.28 mg, 794.64 μmol, 2.0 eq) and potassium carbonate (153 mg, 1.19 mmol, 3.0 eq), and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated, and the solution was purified by column chromatography (PE:EA = 0-60%) to obtain a white solid intermediate E-10f (125 mg, 75%).

[0832] LC-MS(ESI):[M+H-Boc] + =319.48.

[0833] Step 7: tert-butyl-5-amino-6-morpholino-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (intermediate E-10)

[0834] Intermediate E-10f (100 mg, 238.39 μmol, 1.0 eq) was dissolved in methanol (1 mL), purged under hydrogen protection, and palladium on carbon (21.17 mg, 10% wt) was added. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the mixture was filtered under reduced pressure, and the filtrate was concentrated to obtain a black solid intermediate E-10 (100 mg, 96.93%).

[0835] LC-MS(ESI):[M+H] + =389.50.

[0836] 12) Synthesis of intermediate E-11

[0837] Step 1: Methyl (1R,4R)-4-(5-bromo-6-cyclopropoxy-2H-indazol-2-yl)cyclohexane-1-carboxylic acid ester (intermediate E-11a)

[0838] 5-Bromo-4-cyclopropoxy-2-nitrobenzaldehyde (refer to patent WO2020264499) (603 mg, 2.10 mmol) was dissolved in isopropanol (10 mL), followed by the addition of methyl 4-aminocyclohexane hydrochloride (612 mg, 3.16 mmol) and N,N-diisopropylethylamine (408 mg, 3.16 mmol). The reaction was carried out at 80 °C for 4 hours, followed by the addition of tributylphosphine (1.06 g, 5.26 mmol) and overnight. After the reaction was completed, the solution was concentrated and purified by column chromatography (EA:PE = 0-50%). The solution was then slurried with ice-cold petroleum ether to give a yellow solid intermediate E-11a (500 mg, 60.3%).

[0839] 1 H NMR (600MHz, DMSO-d6) δ8.27(s,1H),7.96(s,1H),7.38(s,1H),4.45(tt,J=11.7,3.9 Hz,1H),3.93(tt,J=6.1,2.9Hz,1H),3.62(s,3H),2.45(tt,J=12.2,3.7Hz,1H),2.13 (dd,J=12.9,3.8Hz,2H),2.06(dt,J=14.6,3.4Hz,2H),1.94(qd,J=12.8,3.6Hz,2H), 1.58(qd,J=13.3,3.4Hz,2H), 0.86(dt,J=7.7,5.7Hz,2H), 0.71(q,J=3.8,2.7Hz,2H).

[0840] LC-MS(ESI):[M+H] + =393.19.

[0841] Step 2: Methyl (1R,4R)-4-(6-cyclopropoxy-5-((diphenylmethylene)amino)-2H-indazol-2-yl)cyclohexane-1-carboxylic acid ester (intermediate E-11b)

[0842] To a solution of intermediate E-11a (500 mg, 1.27 mmol) and 1,4-dioxane (10 mL), benzophenone imine (460.8 mg, 2.54 mmol), cesium carbonate (1.24 g, 3.81 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (147 mg, 0.254 mmol), and tris(dibenzylacetone)dipalladium (116 mg, 0.127 mmol) were added, and the mixture was reacted overnight at 100 °C under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, filtered and concentrated, and purified by column chromatography (EA:PE = 0-35%) to obtain a yellow solid intermediate E-11b (510 mg, 81.27%).

[0843] 1 H NMR(600MHz, DMSO-d6)δ8.03(s,1H),7.64–7.60(m,2H),7.52(t,J=7.4Hz,1H),7.45(t,J=7.6Hz,2H),7.3 0–7.20(m,3H),7.11(s,1H),7.08(dd,J=6.7,2.8Hz,2H),6.73(s,1H),4.33(tt,J=11.8,3.9Hz,1H),3.69( tt,J=6.1,3.0Hz,1H),3.62(s,3H),2.42(tt,J=12.3,3.7Hz,1H),2.10(dd,J=13.1,3.7Hz,2H),2.07–2.01 (m,2H),1.89(qd,J=12.8,3.5Hz,2H),1.55(qd,J=13.3,3.4Hz,2H),0.77–0.70(m,2H),0.49–0.44(m,2H).

[0844] LC-MS(ESI):[M+H] + =494.39.

[0845] Step 3: Methyl (1R,4R)-4-(5-amino-6-cyclopropoxy-2H-indazole-2-yl)cyclohexane-1-carboxylate (intermediate E-11)

[0846] Dioxane hydrochloride (10 mL) was added to a solution of intermediate E-11b (510 mg, 1.03 mmol) and 1,4-dioxane (5 mL), and the reaction was carried out overnight at room temperature. After the reaction was complete, the solution was directly evaporated to dryness and slurried with DCM / EA to obtain a yellow solid intermediate E-11 (340 mg, 99.99%).

[0847] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),7.82(s,1H),7.42(s,1H),4.43(s,1H),4.05(tt,J=6.2,2.7Hz,1H),3.63(s,3H),2.44(dt,J=12.2,3.5Hz ,1H),2.18–2.05(m,4H),1.92(td,J=12.4,3.4Hz,2H),1.59(qd,J=13.1,3.3Hz,2H),0.88(dt,J=7.2,5.6Hz,2H),0.77(tt,J=6.1,3.1Hz,2H).

[0848] LC-MS(ESI):[M+H]+ =330.38.

[0849] 13) Synthesis of intermediate F-1

[0850] Step 1: (1R,4R)-4-formylcyclohexane carboxylate methyl ester (intermediate F-1a)

[0851] DMSO (21.8 g, 278.71 mmol) was dissolved in dichloromethane (100 mL), and oxaloyl chloride (17.70 g, 139.35 mmol) was added dropwise at -78 °C. After reacting for 0.5 hours, methyl trans-4-(hydroxymethyl)cyclohexanecarboxylate (20 g, 116.13 mmol) was dissolved in dichloromethane (100 mL) and added dropwise to the reaction solution. The reaction was carried out at -65 °C for 2 hours, followed by the dropwise addition of triethylamine (58.76 g, 580.64 mmol), and the reaction was continued for 1 hour. The reaction solution was heated to -10 °C, and 1N dilute hydrochloric acid (100 mL) was added. After the addition was complete, the organic phase was separated and concentrated to obtain a yellow oily liquid intermediate F-1a (10.4 g, 53%).

[0852] Step 2: trans-methyl(1R,4R)-4-ethynylcyclohexane-1-carboxylate (intermediate F-1b)

[0853] p-Toluenesulfonyl azide (20.5 g, 103.99 mmol), dimethyl pyruvate (13.76 g, 82.84 mmol), and potassium carbonate (28.42 g, 205.63 mmol) were dispersed in acetonitrile (30 mL) and stirred at room temperature for 2 hours. Intermediate F-1a (10.0 g, 58.75 mmol) was dissolved in methanol (20 mL) and added to the reaction mixture, which was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated solution was then subjected to column chromatography to obtain a white solid intermediate F-1b (5 g, 51%).

[0854] Step 3: 2-Chloro-N-isopropyl-5-nitropyridine-4-amine (intermediate F-1c)

[0855] Et3N (6.29 g, 62.18 mmol) and isopropylamine (2.45 g, 41.45 mmol) were added to an acetonitrile solution (50 mL) of 2,4-dichloro-5-nitropyridine (8.0 g, 41.45 mmol), and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, slurried with a 1:10 EA:PE mixture, filtered, and concentrated to obtain a white solid intermediate F-1c (7.44 g, 83%).

[0856] 1 H NMR (600MHz, DMSO-d6) δ8.88–8.85(s,1H),8.04(d,J=7.9Hz,1H),7.17–7.13(s,1H),4.08–3.99(m,1H),1.25(dd,J=6.4,2.0Hz,6H).

[0857] LC-MS(ESI):[M+H] + =216.20.

[0858] Step 4: 6-Chloro-N-(1-Methylethyl)-3,4-pyridinediamine (intermediate F-1d)

[0859] Ammonium chloride (4.96 g, 92.75 mmol) and iron powder (5.18 g, 92.75 mmol) were added to a methanol:tetrahydrofuran:water solution of intermediate F-1c (4.0 g, 18.55 mmol) in a ratio of 3:3:2 (80 mL). The mixture was reacted at 60 °C for 16 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth. The filter cake was washed three times with methanol. The filtrate was concentrated under reduced pressure, then slurried with a mixed solvent of EA:PE = 1:8, filtered, and concentrated to obtain a white solid intermediate F-1d (2.58 g, 75%).

[0860] 1 H NMR (400MHz, DMSO-d6) δ7.37(s,1H),6.30(s,1H),5.39(d,J=7.6Hz,1H),4.76(s,2H),3.63(dq,J=13.0,6.4Hz,1H),1.16(d,J=6.4Hz,6H).

[0861] LC-MS(ESI):[M+H] + =186.20.

[0862] Step 5: 5-Azide-2-chloro-N-isopropylpyridine-4-amine (intermediate F-1e)

[0863] To a solution of intermediate F-1d (500 mg, 2.69 mmol) in acetonitrile (10 mL), DMAP (493 mg, 4.04 mmol) and 2-azido-1,3-dimethylimidazolium hexafluorophosphate (1.92 g, 6.73 mmol) were added, and the reaction was carried out at room temperature for 3.5 hours. After the reaction was complete, the reaction solution was diluted with water, extracted twice with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated under reduced pressure to obtain a brown oily intermediate F-1e (1.18 g, crude), which could be used directly in the next step without purification.

[0864] Step 6: (1r,4r)-4-(1-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1H-1,2,3-triazol-4-yl)cyclohexane-1-carboxylic acid methyl ester (intermediate F-1)

[0865] Sodium ascorbate (552 mg, 2.79 mmol) and copper sulfate pentahydrate (670 mg, 2.79 mmol) were added to a solution of intermediates F-1b (1.18 g, 5.58 mmol) and F-1e (556 mg, 3.35 mmol) in an acetonitrile:water ratio of 11:1 (12 mL), and the mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solution was concentrated under reduced pressure and subjected to column chromatography to obtain a white solid intermediate F-1 (675 mg, 32%).

[0866] 1 H NMR (600MHz, DMSO-d6) δ8.33(s,1H),8.09(d,J=1.5Hz,1H),6.92(s,1H),6.54(d,J=8.0Hz,1H),3.86–3.79(m,1H),3.62(s, 3H),2.78–2.70(m,1H),2.41–2.35(m,1H),2.17–2.11(m,2H),2.05–1.98(m,2H),1.57–1.44(m,4H),1.16(d,J=6.3Hz,6H).

[0867] LC-MS(ESI):[M+H] + =378.30.

[0868] 14) Synthesis of intermediate F-2

[0869] Step 1: Methyl 6-chloro-4-(isopropylamino)nicotinic acid (intermediate F-2a)

[0870] Methyl 4,6-dichloronicotinic acid (5 g, 24.4 mmol) was dissolved in anhydrous ethanol (50 mL), and isopropylamine (4 g, 67.8 mmol) was added. The mixture was stirred overnight at 80 °C. After the reaction was completed, the solution was directly concentrated and separated by column chromatography to obtain a pale yellow oily intermediate F-2a (5.3 g, 95%).

[0871] LC-MS(ESI):[M+H] + =229.20.

[0872] Step 2: 6-Chloro-4-(isopropylamino)nicotinamide (intermediate F-2b)

[0873] Intermediate F-2a (5.3 g, 23.2 mmol) was dissolved in anhydrous ethanol (80 mL), and hydrazine hydrate (20 mL) was added. The mixture was stirred overnight at 80 °C. After the reaction was completed, the ethanol and a large amount of hydrazine hydrate were removed by concentration, and acetonitrile was added and slurry was added to obtain a white solid intermediate F-2b (2 g, 38%).

[0874] 1 H NMR (400MHz, DMSO-d6) δ9.85(s,1H),8.25(s,1H),6.69(s,1H),4.53(s,2H),3.75(dp,J=7.8,6.2Hz,1H),1.16(d,J=6.3Hz,6H).

[0875] LC-MS(ESI):[M+H] + =229.25.

[0876] Step 3: Trans-4-(2-(6-chloro-4-(isopropylamino)nicotinyl)hydrazine-1-carbonyl)cyclohexane-1-carboxylic acid methyl ester (intermediate F-2c)

[0877] Intermediate F-2b (420 mg, 1.84 mmol) and trans-4-(methoxycarbonyl)hexane-1-carboxylic acid (420 mg, 2.26 mmol) were dissolved in 5 mL of DMF. DIEA (720 mg, 5.58 mmol) and HATU (840 mg, 2.21 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, and the combined organic phases were washed twice with saturated brine and concentrated. The solution was then purified by column chromatography (EA:PE = 0-50%) to obtain a white solid intermediate F-2c (550 mg, 75%).

[0878] LC-MS(ESI):[M+H] + =397.20.

[0879] Step 4: Trans-4-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexane-1-carboxylic acid methyl ester (intermediate F-2)

[0880] Intermediate F-2c (1 g, 2.53 mmol) was dissolved in 30 mL of anhydrous THF, and phosphorus pentasulfide (1.7 g, 3.83 mmol) was added. The mixture was stirred at 70 °C for 1 hour. After the reaction was completed, sodium bicarbonate solution was added to quench the reaction. The mixture was diluted with water and extracted three times with EA. The combined organic phases were concentrated and purified by column chromatography (EA:PE = 0-50%) to obtain a white solid intermediate F-2 (350 mg, 35%).

[0881] 1H NMR (400MHz, DMSO-d6) δ8.77(d,J=7.7Hz,1H),8.41(s,1H),6.91(s,1H),3.98–3.89(m,1H),3.62(s,3 H),2.48–2.38(m,1H),2.22–2.13(m,2H),2.08–1.98(m,2H),1.67–1.51(m,4H),1.25(d,J=6.3Hz,6H).

[0882] LC-MS(ESI):[M+H] + =395.20.

[0883] 15) Synthesis of intermediate F-3

[0884] The procedure is the same as that for the synthesis of intermediate F-1, except that isopropylamine is replaced with cyclopropanol.

[0885] 1 H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.17(s,1H),7.69(s,1H),4.24–4.17(m,1H),3.62(s,3H), 2.81–2.68(m,1H),2.43–2.32(m,1H),2.12–1.97(m,4H),1.56–1.43(m,4H),0.93–0.80(m,4H).

[0886] LC-MS(ESI):[M+H] + =377.30.

[0887] 16) Synthesis of intermediate F-4

[0888] Step 1: Ethyl 6-chloro-4-(methylamino)nicotinic acid (intermediate F-4a)

[0889] Ethyl 4,6-dichloronicotinate (10 g, 45.44 mmol) was dissolved in acetonitrile (100 mL), and methylamine aqueous solution (29 mL, 30%) was added dropwise at low temperature. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography (EA:PE = 0-50%) to obtain a white solid intermediate F-4a (6.5 g, 67%).

[0890] LC-MS(ESI):[M+H] + =215.20.

[0891] Step 2: 6-Chloro-4-(methylamino)nicotinamide (intermediate F-4b)

[0892] Intermediate F-4a (3 g, 13.98 mmol) was dissolved in ethanol (3 mL), and hydrazine hydrate (7 mL, 111.8 mmol) was added. The mixture was reacted at 80 °C for 3 hours. After the reaction was completed, the reaction solution was concentrated, extracted multiple times with DCM, and the concentrated solution was then slurried with petroleum ether / ethyl acetate to obtain crude intermediate F-4b.

[0893] LC-MS(ESI):[M+H] + =201.20.

[0894] Step 3: Methyl(1R,4R)-4-(2-(6-chloro-4-(methylamino)nicotinyl)hydrazide-1-carbonyl)cyclohexane-1-carboxylate (intermediate F-4c)

[0895] To a DMF solution (30 mL) of intermediate F-4b (1.76 g, 8.77 mmol) and (1r, 4r)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (2.45 g, 13.16 mmol), HATU (5 g, 13.16 mmol) and DIEA (3.4 g, 26.32 mmol) were added, and the mixture was reacted at room temperature for half an hour. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, filtered and concentrated, and column chromatography was performed to obtain a white solid intermediate F-4c (2 g, 62%).

[0896] LC-MS(ESI):[M+H] + =369.54.

[0897] Step 4: Methyl(1R,4R)-4-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexane-1-carboxylate (intermediate F-4)

[0898] Intermediate F-4c (500 mg, 1.36 mmol) was dissolved in tetrahydrofuran (50 mL), and phosphorus pentasulfide (392 mg, 1.76 mmol) was added. The mixture was reacted at 50 °C for 3 hours. After the reaction was completed, the mixture was extracted with EA, washed with sodium bicarbonate solution, and column chromatography was performed to obtain a yellow solid intermediate F-4 (190 mg, 38%).

[0899] 1H NMR(400MHz,DMSO-d6)δ8.66(d,J=5.2Hz,1H),8.40(s,1H),6.83(s,1H),3.62(s,3H),3.22(tq,J=11.1,3.6Hz,1H), 2.98(d,J=4.9Hz,3H),2.44(ddd,J=11.6,8.0,3.6Hz,1H),2.23–2.14(m,2H),2.08–1.99(m,2H),1.68–1.51(m,4H).

[0900] LC-MS(ESI):[M+H] + =511.20.

[0901] 17) Synthesis of intermediate F-6

[0902] Step 1: (6-chloro-4-(methylamino)pyridin-3-yl)methanol (intermediate F-6a)

[0903] Methyl 6-chloro-4-(methylamino)nicotinic acid (16.38 g, 76.3 mmol) was dissolved in THF (200 mL), cooled to -78 °C, and lithium aluminum hydride (92 mL, 230 mmol) was slowly added. The mixture was stirred at low temperature for 10 minutes, then brought to room temperature and reacted for 2 hours. After the reaction was complete, the reaction was quenched with water and 1 M sodium hydroxide solution. The mixture was extracted three times with EA and concentrated to give a pale yellow oily intermediate F-6a (10 g, 76%).

[0904] LC-MS(ESI):[M+H] + =172.20.

[0905] Step 2: 6-Chloro-4-(methylamino)nicotinaldehyde (intermediate F-6b)

[0906] (6-chloro-4-(methylamino)pyridin-3-yl)methanol (7 g, 40.7 mmol) was dissolved in DCM (100 mL), and manganese dioxide (17.7 g, 203 mmol) was added in portions. The mixture was stirred overnight at room temperature. After the reaction was complete, the solid manganese dioxide was removed by filtration, and the filtrate was concentrated to give a pale yellow oily intermediate F-6b (6.9 g, 99%).

[0907] LC-MS(ESI):[M+H] + =170.20.

[0908] Step 3: 2-Chloro-5-ethynyl-N-methylpyridin-4-amine (intermediate F-6c)

[0909] 6-Chloro-4-(methylamino)nicotinaldehyde (6.9 g, 40.6 mmol) was dissolved in methanol (100 mL), and potassium carbonate (16.7 g, 121 mmol) was added. The mixture was cooled to -5°C, and dimethyl (1-diazo-2-oxopropyl)phosphonate (15.5 g, 80.7 mmol) was added dropwise at low temperature. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was completed, the solution was directly concentrated and separated by column chromatography (EA:PE = 0-20%) to obtain a light brown oily intermediate F-6c (4.2 g, 62%).

[0910] LC-MS(ESI):[M+H] + =167.25.

[0911] Step 4: Methyl 4-(4-(6-chloro-4-(methylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)cyclohexane-1-carboxylate (intermediate F-6)

[0912] 2-Chloro-5-ethynyl-N-methylpyridin-4-amine (1.0 g, 6.02 mmol) and methyl 4-azidocyclohexane-1-carboxylate (1.3 g, 6.16 mmol) were dissolved in anhydrous acetonitrile (22 mL) and water (2 mL). Sodium ascorbate (600 mg, 3.03 mmol) and copper sulfate pentahydrate (760 mg, 3.04 mmol) were added at room temperature, and the mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was extracted three times with water and EA, concentrated, and purified by column chromatography (EA:PE = 0-50%) to give a yellow solid intermediate F-6 (600 mg, 29%).

[0913] LC-MS(ESI):[M+H] + =350.25.

[0914] 18) Synthesis of intermediate F-7

[0915] Step 1: 2-Chloro-5-iodo-N-methylpyridin-4-amine (Intermediate F-7a)

[0916] 2,4-Dichloro-5-iodopyridine (5.0 g, 18.26 mmol, 1 eq) was dissolved in N,N-dimethylacetamide (50 mL), and DIEA (23.6 g, 182.56 mmol, 10 eq) was added. The reaction was carried out at 100 °C for 48 hours. After the reaction was completed, the mixture was extracted three times with EA, washed with brine, and purified by column chromatography (PE:EA = 1:1) to obtain a white solid intermediate F-7a (3 g, 61%).

[0917] LC-MS(ESI):[M+H] + =268.93.

[0918] Step 2: 2-Chloro-N-methyl-5-(1H-pyrazol-4-yl)pyridin-4-amine (intermediate F-7b)

[0919] Intermediate F-7a (3 g, 11.17 mmol) was dissolved in 1,4-dioxane / water (30 mL, V / V = 5 / 1), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazole (2.6 g, 13.41 mmol), potassium carbonate (4.63 g, 33.52 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (912 mg, 1.12 mmol) were added. The mixture was purged with nitrogen and reacted at 100 °C for 48 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth, extracted three times with EA, washed with brine, and purified by column chromatography (DCM:MeOH = 14:1) to obtain a white solid intermediate F-7b (1.2 g, 52%).

[0920] LC-MS(ESI):[M+H] + =209.20.

[0921] Step 3: Methyl (1S,4S)-4-((methylsulfonyl)oxy)cyclohexane-1-carboxylic acid ester (intermediate F-7c)

[0922] Methyl(1S,4S)-4-hydroxycyclohexane-1-carboxylate (3 g, 18.96 mmol) was dissolved in dichloromethane (30 mL), and triethylamine (3.84 g, 37.95 mmol) was added. Methanesulfonyl chloride (2.17 g, 18.96 mmol) was then added dropwise at low temperature, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the mixture was extracted three times with DCM, and the reaction solution was concentrated to give intermediate F-7b (Crude).

[0923] Step 4: (1r,4r)-4-[4-(6-chloro-4-(methylamino)pyridin-3-yl)-1H-pyrazol-1-yl]cyclohexane-1-carboxylic acid methyl ester (intermediate F-7)

[0924] Intermediate F-7b (1.2 g, 5.75 mmol) was dissolved in acetonitrile (20 mL), and cesium carbonate (3.75 g, 11.5 mmol) and intermediate F-7c (1.63 g, 6.9 mmol) were added. The reaction was carried out at 100 °C for 14 hours. After the reaction was completed, the mixture was extracted three times with EA, the reaction solution was concentrated, and purified by column chromatography (DCM:MeOH = 14:1) to obtain a white solid intermediate F-7 (1.0 g, 50%).

[0925] LC-MS(ESI):[M+H] + =349.20.

[0926] 19) Synthesis of intermediate F-11

[0927] Step 1: 2-Bromo-5-(4-((((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-1,3,4-thiadiazole (intermediate F-11a)

[0928] 2,5-Dibromo-1,3,4-thiadiazole (5 g, 20.7 mmol) and 4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine (5 g, 19.44 mmol) were dissolved in DMF (100 mL), and cesium carbonate (20 g, 61.3 mmol) was added. The mixture was heated to 100 °C and reacted for 1 hour. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, and the combined organic phases were washed twice with saturated brine and concentrated by column chromatography (EA:PE = 0-50%) to give a red solid intermediate F-11a (8 g, 92%).

[0929] LC-MS(ESI):[M+H] + =420.15.

[0930] Step 2: 2-(4,6-dichloropyridin-3-yl)-5-(4-((((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-1,3,4-thiadiazole (intermediate F-11b)

[0931] Intermediate F-11a (500 mg, 1.19 mmol) and (4,6-dichloropyridin-3-yl)boronic acid (270 mg, 1.41 mmol) were dissolved in 10 mL of dioxane and 2.5 mL of water. Pd(dppf)Cl2·DCM (100 mg, 0.122 mmol) and potassium carbonate (500 mg, 3.62 mmol) were added. After nitrogen purging, the mixture was heated to 100 °C and stirred for 3 hours. Boric acid was added as needed to monitor for incomplete reaction. After the reaction was complete, the reaction solution was diluted with water and extracted three times with EA. The combined organic phases were concentrated and then subjected to column chromatography (PE:EA = 0-50%) to obtain a pale yellow solid intermediate F-11a (140 mg, 24%).

[0932] LC-MS(ESI):[M+H] + =487.20.

[0933] Step 3: 2-Chloro-5-(5-(4-((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-1,3,4-thiadiazol-2-yl)-N-isopropylpyridine-4-amine (intermediate F-11)

[0934] Intermediate F-11b (70 mg, 0.144 mmol) was dissolved in anhydrous THF (2 mL), and isopropylamine (85 mg, 1.44 mmol) was added. The mixture was incubated overnight in an oil bath at 100 °C. After the reaction was complete, the solution was directly concentrated and then subjected to column chromatography (EA:PE = 0-50%) to give a pale yellow solid intermediate F-11 (15 mg, 20%).

[0935] LC-MS(ESI):[M+H] + =510.20.

[0936] 20) Synthesis of intermediate F-12

[0937] Step 1: 2-[6-chloro-4-isopropoxypyridin-3-yl]-5-[4-([(1r,4r)-4-(dimethoxymethyl)cyclohexyl]oxy)piperidin-1-yl]-1,3,4-thiadiazole (intermediate F-12)

[0938] Intermediate F-11b (70 mg, 0.144 mmol) was dissolved in anhydrous THF (2 mL), and isopropanol (87 mg, 1.44 mmol) was added. The mixture was incubated overnight in an oil bath at 100 °C. After the reaction was complete, the solution was directly concentrated and then subjected to column chromatography (EA:PE = 0-50%) to give a pale yellow solid intermediate F-12 (15 mg, 20%).

[0939] 1 H NMR(400MHz, DMSO-d6)δ8.94(s,1H),8.03(s,1H),3.99(d,J=6.6Hz,1H),3.80–3.70(m,3H),3.45–3.35 (m,3H),3.30–3.20(m,8H),2.01–1.85(m,5H),1.75–1.65(m,3H),1.60–1.50(m,4H),1.20–0.95(m,6H).

[0940] LC-MS(ESI):[M+H] + =511.20.

[0941] 21) Synthesis of intermediate F-14

[0942] Step 1: Ethyl 2-(bromomethyl)-4,6-dichloronicotinate (intermediate F-14a)

[0943] The synthesis steps are based on Example 68C of document WO 2012 / 97682A1.

[0944] Step 2: Synthesis of tert-butyl 4-(2,4-dichloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-1-carboxylate (intermediate F-14b)

[0945] Intermediate F-14a (4 g, 12.78 mmol, 1.0 eq) and tert-butyl 4-aminopiperidine-1-carboxylate (3.84 g, 19.17 mmol, 1.5 eq) were dissolved in ACN (20 mL), and DIEA (3.3 g, 2 eq) was added. The mixture was reacted at room temperature for 5 h. After the reaction was completed, the solution was concentrated and stirred into silica gel, and then passed through a normal chromatography column (EA:PE = 0-50%) to obtain a colorless oily liquid intermediate F-14b (2.2 g, 45%).

[0946] 1 H NMR (600MHz, DMSO-d6) δ7.87(s,1H),4.52(s,2H),4.21(tt,J=11.8,4.1Hz,1H),4.05(d,J=17.5Hz,4H),1.75-1.62(m,4H),1.42(s,9H).

[0947] LC-MS(ESI):[M+H-Boc] + =286.35.

[0948] Step 3: 4-(2-chloro-4-(isopropylamino)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate F-14)

[0949] Intermediate F-14b (0.4 g, 1.03 mmol, 1 eq) was dissolved in NMP (2 mL), and isopropylamine (1.2 g, 20.71 mmol, 20 eq) was added. The mixture was reacted at 90 °C for 2 hours. After the reaction was complete, water was added, and the mixture was washed three times with ethyl acetate. The organic phase was concentrated, stirred into silica gel, and filtered through a normal phase chromatography column (EA:PE = 0-50%) to obtain a colorless oily liquid intermediate F-14 (0.3 g, 70%).

[0950] 1 H NMR(400MHz,DMSO-d6)δ6.79(d,J=8.5Hz,1H),6.66(s,1H),4.30(s,2H),4.12–3.97(m,2H),3. 83(dp,J=8.1,6.3Hz,1H),2.79(s,2H),1.70-1.53(m,4H),1.40(s,9H),1.18(d,J=6.3Hz,6H).

[0951] LC-MS(ESI):[M+H]+ =409.49.

[0952] 22) Synthesis of intermediate F-15

[0953] Step 1: 6-Chloro-3-nitro-1H-pyrazolo[4,3-c]pyridine (intermediate F-15a)

[0954] At room temperature, tert-butyl nitrite (10.1 g, 97.8 mmol, 3 eq) was added to a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (5.0 g, 32.6 mmol, 1.0 eq) in acetonitrile (50 mL), and the mixture was then transferred to an oil bath at 80 °C and reacted for three days. After the reaction was complete, the solution was filtered through a normal phase chromatography column (EA:PE = 0-50%) to give a colorless oily liquid intermediate F-15a (1.05 g, 16.2%).

[0955] LC-MS(ESI):[M+H] + =199.15.

[0956] Step 2: 6-Chloro-1-cyclopropyl-3-nitro-1H-pyrazolo[4,3-c]pyridine (intermediate F-15b)

[0957] Intermediate F-15a (2.1 g, 10.57 mmol, 1 eq) was dissolved in 1,2-dichloroethane (20 mL), and cyclopropylboronic acid (1.82 g, 21.2 mmol, 2 eq), 2,2'-bipyridine (1.65 g, 10.57 mmol, 1 eq), copper acetate (1.92 g, 10.57 mmol, 1 eq), and sodium carbonate (2.24 g, 21.15 mmol, 2 eq) were added. The reaction was carried out overnight at 70 °C under oxygen protection. After the reaction was completed, the reaction solution was diluted with water, extracted three times with DCM, filtered and concentrated, and purified by column chromatography (EA:PE = 0-30%) to obtain colorless oily intermediate F-15b (0.63 g, 24.8%).

[0958] LC-MS(ESI):[M+H] + =239.26.

[0959] Step 3: 1-(1-Cyclopropyl-3-nitro-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazolo[3,4-b]pyridin-5-onitrile (intermediate F-15c)

[0960] Intermediate F-15b (0.435 g, 1.83 mmol, 1 eq) was dissolved in toluene (10 mL), and 1H-pyrazolo[3,4-b]pyridine-5-onitrile (0.315 g, 2.18 mmol, 1.2 eq), tBu X-phos Pd G3 (0.435 g, 0.547 mmol, 0.3 eq), and sodium tert-butoxide (0.31 g, 3.19 mmol, 1.75 eq) were added. The reaction was carried out overnight at 110 °C under nitrogen protection. After the reaction was completed, the mixture was concentrated and purified by column chromatography (EA:PE = 0-50%) to obtain a colorless oily intermediate F-15c (0.165 g, 26.1%).

[0961] LC-MS(ESI):[M+H] + =347.29.

[0962] Step 4: 1-(3-amino-1-cyclopropyl-1H-pyrazolopyrimidine[4,3-c]pyridin-6-yl)-1H-pyrazolopyrimidine[3,4-b]pyridin-5-nitrile (intermediate F-15)

[0963] Intermediate F-15c (0.16 g, 0.46 mmol, 1 eq) was dissolved in a mixture of ethanol and water (5 mL, v / v = 4 / 1), and iron powder (0.13 g, 2.31 mmol, 5.0 eq) and ammonium chloride (0.25 g, 4.62 mmol, 10 eq) were added. The reaction was carried out overnight at 80 °C. After the reaction was completed, the mixture was filtered and concentrated, and purified by column chromatography (EA:PE = 0-50%) to obtain a colorless oily intermediate F-15 (0.036 g, 24.6%).

[0964] LC-MS(ESI):[M+H] + =317.28.

[0965] 23) Synthesis of intermediate F-16

[0966] Step 1: 6-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (intermediate F-16a)

[0967] NIS (12.38 g, 55.02 mmol) was added to a DMF (130 mL) solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (6.5 g, 42.33 mmol) at room temperature. The reaction mixture was stirred at 60 °C under N2 for 3 hours. After the reaction was complete, the mixture was quenched with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. Column chromatography gave an orange solid intermediate F-16a (10 g, 84.5%).

[0968] 1H NMR (400MHz, DMSO-d6) δ14.01(s,1H),8.64(s,1H),7.69(s,1H).

[0969] LC-MS(ESI):[M+H] + =280.08.

[0970] Step 2: 6-Chloro-3-iodo-1-isopropyl-1H-pyrazolo[4,3-c]pyridine (intermediate F-16b)

[0971] NaH (171.74 mg, 4.29 mmol) was added to a DMF (10 mL) solution of intermediate F-16a (1 g, 3.58 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 minutes, followed by the addition of 2-iodopropane (912.42 mg, 5.37 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with water, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. Column chromatography yielded an orange solid intermediate F-16b (730 mg, 63.4%).

[0972] 1 H NMR (400MHz, DMSO-d6) δ8.59 (s, 1H), 7.99 (s, 1H), 5.11–4.98 (m, 1H), 1.46 (d, J = 6.6Hz, 6H).

[0973] LC-MS(ESI):[M+H] + =322.08.

[0974] Step 3: Methyl 6-chloro-1-isopropyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (intermediate F-16c)

[0975] Palladium acetate (50.97 mg, 227.03 μmol) and TEA (436.5 mg, 4.31 mmol) were added to a methanol (7 mL) solution of intermediate F-16b (730 mg, 2.27 mmol) at room temperature. The reaction mixture was stirred in CO at 65 °C for 16 hours. After the reaction was completed, the mixture was concentrated and subjected to column chromatography to give a white solid intermediate F-16c (430 mg, 74.6%).

[0976] 1H NMR (400MHz, DMSO-d6) δ9.13 (d, J = 0.9Hz, 1H), 8.16 (d, J = 0.8Hz, 1H), 5.21–5.08 (m, 1H), 3.96 (s, 3H), 1.51 (d, J = 6.6Hz, 6H).

[0977] LC-MS(ESI):[M+H] + =254.27.

[0978] Step 4: 6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-1-isopropyl-1H-pyrazole[4,3-c]pyridine-3-carboxylic acid methyl ester (intermediate F-16d)

[0979] At room temperature, 1H-pyrazolo[3,4-b]pyridine-5-onitrile (293.18 mg, 2.03 mmol), tBuXPhosPdG3 (673.24 mg, 847.50 μmol), and sodium tert-butoxide (285.07 mg, 2.97 mmol) were added to a 6 mL toluene solution of intermediate F-16c (430 mg, 1.70 mmol). The reaction mixture was stirred at 110 °C for 16 hours under nitrogen. After the reaction was complete, the mixture was concentrated and subjected to column chromatography to give a white solid intermediate F-16d (70 mg, 11.4%).

[0980] LC-MS(ESI):[M+H] + =362.37.

[0981] Step 5: 6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-1-isopropyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (intermediate F-16e)

[0982] LiOH (9.28 mg, 387.42 μmol) was added to a MeOH / THF / H₂O (1.0 / 1.0 / 0.5 mL) solution of intermediate F-16d (70 mg, 193.71 μmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 4–5 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography yielded a yellow solid intermediate F-16e (38 mg, 56.4%).

[0983] LC-MS(ESI):[M+H] + =348.39.

[0984] Step 6: 1-(3-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine-1-carbonyl)-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrazolo[3,4-b]pyridin-5-nitrile (intermediate F-16f)

[0985] A mixture of intermediate F-16e (38 mg, 109.40 μmol), 4-(((1r, 4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine (42.24 mg, 164.11 μmol), HATU (83.20 mg, 218.81 μmol), and DIEA (42.42 mg, 328.21 μmol) in DMF (1.0 mL) was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated solution was then subjected to column chromatography to give a white solid intermediate F-16f (10 mg, 15.5%).

[0986] LC-MS(ESI):[M+H] + =587.50.

[0987] 24) Synthesis of intermediate F-17

[0988] Step 1: 6-Chloro-1-cyclopropyl-3-iodo-1H-pyrazolo[4,3-c]pyridine (intermediate F-17b)

[0989] At room temperature, cyclopropylboronic acid (553.25 mg, 6.44 mmol), copper acetate (584.94 mg, 3.22 mmol), sodium carbonate (682.65 mg, 6.44 mmol), and 2,2'-bipyridine (502.99 mg, 3.22 mmol) were added to a DCE (20 mL) solution of intermediate F-17a (1.0 g, 3.58 mmol). The reaction mixture was stirred at 70 °C for 3 hours. After the reaction was complete, the mixture was concentrated and subjected to column chromatography to give a white solid intermediate F-17b (600 mg, 52.4%).

[0990] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=0.7Hz,1H),7.84(d,J=0.7Hz,1H),3.84–3.79(m,1H),1.14(d,J=5.3Hz,4H).

[0991] LC-MS(ESI):[M+H] + =320.18.

[0992] Step 2: Methyl 6-chloro-1-cyclopropyl-1H-pyrazolo[4,3-c]pyridine-3-carboxylate (intermediate F-17c)

[0993] Palladium acetate (63.24 mg, 281.66 μmol) and TEA (541.54 mg, 5.35 mmol) were added to a methanol (7 mL) solution of intermediate F-17b (900 mg, 2.82 mmol) at room temperature. The reaction mixture was stirred at 65 °C under a CO atmosphere for 16 hours. After the reaction was complete, the mixture was concentrated and subjected to column chromatography to give a white solid intermediate F-17c (570 mg, 80.4%).

[0994] 1 H NMR (600MHz, DMSO-d6) δ9.11 (s, 1H), 8.02 (s, 1H), 4.03–3.92 (m, 4H), 1.20 (d, J = 5.4Hz, 4H).

[0995] LC-MS(ESI):[M+H] + =252.17.

[0996] Step 3: Methyl 6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-1-cyclopropyl-1H-pyrazole[4,3-c]pyridine-3-carboxylic acid ester (intermediate F-17d)

[0997] At room temperature, 1H-pyrazolo[3,4-b]pyridine-5-onitrile (359.10 mg, 2.49 mmol) was added to a 6 mL toluene solution of intermediate F-17c (570.0 mg, 2.26 mmol). t BuXPhosPdG3 (899.59 mg, 1.13 mmol) and sodium tert-butoxide (380.91 mg, 3.96 mmol) were added. The reaction mixture was stirred in an oil bath at 110 °C for 16 hours under nitrogen. After the reaction was completed, the mixture was concentrated and stirred, and column chromatography was performed to give a white solid intermediate F-17d (80.0 mg, 9.8%).

[0998] LC-MS(ESI):[M+H] + =360.29.

[0999] Step 4: 6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-1-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-3-carboxylic acid (intermediate F-17e)

[1000] LiOH (10.66 mg, 445.25 μmol) was added to a MeOH / THF / H₂O (2.5 mL, 2 / 2 / 1) solution of intermediate F-17d (80.0 mg, 222.62 μmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 4–5 with 2N hydrochloric acid, extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration, column chromatography yielded a yellow solid intermediate F-17e (40 mg, 52.0%).

[1001] LC-MS(ESI):[M+H] + =346.29.

[1002] Step 5: 1-(1-cyclopropyl-3-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine-1-carbonyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-1H-pyrido[3,4-b]pyridin-5-nitrile (intermediate F-17)

[1003] A mixture of intermediate F-17e (20 mg, 57.92 μmol), 4-(((1r, 4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidine (22.36 mg, 86.88 μmol), HATU (44.04 mg, 115.83 μmol), and DIEA (22.46 mg, 173.75 μmol) in DMF (1.0 mL) was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was extracted three times with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The concentrated solution was then subjected to column chromatography to give a white solid intermediate F-17 (15 mg, 44.30%).

[1004] LC-MS(ESI):[M+H] + =585.58.

[1005] 25) Synthesis of intermediate G-2

[1006] The experimental procedures are referenced on page 233 of patent CN104781251B.

[1007] 1 H NMR (600MHz, DMSO-d6) δ8.99(d,J=6.4Hz,1H),7.81(d,J=2.2Hz,1H),7.21(s,2H),5.98(d,J=2.2Hz,1H).

[1008] 26) Synthesis of intermediate H-1

[1009] Step 1: 4-(4-nitro-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate H-1a)

[1010] 4-Bromopiperidin-1-carboxylic acid tert-butyl ester (1.4 g, 5.31 mmol) was dissolved in DMF (14 mL), and 4-nitro-1H-pyrazole (500 mg, 4.42 mmol) and cesium carbonate (2.88 g, 8.84 mmol) were added. The reaction mixture was reacted overnight at 120 °C. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, concentrated by filtration, and purified by column chromatography (EA:PE = 0-50%) to obtain a yellow solid intermediate H-1a (830 mg, 63.34%).

[1011] LC-MS(ESI):[M+H-tBu] + =241.26.

[1012] Step 2: 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate H-1b)

[1013] Palladium on carbon (1.4 g, 613.14 mmol) was added to a tetrahydrofuran (65 mL) solution of intermediate H-1a (6.49 g, 21.90 mmol), and the reaction was carried out overnight at room temperature. After the reaction was completed, the mixture was filtered and concentrated to obtain a black solid intermediate H-1b (5.67 g, 97.20%).

[1014] 1 H NMR(400MHz,DMSO-d6)δ7.06(s,1H),6.92(s,1H),4.06–4.07(m,1H),4.00(d,J=12.0 Hz,2H),3.76(s,2H),2.85(s,2H),1.93–1.88(m,2H),1.73–1.63(m,2H),1.41(s,9H).

[1015] LC-MS(ESI):[M-tBu+H] + =211.35.

[1016] Step 3: 4-(4-((6-chloro-4-((1-methylcyclopropyl)amino)pyrido[3,2-d]pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidin-1-carboxylic acid tert-butyl ester (intermediate H-1)

[1017] 2,6-Dichloro-N-(1-methylcyclopropyl)pyrido[3,2-d]pyrimidin-4-amine (1.01 g, 3.75 mmol) and trifluoroacetic acid (0.5%) were added to an isopropanol solution of intermediate H-1b (1.0 g, 3.75 mmol), and the mixture was reacted in an oil bath at 82.5 °C for 8 hours under a nitrogen atmosphere. After the reaction was completed, the isopropanol was removed by concentration under reduced pressure, and 10 mL of 10% sodium bicarbonate solution was added. The mixture was stirred for 30 minutes, filtered, and concentrated to a yellow solid intermediate H-1 (1.44 g, 76.86%).

[1018] 1 H NMR (600MHz, CDCl3) δ8.10(s,1H),7.73(s,1H),7.61(s,1H),7.45(d,J=8.7Hz,1H),7.29(s,1H),4.31–4.24(m,2H),2.92( s,2H),2.18(d,J=12.3Hz,2H),2.01–1.90(m,2H),1.57(s,3H),1.50(s,9H),1.36–1.25(m,2H),0.99(s,2H),0.82(s,2H).

[1019] LC-MS(ESI):[M+H] + =499.49.

[1020] The following intermediates were prepared using reference WO2025149070A1 and the aforementioned preparation method, and used as starting materials for, for example, the PTM moiety (see, for example, the general synthetic formula IR-T-1 described herein), to prepare the compounds disclosed herein:

[1021] II. CLM Synthesis

[1022] 1) Synthesis of CLM-1

[1023] Step 1: tert-Butyl(S)-11-bromo-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazoline-3-carboxylic acid ester (compound CLM-1a)

[1024] Under a nitrogen atmosphere, (3S)-3-(2-hydroxyethyl)-1-piperazinic acid tert-butyl ester (14.32 g, 62.18 mmol) and potassium hydroxide (10.46 g, 186.56 mmol) were added to a dimethyl sulfoxide (60 mL) solution of 1-bromo-2,3-difluoro-5-nitrobenzene (14.8 g, 62.18 mmol) and reacted at room temperature for 2 hours, followed by reaction at 60 °C for 3 hours. After the reaction was complete, the reaction solution was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the solution was purified by column chromatography (EA:PE = 0-20%) to give a yellow solid compound CLM-1a (1.81 g, 6.7%).

[1025] LC-MS(ESI):[M+H] + =372.19.

[1026] Step 2: Tert-butyl(S)-11-hydroxy-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazoline-3-carboxylic acid ester (compound CLM-1b)

[1027] In an air atmosphere, potassium hydroxide (1.75 g, 31.13 mmol), 2-di-tert-butylphospho-2',4',6'-triisopropylbiphenyl (0.38 g, 0.89 mmol), and tris(dibenzylacetone)palladium (0.81 g, 0.89 mmol) were added to a mixed solution of 1,4-dioxane and water (50 mL, v / v = 4 / 1), and the mixture was reacted overnight at 100 °C. After the reaction was complete, the reaction solution was extracted with EA, washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the mixture was purified by column chromatography (EA:PE = 0-50%) to give a yellow solid compound CLM-1b (2.90 g, 89.21%).

[1028] 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),7.34(d,J=2.7Hz,1H),7.16(d,J=2.7Hz,1H),4.40–4.28(m,1H),4.06–3.89(m,1H),3.88–3.68( m,1H),3.62–3.54(m,2H),3.46–3.38(m,1H),3.28–3.08(m,2H),3.05–2.94(m,1H),2.17–2.02(m,1H),1.99–1.88(m,1H),1.41(s,9H).

[1029] LC-MS(ESI):[M+H] + =366.39.

[1030] Step 3: Tert-butyl(S)-11-methoxy-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazolidine-3-carboxylic acid ester (compound CLM-1c)

[1031] Under a nitrogen atmosphere, potassium carbonate (2.19 g, 15.87 mmol) and methyl iodide (1.69 g, 11.90 mmol) were added to a solution of intermediate CLM-1b (2.90 g, 7.93 mmol) in N,N-dimethylformamide (30 mL), and the mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the mixture was purified by column chromatography (PE:EA = 0-50%) to give a yellow solid compound CLM-1c (2.76 g, 91.65%).

[1032] 1 H NMR (400MHz, DMSO-d6) δ7.42(d,J=2.6Hz,1H),7.33(d,J=2.6Hz,1H),4.42–4.34(m,1H),4.00–3.90(m,1H),3.88(s,3H),3.8 3–3.71(m,1H),3.65–3.51(m,2H),3.33–3.28(m,2H),3.26–3.17(m,1H),3.05–2.94(m,1H),2.14–1.91(m,2H),1.41(s,9H).

[1033] LC-MS(ESI):[M+H] + =380.49.

[1034] Step 4: Tert-butyl(S)-9-amino-11-methoxy-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazoline-3-carboxylic acid ester (compound CLM-1d)

[1035] Under a hydrogen atmosphere, palladium on carbon (540 mg, 1.42 mmol) was added to a methanol (30 mL) solution of intermediate CLM-1c (2.7 g, 7.11 mmol), and the reaction was carried out overnight at room temperature. After the reaction was complete, the solution was filtered through diatomaceous earth, and the solvent was evaporated to obtain a brown solid compound CLM-1d (2.24 g, 90.08%).

[1036] 1H NMR (400MHz, DMSO-d6) δ5.88(d,J=2.4Hz,1H),5.67(d,J=2.4Hz,1H),4.75(s,2H),4.13–4.02(m,1H),3.97–3.85(m,1H), 3.64(s,3H),3.34–3.33(m,4H),3.31–3.21(m,1H),2.94–2.81(m,2H),2.17–2.03(m,1H),1.85–1.73(m,1H),1.40(s,9H).

[1037] LC-MS(ESI):[M+H] + =350.49.

[1038] Step 5: Tert-butyl(S)-9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-11-methoxy-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazolium heterocyclic-3-carboxylic acid ester (compound CLM-1e)

[1039] Under a nitrogen atmosphere, acrylic acid (0.69 g, 9.61 mmol) was added to a toluene (22 mL) solution of intermediate CLM-1d (2.24 g, 6.41 mmol), and the reaction was carried out overnight at 100 °C. Then, urea (1.92 g, 32.02 mmol) and acetic acid (11 mL) were added, and the reaction was carried out overnight at 100 °C. After the reaction was complete, the reaction mixture was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the mixture was slurried with EA to give a pale yellow solid compound CLM-1e (1.03 g, 35.99%).

[1040] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),6.59(d,J=2.4Hz,1H),6.41(d,J=2.4Hz,1 H),4.33–4.24(m,1H),3.97–3.86(m,1H),3.74(s,3H),3.71–3.65(m,2H),3.64– 3.56(m,1H),3.52–3.44(m,1H),3.34–3.30(m,2H),3.23–3.20(m,2H),2.97–2.8 4(m,1H),2.70–2.62(m,2H),2.16–2.01(m,1H),1.97–1.86(m,1H),1.41(s,9H).

[1041] LC-MS(ESI):[M+H] + =447.39.

[1042] Step 6: (S)-1-(11-methoxy-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazoline-9-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound CLM-1)

[1043] A solution of dioxane-1e (1.00 g, 2.24 mmol) in dichloromethane was added to 4 mL of dioxane-1e solution (10 mL, 4 M), and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the mixture was filtered to obtain a gray solid compound CLM-1 (940 mg, 100%).

[1044] 1 H NMR(400MHz, DMSO-d6)δ10.30(s,1H),6.66(s,1H),6.46(d,J=2.5Hz,1H),4.30–4.21(m,1H),3.99–3.90 (m,5H),3.77–3.74(m,3H),3.72–3.64(m,2H),3.34–3.60(m,5H),2.70–2.62(m,2H),2.00–1.83(m,1H).

[1045] LC-MS(ESI):[M+H] + =347.39.

[1046] 2) Synthesis of CLM-2

[1047] Step 1: (S)-4-(2-fluoro-3-methoxy-4-nitrophenyl)-3-(2-hydroxyethyl)piperazine-1-tert-butyrate (compound CLM-2a)

[1048] 2,3-Difluoro-6-nitrobenzene ether (19 g, 0.10 mol) was dissolved in DMSO (200 mL), and (3S)-3-(2-hydroxyethyl)-1-piperazinic acid tert-butyl ester (25.4 g, 0.11 mol) and DIEA (38.9 g, 0.3 mol) were added. The reaction was carried out overnight at 80 °C under nitrogen atmosphere. After cooling the reaction system to room temperature, water was added to the reaction system, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give a yellow oily intermediate CLM-2a (7.8 g, 19.44%).

[1049] LC-MS(ESI):[M+H] + =400.30

[1050] Step 2: (S)-8-methoxy-9-nitro-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazine 3-tert-butyrate (intermediate CLM-2b)

[1051] Intermediate CLM-2a (7.8 g, 0.02 mol) was dissolved in DMF (300 mL), and potassium tert-butoxide (3.36 g, 0.03 mol) was added. The reaction was carried out at 60 °C for 2 h under nitrogen atmosphere. After cooling the reaction system to room temperature, ammonium chloride solution was added to the reaction system, and the mixture was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give intermediate CLM-2b (7 g, 94.47%).

[1052] LC-MS(ESI):[M+H] + =380.30.

[1053] Step 3: (S)-9-amino-8-methoxy-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazine -3-tert-butyrate (CLM-2c)

[1054] Intermediate CLM-2b (7 g, 0.018 mol) was dissolved in ethanol:water = 4:1 (80:20 mL), and iron powder (6 g, 0.11 mol) and ammonium chloride (6 g, 0.11 mol) were added. The reaction mixture was incubated at 70 °C for 2 h under nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth while hot, concentrated, and extracted. The combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained from the concentrated organic phase was purified by column chromatography to give intermediate CLM-2c (3.3 g, 51.20%).

[1055] LC-MS(ESI):[M+H] + =350.30.

[1056] Step 4: (S)-9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-8-methoxy-1,2,4,4a,5,6-hexahydro-3H-benzo[b]pyrazino[1,2-d][1,4]oxazine -3-tert-butyrate (CLM-2d)

[1057] Intermediate CLM-2c (3.3 g, 0.01 mol) was dissolved in toluene (40 mL), and acrylic acid (1.02 g, 0.014 mol) was added. The reaction was carried out at 90 °C for 14 h under nitrogen atmosphere. The reaction system was cooled to room temperature, and urea (5.66 g, 0.094 mol) and acetic acid (0.54 mL, 0.01 mol) were added. The reaction was carried out at 110 °C for 48 h. The mixture was extracted with ethyl acetate, washed with sodium bicarbonate, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to obtain intermediate CLM-2d (1.3 g, 30.83%).

[1058] LC-MS(ESI):[M+H] + =447.20.

[1059] Step 5: (S)-1-(8-methoxy-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazine) -9-yl)dihydropyrimidine-2,4(1H,3H)-dione (CLM-2)

[1060] Intermediate CLM-2d (1.3 g, 0.03 mmol) was dissolved in dichloromethane:dioxane hydrochloride = 10:1 (2 mL) and reacted at room temperature for 2 hours. The reaction solution was filtered to give a white solid intermediate CLM-2 (500 mg, 49.55%).

[1061] 1 H NMR (400MHz, DMSO) δ10.31(s,1H),6.89(d,J=8.6Hz,1H),6.76(d,J=8.7Hz ,1H),4.43(td,J=10.7,3.0Hz,1H),4.22(s,1H),3.73(s,3H),3.55(t,J=6. 7Hz,2H),3.41–3.25(m,4H),3.19(dd,J=12.4,3.1Hz,1H),3.08(s,2H),2. 66(t,J=6.7Hz,2H),2.09(ddt,J=15.3,9.8,4.6Hz,1H),2.01–1.88(m,1H).

[1062] LC-MS(ESI):[M+H] + =347.30

[1063] 3) Synthesis of CLM-3

[1064] Step 1: (S)-2-(4-benzyl-1-(2-fluoro-4-nitrophenyl)-1,4-diazaheptane-2-yl)ethanol (intermediate CLM-3b)

[1065] (S)-2-(4-benzyl-1,4-diazaheptane-2-yl)ethanol (1.97 g, 8.41 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (20 mL), and 3,4-difluoronitrobenzene (1.34 g, 8.41 mmol, 1.0 eq) was added. The reaction mixture was heated to 100 °C and reacted at this temperature for 8 hours. After cooling the reaction system to room temperature, it was added to water and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give a yellow solid intermediate CLM-3b (2.0 g, 63.7%).

[1066] LCMS(ESI):[M+H] + =374.29.

[1067] Step 2: (S)-4-benzyl-10-nitro-1,2,3,4,5,5a,6,7-octahydrobenzo[b][1,4]diazaheptano[1,2-d][1,4]oxazoline (intermediate CLM-3c)

[1068] Intermediate CLM-3b (2.0 g, 5.36 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (50 mL), and potassium tert-butoxide (2.05 g, 18.26 mmol, 3.75 eq) was added. The reaction mixture was incubated at 60 °C for 8 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give intermediate CLM-3c (1.0 g, 58.1%) as a yellow solid.

[1069] LCMS(ESI):[M+H] + =354.49.

[1070] Step 3: (S)-4-benzyl-1,2,3,4,5,5a,6,7-octahydrobenzo[b][1,4]diazepine[1,2-d][1,4]oxazoline-10-amine (intermediate CLM-3d)

[1071] Intermediate CLM-3c (1.0 g, 2.83 mmol, 1.0 eq) and tetrahydroxydiboron (0.76 g, 8.49 mmol, 1.0 eq) were dissolved in DMF (10 mL). 4,4'-bipyridine (22.1 mg, 0.05 eq) was slowly added to the system at -20 °C. After the addition was complete, the mixture was allowed to react at room temperature for one hour. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate to obtain crude intermediate CLM-3d (840 mg).

[1072] LCMS(ESI):[M+H] + =324.38.

[1073] Step 4: (S)-1-(4-benzyl-1,2,3,4,5,5a,6,7-octahydrobenzo[b][1,4]diazaporon[1,2-d][1,4]oxazoline-10-yl)dihydropyrimidine-2,4(1H,3H)-dione (intermediate CLM-3e)

[1074] Intermediate CLM-3d (0.5 g, 1.55 mmol, 1.0 eq) was dissolved in toluene (10 mL), and acrylic acid (222.8 mg, 3.09 mmol, 2 eq) was added to the reaction system. The mixture was heated to 90 °C and reacted for 24 hours. The reaction system was then cooled to room temperature, and acetic acid (5 mL) and urea (463.8 mg, 7.72 mmol, 5 eq) were added to the reaction solution. The mixture was heated to 100 °C and reacted for 24 hours. Water (200 mL) and sodium bicarbonate were added to the reaction system to neutralize it to a weakly alkaline state, and the mixture was extracted with ethyl acetate (250 mL × 3 times). The mixture was washed with saturated brine (250 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give a light yellow solid intermediate CLM-3e (0.18 g, 27.7%).

[1075] 1 H NMR(400MHz,MeOD)δ7.65–7.49(m,5H),7.08–6.80(m,3H),4.55–4.39(m,2H),4.25–3.99(m,3H),3.79(t,J=6 .6Hz,2H),3.70–3.48(m,5H),3.31–3.20(m,1H),2.80(t,J=6.8Hz,2H),2.35–2.12(m,3H),1.89–1.80(m,1H).

[1076] LCMS(ESI):[M+H] + =421.49.

[1077] Step 5: (S)-1-(1,2,3,4,5,5a,6,7-octahydrobenzo[b][1,4]diazazo[1,2-d][1,4]oxazoline-10-yl)dihydropyrimidine-2,4(1H,3H)-dione (intermediate CLM-3)

[1078] Intermediate CLM-3e (1.9 g, 4.52 mmol, 1.0 eq) was dissolved in methanol (20 mL), and palladium on carbon (2 g, 10% wt) was added to the system. The reaction was then carried out overnight under a hydrogen atmosphere. The reaction system was concentrated under reduced pressure, and the crude product was slurried with n-hexane to give a light yellow solid intermediate CLM-3 (1.56 g, >99%).

[1079] 1 H NMR(400MHz,MeOD)δ6.96(d,J=8.7Hz,1H),6.92(dd,J=8.6,2.4Hz,1H),6.85(d,J=2.3Hz,1H),4.31–4.17(m,2H),4.17–4.05(m ,1H),3.79(t,J=6.8Hz,2H),3.71–3.45(m,5H),3.21–3.09(m,1H),2.80(t,J=6.8Hz,2H),2.30–2.10(m,3H),1.92–1.84(m,1H).

[1080] LCMS(ESI):[M+H] + =331.29.

[1081] 4) Synthesis of CLM-4

[1082] Step 1: (R)-4-(2-fluoro-5-methoxy-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (compound CLM-4a)

[1083] In an air atmosphere, 1,2-difluoro-4-methoxy-5-nitrobenzene (32.50 g, 171.85 mmol) was added to a solution of tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylate (37.17 g, 171.85 mmol) in dimethyl sulfoxide (370 mL), and the reaction was carried out overnight at 120 °C. After the reaction was completed, the reaction solution was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the solution was purified by column chromatography (PE:EA = 0-30%) to give a yellow solid compound CLM-4a (38 g, 57.38%).

[1084] 1H NMR (400MHz, DMSO-d6) δ7.80(d,J=13.8Hz,1H),6.69(d,J=7.6Hz,1H),4.77(t,J=5.3Hz,1H),4.03(q,J=7.2Hz,1H),3.91(s ,3H),3.56–3.46(m,2H),3.31(dd,J=12.8,3.1Hz,2H),3.23–2.94(m,2H),1.99(s,1H),1.42(s,9H),1.17(t,J=7.1Hz,1H).

[1085] LC-MS(ESI):[M+H- t Bu] + =330.38.

[1086] Step 2: (R)-9-methoxy-8-nitro-1,2,4-,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (compound CLM-4b)

[1087] Under a nitrogen atmosphere and at 0°C, potassium tert-butoxide (16.60 g, 147.90 mmol) was added in portions to a DMF solution (380 mL) of compound CLM-4a (38 g, 98.60 mmol), and the reaction was carried out at 60°C for 2 hours. After the reaction was completed, the reaction solution was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the solution was purified by column chromatography (PE:EA = 0-30%) to give a yellow solid compound CLM-4b (25.31 g, 70.25%).

[1088] LC-MS(ESI):[M+H- t Bu] + =310.28.

[1089] Step 3: (R)-8-amino-9-methoxy-1,2,4-,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (compound CLM-4c)

[1090] Palladium on carbon (2.46 g, 20.78 mmol) was added to a methanol (25 mL) solution of compound CLM-4b (25.31 g, 69.27 mmol) under a hydrogen atmosphere, and the reaction was carried out overnight at room temperature. After the reaction was complete, the solution was filtered through diatomaceous earth, and the solvent was evaporated to obtain a brown solid compound CLM-4c (19.93 g, 85.78%).

[1091] LC-MS(ESI):[M+H] + =336.49.

[1092] Step 4: (R)-3-((3-(tert-butoxycarbonyl)-9-methoxy-1,2,3,4-4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)amino)propionic acid (compound CLM-4d)

[1093] Under a nitrogen atmosphere, acrylic acid (6.42 g, 89.13 mmol) was added to a 100 mL toluene solution of compound CLM-4c (19.93 g, 59.42 mmol), and the reaction was carried out overnight at 90 °C. After the reaction was completed, the next reaction was carried out according to the theoretical yield.

[1094] LC-MS(ESI):[M+H] + =407.39.

[1095] Step 5: (R)-8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-9-methoxy-1,2,4-a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (compound CLM-4e)

[1096] Under a nitrogen atmosphere, urea (17.84 g, 297.08 mmol) and acetic acid (120 mL) were added to a toluene solution (100 mL) of compound CLM-4d (24.21 g, 59.42 mmol), and the reaction was carried out overnight at 110 °C. After the reaction was complete, the reaction solution was extracted with EA, the organic phase was neutralized with saturated sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The solution was then slurried with a PE:EA mixture of 1:2, filtered, and concentrated to obtain a brown solid compound CLM-4e (5.23 g, 20.35%).

[1097] LC-MS(ESI):[M+H- t Bu] + =377.39.

[1098] Step 6: (R)-1-(9-methoxy-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound CLM-4)

[1099] Compound CLM-4e (2.50 g, 5.78 mmol) was dissolved in 25 mL of dichloromethane solution under air atmosphere and reacted at room temperature for two hours. After concentration under reduced pressure, a white solid compound CLM-4 (2.37 g, 123.36%) was given.

[1100] 1H NMR (400MHz, DMSO-d6) δ10.22(s,1H),6.67(s,1H),6.66(s,1H),4.25(dd,J=11.0,2.5Hz,1H),4.11(d,J=12.1Hz,1H),3.92(dd,J= 11.0,7.5Hz,1H),3.73(s,3H),3.71–3.65(m,2H),3.43–3.39(m,3H),3.08–2.93(m,2H),2.85–2.72(m,1H),2.63(t,J=6.7Hz,2H).

[1101] LC-MS(ESI):[M+H] + =333.39.

[1102] 5) Synthesis of CLM-5

[1103] Step 1: tert-butyl(R)-4-(5-chloro-2-fluoro-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylic acid ester (compound CLM-5a)

[1104] In an air atmosphere, 1-chloro-4,5-difluoro-2-nitrobenzene (35.79 g, 184.94 mmol) was added to a dimethyl sulfoxide (400 mL) solution of tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylic acid ester (40.0 g, 184.94 mmol) and reacted overnight at 120 °C. After the reaction was complete, the reaction solution was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the solution was purified by column chromatography (EA:PE = 0-40%) to give a yellow solid compound CLM-5a (67.26 g, 93.30%).

[1105] 1 H NMR (400MHz, DMSO-d6) δ8.02(d,J=13.7Hz,1H),7.20(d,J=8.1Hz,1H),4.78(t,J=5.3Hz,1H),3. 93(d,J=13.3Hz,2H),3.58–3.43(m,2H),3.08(d,J=64.5Hz,2H),2.54–2.45(m,3H),1.41(s,9H).

[1106] LC-MS(ESI):[M+H] + =390.49.

[1107] Step 2: Tert-butyl(R)-9-chloro-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid ester (compound CLM-5b)

[1108] Under atmospheric conditions at 0°C, potassium tert-butoxide (13.60 g, 121.12 mmol) was added to a solution of compound CLM-5a (31.50 g, 80.81 mmol) in N,N-dimethylformamide (300 mL), and the mixture was reacted at 60°C for 2 hours. After the reaction was complete, the reaction mixture was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the mixture was purified by column chromatography (EA:PE = 0-30%) to give a yellow oily compound CLM-5b (19.80 g, 62.26%).

[1109] LC-MS(ESI):[M-Boc+H] + =270.17.

[1110] Step 3: Tert-butyl(R)-8-amino-9-chloro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid ester (compound CLM-5c)

[1111] In an atmosphere at 25°C, tetrahydroxydiboron (28.22 g, 314.76 mmol) was slowly added to a solution of compound CLM-5b (38.80 g, 104.92 mmol) in N,N-dimethylformamide (400 mL). The mixture was then moved to -10°C and 4,4'-bipyridine (819.37 mg, 5.25 mmol) was slowly added in portions. The reaction was then allowed to proceed at room temperature for 0.5 hours. The reaction was quenched with water, and the reaction mixture was extracted with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography (EA:PE = 0-30%) to obtain a yellow solid compound CLM-5c (29.95 g, 84.00%).

[1112] LC-MS(ESI):[M+H] + =339.39.

[1113] Step 4: (R)-3-((3-(tert-butoxycarbonyl)-9-chloro-1,2,3,4,4a-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazoline-8-yl)amino)propionic acid (compound CLM-5d)

[1114] Under a nitrogen atmosphere, acrylic acid (50.81 g, 705.08 mmol) was added to a toluene (300 mL) solution of compound CLM-5c (29.95 g, 88.13 mmol), and the reaction was carried out overnight at 100 °C. After the reaction was complete, the reaction solution was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a brown solid compound CLM-5d (34.37 g, 94.68%).

[1115] LC-MS(ESI):[M+H] + =412.39.

[1116] Step 5: Tert-butyl(R)-9-chloro-8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid ester (compound CLM-5e)

[1117] Under a nitrogen atmosphere, urea (25.06 g, 417.23 mmol) was added to toluene (350 mL) containing compound CLM-5d (34.37 g, 83.45 mmol), and the reaction was carried out overnight at 100 °C. After the reaction was complete, the reaction solution was extracted with EA, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the solution was purified by column chromatography (PE:EA = 0-30%) to give a black solid compound CLM-5e (1.06 g, 2.91%).

[1118] LC-MS(ESI):[M+H] + =437.39.

[1119] Step 6: (R)-1-(9-chloro-1,2,3,4,4a-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound CLM-5)

[1120] In an air atmosphere, a solution of 1,4-dioxane containing hydrogen chloride (3 mL) was added to a dichloromethane solution of compound CLM-5e (86.00 mg, 0.196 mmol), and the reaction was carried out at 25 °C for 1 hour. The solvent was evaporated, purified by preparative liquid chromatography, and lyophilized to give a yellow solid compound CLM-5 (65.00 mg, 99%).

[1121] LC-MS(ESI):[M+H] + =337.29.

[1122] 6) Synthesis of CLM-6

[1123] Step 1: (R)-9-fluoro-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (compound CLM-6b)

[1124] Under a nitrogen atmosphere, CMBP (2.23 g, 9.25 mmol) was added to a solution of CLM-6a (1 g, 4.62 mmol) and 2,4-difluoro-5-nitrophenol (809.55 mg, 4.62 mmol) in toluene (20 mL), and the mixture was stirred at 115 °C for 10 hours. After the reaction was complete, the solvent was evaporated, and the mixture was purified by column chromatography (EA:PE = 0-30%) to give a yellow oily compound CLM-6b (690 mg, 42.23%).

[1125] 1 H NMR (400MHz, DMSO-d6) δ7.43(d,J=7.5Hz,1H),7.01(d,J=14.8Hz,1H),4.38(dd,J=11.3,3.3Hz,1 H),4.04–3.87(m,4H),2.97(d,J=9.0Hz,2H),2.77–2.57(m,1H),1.42(s,9H),1.29–1.18(m,1H).

[1126] LC-MS(ESI):[M- t Bu+H] + =298.38.

[1127] Step 2: (R)-8-amino-9-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazino[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (compound CLM-6c)

[1128] Palladium on carbon (60 mg, 0.51 mmol) was added to a methanol (7 mL) solution of compound CLM-6b (690 mg, 1.95 mmol) under a hydrogen atmosphere, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solution was filtered through diatomaceous earth, and the solvent was evaporated to obtain a purple oily compound CLM-6c (580 mg, 91.85%).

[1129] 1H NMR (400MHz, DMSO-d6) δ6.65(d,J=13.5Hz,1H),6.19(d,J=8.8Hz,1H),4.51(s,2H),4.20(dd,J=10.7,2.6Hz,1H),4.08–4.00(m ,1H),3.97–3.84(m,2H),3.83–3.76(m,1H),3.63–3.54(m,1H),2.82–2.70(m,1H),2.43–2.33(m,1H),1.99(s,1H),1.41(s,9H).

[1130] LC-MS(ESI):[M- t Bu+H] + =268.37.

[1131] Step 3: (R)-8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-9-fluoro-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3(4H)-carboxylic acid tert-butyl ester (compound CLM-6d)

[1132] Acrylic acid (387.76 mg, 5.38 mmol) was added to a toluene (6 mL) solution of CLM-6c (580 mg, 1.79 mmol) at room temperature, and the reaction mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. After the reactants had reacted completely, the mixture was cooled to room temperature, and urea (538.40 mg, 8.96 mmol) and acetic acid (3 mL) were added. The mixture was then heated to 100 °C for 12 hours under a nitrogen atmosphere. After the reaction was complete, the solvent was evaporated, and the mixture was purified by column chromatography (EA:PE 0-50%) to give a yellow oily compound CLM-6d (170 mg, 22.84%).

[1133] LC-MS(ESI):[M+H] + =421.49.

[1134] Step 4: (R)-1-(9-fluoro-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazino[1,2-d][1,4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound CLM-6)

[1135] Compound CLM-6d (170 mg, 0.40 mmol) was dissolved in dichloromethane, and dioxane hydrochloride solution was added while stirring. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was filtered to obtain a gray solid compound CLM-6 (105 mg, 81.07%).

[1136] 1H NMR (400MHz, DMSO-d6) δ10.39(s,1H),6.95(d,J=12.8Hz,1H),6.83(d,J=7.6Hz,1H),4.30(dd,J=11.1,2.7Hz,1H),4.07–3.93 (m,2H),3.66–3.58(m,2H),3.53–3.46(m,2H),3.39–3.32(m,2H),3.08–2.98(m,2H),2.84–2.72(m,1H),2.68(t,J=6.7Hz,2H).

[1137] LC-MS(ESI):[M+H] + =321.38.

[1138] 7) Synthesis of CLM-7

[1139] Step 1: 2-Bromo-5-fluorophenylacetic acid ester (compound CLM-7b)

[1140] Compound CLM-7a (10.0 g, 52.4 mmol) and triethylamine (15.9 g, 157 mmol) were dissolved in dichloromethane (20 mL). Acetyl chloride (4.5 g, 57.6 mmol) was added dropwise to the reaction solution at 0 °C. The reaction was carried out at room temperature for 1 hour. The mixture was washed with water, extracted with ethyl acetate, washed with saturated brine, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain a yellow liquid compound CLM-7b (10 g, 81.9%).

[1141] 1 H NMR (600MHz, CDCl3) δ7.60–7.57(m,1H),6.99–6.86(m,2H),2.39(s,3H).

[1142] Step 2: 1-(3-bromo-6-fluoro-2-hydroxyphenyl) ethyl-1-one (compound CLM-7c)

[1143] Aluminum trichloride (8.5 g, 64.3 mmol) was added to compound CLM-7b (10.0 g, 42.8 mmol), and the reaction was carried out at 160 °C for 0.5 h. The reaction was quenched with saturated ammonium chloride in an ice-water bath, washed with water, extracted with ethyl acetate, washed with saturated brine, concentrated under reduced pressure to obtain a crude product, and purified by column chromatography to give a yellow solid compound CLM-7c (2.0 g, 20.0%).

[1144] 1H NMR (600MHz, CDCl3) δ8.12 (d, J = 7.5Hz, 1H), 6.83 (d, J = 11.7Hz, 1H), 6.24 (s, 1H), 2.62 (d, J = 5.2Hz, 3H).

[1145] LC-MS(ESI):[M+H] + =235.10.

[1146] Step 3: Tert-butyl 4-((4-acetyl-2-bromo-5-fluorophenoxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylate (compound CLM-7e)

[1147] Compound CLM-7c (2.0 g, 8.5 mmol) was dissolved in tetrahydrofuran (20 mL), followed by the addition of CLM-7d (1.9 g, 9.3 mmol) and PPh3 (2.5 g, 9.4 mmol). Under nitrogen protection, DEAD (1.6 g, 9.4 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 2 hours. The crude product was concentrated under reduced pressure and purified by column chromatography to give a yellow solid compound CLM-7e (2.6 g, 70.7%).

[1148] 1 H NMR (400MHz, CDCl3) δ8.15(d,J=7.9Hz,1H),6.64(d,J=12.4Hz,1H),5.88(s,1H),4.55(s,2H ),4.00–3.98(m,2H),3.59(t,J=5.7Hz,2H),2.61(d,J=5.1Hz,3H),2.24(s,2H),1.50(s,9H).

[1149] LC-MS(ESI):[M+H- t Bu] + =372.20.

[1150] Step 4: Tert-butyl-5-acetyl-6-fluoro-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (compound CLM-7f)

[1151] Compound CLM-7e (500 mg, 1.2 mmol) was dissolved in toluene (5 mL), and AIBN (95 mg, 0.12 mmol) and (n-Bu)3SnH (1.0 g, 3.6 mmol) were added. The mixture was reacted under nitrogen protection at 110 °C for 2 hours. After concentration under reduced pressure and purification by column chromatography, a brown oily compound CLM-7f (90 mg, 22.1%) was obtained.

[1152] 1H NMR (400MHz, CDCl3) δ7.72(d,J=7.4Hz,1H),6.56(d,J=11.6Hz,1H),4.53(s,2H),4.11(s,2H),2.9 0(t,J=12.8Hz,2H),2.60(d,J=5.9Hz,3H),1.92-1.85(m,2H),1.71(d,J=13.6Hz,2H),1.51(s,9H).

[1153] LC-MS(ESI):[M+H- t Bu] + =294.25.

[1154] Step 5: tert-butyl(Z)-6-fluoro-5-(1-acylhydrazide ethylidene)-2H-spiro[benzofuran-3,4'-piperidine]-1'-carboxylate (compound CLM-7g)

[1155] Compound CLM-7f (80 mg, 0.23 mmol) was dissolved in ethanol (2 mL), and hydrazine hydrate (1 mL) was added. The reaction was carried out at 95 °C for 1 hour. The solution was concentrated under reduced pressure to obtain crude yellow oily compound CLM-7 g (100 mg, 120%). The crude product was used directly in the next reaction step.

[1156] LC-MS(ESI):[M+H] + =364.35.

[1157] Step 6: 3-Methyl-1H,6H-spiro[furan[3,2-f]indazole-5,4'-piperidine] (compound CLM-7h)

[1158] Compound CLM-7g (100 mg, 0.27 mmol) was dissolved in ethylene glycol (2 mL) and reacted at 165 °C for 9 hours. The solution was concentrated under reduced pressure to obtain a crude, yellow, oily compound CLM-7h (100 mg, 150%). The crude product was used directly in the next reaction step.

[1159] LC-MS(ESI):[M+H] + =244.30.

[1160] Step 7: Tert-butyl-3-methyl-1H,6H-spiro[furan[3,2-f]indazole-5,4'-piperidine]-1'-carboxylate (compound CLM-7i)

[1161] Compound CLM-7h (100 mg, 0.41 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (120 mg, 1.23 mmol) and (Boc)₂O (135 mg, 0.62 mmol) were added sequentially. The reaction was carried out at room temperature for 2 hours. The crude product was concentrated under reduced pressure and purified by column chromatography to obtain a yellow solid compound CLM-7i (80 mg, 56.6%).

[1162] 1 H NMR(400MHz, CDCl3)δ7.32(d,J=0.8Hz,1H),6.75(d,J=0.7Hz,1H),5.86(s,1H),4.50(s,2H),4.19–4 .09(m,2H),2.93(t,J=12.7Hz,2H),2.54(s,3H),1.96-1.88(m,2H),1.84–1.76(m,2H),1.52(s,9H).

[1163] LC-MS(ESI):[M+H] + =344.35.

[1164] Step 8: Tert-butyl 1-(2,6-dioxadiazin-3-yl)-3-methyl-1H,6H-spiro[furan[3,2-f]indazole-5,4'-piperidine]-1'-carboxylate (compound CLM-7k)

[1165] Compound CLM-7i (80 mg, 0.22 mmol) was dissolved in tetrahydrofuran:dimethyl sulfoxide = 1:1 (2 mL), and sodium hydride (16 mg, 0.66 mmol) was added at 0 °C. The reaction was carried out at 0 °C for 0.5 h. CLM-7j (63 mg, 0.33 mmol) and potassium iodide (36.5 mg, 0.22 mmol) were added to the reaction solution, and the reaction was carried out at room temperature for 1 h. The reaction was quenched by saturated ammonium chloride. The crude product was concentrated under reduced pressure and purified to obtain a white solid compound CLM-7k (10 mg, 9.7%).

[1166] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.56(s,1H),6.84(s,1H),5.57(dd,J=11.8,5.1Hz,1H),4.50(s,2H),3.95(d,J=13.3Hz,2H),2 .93(s,2H),2.81–2.75(m,1H),2.71–2.62(m,2H),2.39(s,3H),2.19-2.15(m,1H),1.85–1.76(m,2H),1.70-1.65(m,2H),1.44(s,9H).

[1167] LC-MS(ESI):[M+H] + =455.40.

[1168] Step 9: 3-(3-methyl-1H,6H-spiro[furan[3,2-f]indazole-5,4'-piperidin]-1-yl)piperidin-2,6-dione (compound CLM-7)

[1169] The compound CLM-7k (10 mg, 22 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added to the reaction solution. The mixture was reacted at room temperature for 1 hour, and the crude product was concentrated under reduced pressure. After purification, the white solid compound CLM-7 (5.5 mg, 70.5%) was obtained.

[1170] 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),7.39(s,1H),6.89(s,1H),5.59(dd,J=11.8,5.0Hz,1H),4.56(s,2H),3.39(s,2H),3.0 8–3.01(m,2H),2.82–2.77(m,1H),2.73–2.63(m,2H),2.42(s,3H),2.22–2.12(m,1H),2.10–1.96(m,2H),1.93–1.82(m,2H).

[1171] LC-MS(ESI):[M+H] + =355.30.

[1172] 8) Synthesis of CLM-8

[1173] Step 1: tert-butyl 3-formyl-4-hydroxy-1H-indole-1-carboxylic acid (CLM-8b)

[1174] Compound CLM-8a (5 g, 31 mmol) was dissolved in a mixed solvent of dichloromethane (450 mL) and triethylamine (50 mL), and DMAP (0.57 g, 4.65 mmol) was added. A solution of Boc₂O (6.77 g, 31 mmol) in dichloromethane (50 mL) was added dropwise under ice bath conditions, and the mixture was stirred overnight at room temperature. The reaction was detected by TLC upon completion. The reaction solution was concentrated and purified by column chromatography (PE:EA = 5:1) to obtain a pale yellow solid CLM-8b (6.2 g, 76.5%).

[1175] 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.92(s,1H),8.72(s,1H),7.59(d,J=8. 3,0.7Hz,1H),7.31(t,J=8.2Hz,1H),6.74(d,J=8.0,0.8Hz,1H),1.66(s,9H).

[1176] LC-MS(ESI):[M- t Bu+H] + =206.25.

[1177] Step 2: tert-butyl 5-bromo-3-formyl-4-hydroxy-1H-indole-1-carboxylic acid (CLM-8c)

[1178] CLM-8b (6.2 g, 23.7 mmol) was dissolved in a mixed solvent of chloroform (30 mL) and tetrahydrofuran (30 mL), and PHBP (7.59 g, 23.7 mmol) was added. The mixture was stirred overnight at room temperature. The reaction was detected by TLC after completion. The reaction solution was concentrated and purified by column chromatography (PE:EA = 5:1) to obtain a pale yellow solid CLM-8c (8.1 g, 100%).

[1179] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),9.88(s,1H),8.81(s,1H),7.57(d,J=8.8Hz,1H),7.52(d,J=8.8Hz,1H),1.65(s,9H).

[1180] LC-MS(ESI):[M- t Bu+H] + =284.06.

[1181] Step 3: 5-Bromo-4-((1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-3-formyl-1H-indole-1-carboxylic acid tert-butyl ester (CLM-8d)

[1182] 4-(((methanesulfonyl)oxy)methyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (10.10 g, 34.69 mmol) (see synthesis on page 71 of WO2022253309) and potassium carbonate (7.27 g, 52.03 mmol) were dissolved in acetonitrile (100 mL). After stirring at 60 °C for 5 min, CLM-8c (5.9 g, 17.34 mmol) was added, and the reaction was carried out at 60 °C for 2 h. The reaction was completed by TLC. The reaction solution was concentrated and purified by column chromatography (PE:EA = 3:1) to obtain a pale yellow solid CLM-8d (5 g, 53.8%).

[1183] 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.39(s,1H),7.89(d,J=8.9Hz,1H),7.67(d,J=8.8Hz,1H),5.8 7(s,1H),4.46(s,2H),3.92–3.83(m,2H),3.53–3.43(m,2H),2.27(s,2H),1.65(s,9H),1.42(s,9H).

[1184] Step 4: 5-Bromo-4-((1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-3-(hydroxymethyl)-1H-indole-1-carboxylic acid tert-butyl ester (CLM-8e)

[1185] CLM-8d (7.4 g, 13.82 mmol) was dissolved in a mixed solvent of tetrahydrofuran (30 mL) and methanol (30 mL). Sodium borohydride (0.63 g, 16.58 mmol) was added in portions under ice bath conditions, and the mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until complete. The reaction solution was concentrated and purified by column chromatography (PE:EA = 3:1) to obtain a pale yellow solid, CLM-8e (6.8 g, 91.5%).

[1186] 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=8.8Hz,1H),7.57–7.44(m,2H),5.91(s,1H),5.16(t,J=5.3Hz,1H),4.73(dd,J =5.3,1.4Hz,2H),4.41(s,2H),3.90(s,2H),3.50(t,J=5.6Hz,2H),2.32–2.25(m,2H),1.62(s,9H),1.43(s,9H).

[1187] Step 5: 8-(hydroxymethyl)-2H,6H-spiro[furano[2,3-e]indole-3,4'-piperidine]-1',6-dicarboxylic acid di-tert-butyl ester (CLM-8f)

[1188] CLM-8e (6.8 g, 12.65 mmol) was dissolved in toluene (70 mL), and AIBN (6.23 g, 37.96 mmol) and tri-n-butyltin hydrogen (7.36 g, 25.30 mmol) were added. The reaction was carried out at 110 °C for 1 hour. The reaction was detected by TLC after completion. The reaction solution was concentrated and purified by column chromatography (PE:EA = 3:1) to obtain a white solid CLM-8f (4.7 g, 81%).

[1189] Step 6: Synthesis of 8-methyl-2H,6H-spiro[furano[2,3-e]indole-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (CLM-8g)

[1190] CLM-8f (0.5 g, 1.09 mmol) and sodium iodide (1.31 g, 8.72 mmol) were dissolved in acetonitrile (5 mL), purged three times with nitrogen, and trichlorosilane (1.11 mL, 8.72 mmol) was added dropwise to the reaction system. The reaction was carried out at 80 °C for 1 hour. After the reaction was completed, 1 mL of sodium thiosulfate aqueous solution was added to quench the reaction system, and the reaction system was concentrated until it reached a solid state. The solid was then dissolved in a mixed solvent of dichloromethane (9 mL) and methanol (1 mL), and triethylamine (0.33 g, 3.22 mmol) and di-tert-butyl dicarbonate (0.35 g, 1.61 mmol) were added. The reaction was carried out at room temperature for 1 hour. The reaction was detected by TLC. The reaction solution was concentrated and purified by column chromatography (PE:EA = 3:1) to obtain a white solid CLM-8g (0.144 g, 39.2%).

[1191] 1 H NMR(400MHz,DMSO-d6)δ10.65(s,1H),6.95(s,1H),6.87–6.79(m,2H),4.49(s,2H),4.00–3.8 5(m,2H),3.06–2.79(m,2H),2.32(s,3H),1.82–1.69(m,2H),1.67–1.56(m,2H),1.43(s,9H).

[1192] LC-MS(ESI):[M- t Bu+H] + =287.38

[1193] Step 7: 6-(2,6-bis(benzyloxy)pyridin-3-yl)-8-methyl-2H,6H-spiro[furano[2,3-e]indole-3,4'-piperidine]-1'-carboxylic acid tert-butyl ester (CLM-8h) [119...

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