Compounds with STAT6 degradation activity, pharmaceutical compositions containing them, and their applications.

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a compound with STAT6 degradation activity, a pharmaceutical composition comprising the compound, and its applications. The compound has the structure shown in formula (I), which can efficiently and selectively degrade STAT6 protein in cells without biologically significant degradation of other proteins in the STAT family (especially STAT3 protein), and can be used for the prevention and / or treatment of diseases and / or conditions that at least partially respond to STAT6.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a compound with STAT6 degradation activity, a pharmaceutical composition comprising the compound, and the application thereof. The compound is capable of effectively degrading STAT6 protein in cells, without biologically significant degradation of other proteins in the STAT family (especially STAT3 protein), and can be used for the prevention and / or treatment of diseases and / or conditions that at least partially respond to STAT6. Background Technology

[0002] The ubiquitin-proteasome pathway (UPP), or ubiquitin-proteasome system (UPS), plays a crucial role in regulating key regulatory proteins and degrading misfolded and abnormal proteins. Defects or imbalances in this system can lead to a variety of diseases. The covalent linking of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0003] UPP induces selective protein degradation. This includes using fusion protein ubiquitin target proteins and small molecule probes to achieve proteasome-dependent degradation. Bifunctional compounds contain a ligand that binds to the target protein and an E3 ubiquitin ligand, which induces proteasome-dependent degradation of the target protein by recruiting E3 ubiquitin ligand enzymes and subsequent ubiquitination. These drug-like molecules offer the possibility of regulating protein overexpression. These compounds, when added to cells or administered to animals or humans, can inactivate the relevant proteins and can be used as biochemical agents, opening up new modalities for disease treatment by removing pathogenic or carcinogenic proteins (Chemistry & Biology, 2010, 17(6): 551-555; Chembiochem, 2005, 6(1): 40-46).

[0004] In the 1990s, different subtypes of T helper cells (TH cells) were discovered, and the characteristic of B cells driven by TH2 cells to produce IgE was identified, leading to the use of the term type 2 inflammation. In certain situations, abnormal type 2 immune and inflammatory responses occur, resulting in type 2 chronic inflammatory diseases such as atopic dermatitis (AD), chronic pruritus (CPG), chronic urticaria (CU), asthma, chronic rhinitis with nasal polyps (CRSwNP), eosinophilic gastrointestinal disorders, and allergic rhinitis.

[0005] STAT6, a member of the STAT family (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6), plays a crucial role in cytokine signal transduction and mediating type II T helper (Th2) cell differentiation (Immunologic Research 2011, 50(1), 87-96). STAT6 activation is primarily induced by interleukin-4 (IL-4) and interleukin-13 (IL-13). IL-4 and IL-13 bind to the IL-4α receptor (IL-4Rα), leading to phosphorylation of the intracellular tyrosine residues of IL-4Rα by receptor-associated Janus kinases (JAKs) or other kinases, creating a docking site for STAT6. STAT6 binds to IL-4Rα via its Src homology 2 (SH2) domain and is phosphorylated by JAKs or other kinases. Similar to other STAT members, phosphorylated STAT6 protein recognizes a phosphotyrosine-containing peptide through its SH2 domain, forming a homodimer. The dimer form of STAT6 is transported from the cytoplasm to the nucleus, where it binds to target DNA for gene transcription (Cytokine 2015, 75 (1), 38-50; J. Biol. Chem. 1998, 273 (28), 17634-17642.).

[0006] STAT6 is an important target for the treatment of type 2 inflammation. IL-4 and IL-13 are considered mediators of many immune diseases, and they exert physiological effects through STAT6 (J Clin Immunol. 2015 October; 35(7): 615-623.). Dupilumab, targeting IL-4Rα, thereby simultaneously inhibiting the IL-4 and IL-13 mediated signaling pathways, has been approved for the treatment of diseases such as Alzheimer's disease (AD), asthma, CRSwNP, CPG, and eosinophilic esophagitis. Overexpression of STAT6 can lead to severe early-onset atopic diseases, eosinophilic gastrointestinal diseases, recurrent skin and respiratory infections, etc. (J Allergy Clin Immunol. 2023 Jul;152(1):53-55.). - / - The expression of Th2 cytokines (including IL-4, IL-5, and IL-13) in mice was reduced. Consistent with the role of STAT6 in IL-4 and IL-13 signaling, STAT6-deficient mice were unable to generate a type 2 immune response. In various models of allergic airway disease, food allergy, eosinophilic esophagitis, and atopic dermatitis, STAT6-deficient mice showed significantly reduced lung inflammation. - / -The mice showed no significant difference from the control group, indicating good safety (Immunol Res. 2011 May; 50(1): 87-96). Therefore, small molecule compounds that utilize E3 ligand enzyme-mediated protein-targeted degradation of STAT6 hold promise as drugs for treating various diseases.

[0007] As mentioned above, STAT6-mediated type 2 inflammatory diseases are all chronic diseases requiring long-term medication, placing high demands on drug safety. It is well known that high drug selectivity for a target is a crucial property affecting drug safety; therefore, the development of highly selective STAT6 inhibitors / degraders is a significant challenge for type 2 inflammatory diseases.

[0008] Unfortunately, despite extensive research over the past 20 years, most STAT6 inhibitors or degraders reported to date lack high selectivity. For example, Recludix has released a series of STAT3 / STAT6 degraders (WO2024233639, WO2024238598, WO2024238603) in the past two years, but none have investigated the selectivity for STAT6 and STAT3. Studies have shown that germline deletion of STAT3 in mice leads to early embryonic death, which is the only STAT molecule that causes embryonic death (J Clin Immunol. 2015 October; 35(7): 615-623.), a finding that clearly reveals the importance of STAT3. STAT3 deficiency leads to hyperIgE syndrome in humans (Nature. 2007, 448, 1058), manifested as eczematous dermatitis, recurrent skin and lung infections with hyperIgE. Therefore, obtaining selective STAT6 degraders, especially those with selectivity for STAT3, is crucial. Summary of the Invention

[0009] The problem the invention aims to solve

[0010] The purpose of this invention is to provide a compound with STAT6 degradation activity, a pharmaceutical composition comprising the compound, and the application thereof, wherein the compound can serve as a highly active and selective STAT6 protein degrader, without biologically significant degradation of other proteins in the STATs family (especially STAT3 proteins), and can be used to prevent and / or treat diseases and / or conditions that are at least partially responsive to STAT6.

[0011] Solution for solving the problem

[0012] The objective of this invention is achieved through the following technical solution:

[0013] <First Aspect> This invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof:

[0014]

[0015] in,

[0016] X is selected from NR 6a CHR 6a O, S, S(=O) and S(=O)2; when X and L m When connecting, X is N or CR 6a ;

[0017] Each n is independently selected from 0, 1, 2, and 3;

[0018] m is selected from 1, 2, 3, 4, 5, 6, 7, and 8;

[0019] Ring A is selected from 4-6 member saturated or partially unsaturated heterocyclic groups containing at least one nitrogen atom, 5-6 member heteroaryl groups containing at least one nitrogen atom, 8-10 member fused heterobicyclic groups containing at least one nitrogen atom, and 6-12 member fused heterobicyclic groups containing at least one nitrogen atom.

[0020] The B ring is absent, or is selected from 5-6 membered heteroaryl groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl groups; saturated or partially unsaturated 5-6 membered heterocyclic groups containing 1-2 heteroatoms independently selected from oxygen and nitrogen; and saturated or partially unsaturated C rings. 3-6 Aliphatic ring group; when ring B is absent, ring A is hydrogen-terminated;

[0021] The C ring is selected from phenyl, 5-6-membered heteroaryl, naphthyl, and 8-10-membered fused heterobicyclic groups containing 1-3 heteroatoms, each independently selected from nitrogen, oxygen, and sulfur; each of the phenyl, 5-6-membered heteroaryl, naphthyl, or 8-10-membered fused heterobicyclic group is optionally surrounded by 0, 1, 2, or 3 R atoms. c replace;

[0022] R 1 Selected from -C(R) 1a R 2a )P(=O)(OR b (OR) b ), -C(R 1a R 2a )P(=O)[OR b ][NH(CH2) q C(=O)OR T ]、

[0023] -C(R 1a R2a )P(=O)[NH(CH2) q C(=O)OR T [NH(CH2) q C(=O)OR T 、-C(R 1a R 2a )P(=O)[NHR T [NHR T 、

[0024] -C(R 1a R 2a )P(=O)[NHCH(CH3)C(=O)OR T [NHCH(CH3)C(=O)OR T 、

[0025] -C(R 1a R 2a )P(=O)[OR b [NHCH(CH3)C(=O)OR T 、-C(R 1a R 2a )P(=O)[OR b [NHC(CH3)2C(=O)OR T 、

[0026] -P(=O)(OR b )(OR b )、-P(=O)[OR b [NH(CH2) q ]​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​1a R 2a )P(=O)(OR b )(OR b )、-C(R 1a R 2a )P(=O)[OR b ][NH(CH2) q C(=O)OR T ]、

[0030] -C(R 1a R 2a )P(=O)[NH(CH2) q C(=O)OR T ][NH(CH2) q C(=O)OR T ]、-C(R 1a R 2a )P(=O)[NHR T ][NHR T ]、

[0031] -C(R 1a R 2a )P(=O)[NHCH(CH3)C(=O)OR T ][NHCH(CH3)C(=O)OR T ]、

[0032] -C(R 1a R 2a )P(=O)[OR b ][NHCH(CH3)C(=O)OR T ]、

[0033] -P(=O)(OR b )(OR b )、-P(=O)[OR b ][NH(CH2) q C(=O)OR T ]、

[0034] -P(=O)[NH(CH2) q C(=O)OR T ][NH(CH2) q C(=O)OR T ]、-P(=O)[NHR T ][NHR T ]、

[0035] -P(=O)[NHCH(CH3)C(=O)OR T ][NHCH(CH3)C(=O)ORT ] and -P(=O)[OR b ][NHCH(CH3)C(=O)OR T ];

[0036] Each q is independently selected from 0, 1, 2, and 3;

[0037] If it exists, R 1a and R 2a Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, hydroxyl and -OC 1-4 Alkyl, or R 1a and R 2a The combination forms a carbonyl group, or R 1a and R 2a Together with the carbon atom it is attached to, they form a 4-5 membered heterocycle containing oxygen atoms;

[0038] If it exists, each R b Each is independently selected from hydrogen and C. 1-20 Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, naphthyl, C 1-4 Alkylene-OC 1-20 Alkyl, C 1-4 Alkylene-C(=O)OC 1-10 Alkyl, C 1-4 Alkylene-OC(=O)-C 1-10 Alkyl, C 1-4 Alkylene-OC(=O)NH-C 1-4 Alkylene-C(=O)OC 1-10 Alkyl, C 1-4 Alkylene-OC(=O)OC 1-10 Alkyl, C 1-4 alkylene-C(=O)O-5-7 membered heterocyclic group, C 1-4 alkylene-C(=O)O-phenyl, C 1-4 Alkylene-OC(=O)-5-7 membered heterocyclic group, C 1-4 alkylene-O-5-7-membered heterocyclic group, C 1-4 Alkylene-OC(=O)O-5-7-membered heterocyclic group, C 1-4 Alkylene-C(=O)SC 1-10 Alkyl, C 1-4 Alkylene-SC(=O)-C 1-10 Alkyl, C 1-4 alkylene-C(=O)S-5-7 membered heterocyclic groups and C 1-4 alkylene-SC(=O)-5-7-membered heterocyclic group; the C 1-4 Alkyl, C 1-10 Alkyl, C 1-4Alkylene, C 1-20 Alkyl or 5-7 membered heterocyclic groups are each optionally surrounded by one or more deuterium, halogen, cyano, C 1-3 Alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino substitutions; or, two identical or different R groups. b With R 1 The phosphorus atoms in the group collectively form a 5-7 membered saturated heterocycle, which is optionally bonded by one or more deuterium, halogen, cyano, or C atoms. 1-3 The phenyl group is substituted with alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino, and the phenyl group is optionally substituted with one or more halogens.

[0039] Preferably, if present, each R b Each is independently selected from hydrogen and C. 1-20 Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, naphthyl, C 1-4 Alkylene-OC 1-20 Alkyl, C 1-4 Alkylene-C(=O)OC 1-10 Alkyl, C 1-4 Alkylene-OC(=O)-C 1-10 Alkyl, C 1-4 Alkylene-OC(=O)NH-C 1-4 Alkylene-C(=O)OC 1-10 Alkyl, C 1-4 Alkylene-OC(=O)OC 1-10 Alkyl, C 1-4 alkylene-C(=O)O-5-7 membered heterocyclic group, C 1-4 alkylene-C(=O)O-phenyl, C 1-4 Alkylene-OC(=O)-5-7 membered heterocyclic group, C 1-4 alkylene-O-5-7-membered heterocyclic group, C 1-4 Alkylene-OC(=O)O-5-7-membered heterocyclic group, C 1-4 Alkylene-C(=O)SC 1-10 Alkyl, C 1-4 Alkylene-SC(=O)-C 1-10 Alkyl, C 1-4 alkylene-C(=O)S-5-7 membered heterocyclic groups and C 1-4 alkylene-SC(=O)-5-7-membered heterocyclic group; the C 1-4 Alkyl, C 1-10 Alkyl, C 1-4 Alkylene, C 1-20Alkyl or 5-7 membered heterocyclic groups are each optionally surrounded by one or more deuterium, halogen, cyano, C 1-3 Alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino substitutions; or, two identical or different R groups. b With R 1 Phosphorus atoms in the rings together form 5-7 membered saturated heterocycles;

[0040] If it exists, each R T Each is independently selected from C 1-10 Alkyl, benzyl, and phenyl; the C 1-10 Alkyl, benzyl, or phenyl groups are each optionally radicalized by one or more deuterium, halogen, cyano, or C groups. 1-3 Alkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino substitutions; or, two identical or different R groups. T With R 1 Phosphorus atoms in the rings together form 5-7 membered saturated heterocycles;

[0041] Or, R b With R T With R 1 Phosphorus atoms in the rings together form 5-7 membered saturated heterocycles;

[0042] If it exists, each R c Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino;

[0043] R 2 Selected from hydrogen, phenyl and C 1-4 alkyl;

[0044] If it exists, each R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; or, any two Rs substituted on the same carbon atom. 3 Together with the carbon atoms it is attached to, they form C 3-5 aliphatic ring group;

[0045] If it exists, each R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-10 Alkyl, C 1-10Halogenated alkyl, isopropyl, cyclopropyl, 4-6 membered heterocyclic groups, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, dimethylamino, C 6-11 Spiroalkyl, C 5-8 Bridged alkyl groups, 5-12 spiroheterocyclic groups, 6-10 bridged heterobicyclic groups, and 8-10 fused heterobicyclic groups; the C 1-10 Alkyl, 4-6 membered heterocyclic group, C 6-11 Spiroalkyl, C 5-8 Bridged alkyl, 5-12 spiroheterocyclic, 6-10 bridged heterobicyclic, or 8-10 fused heterobicyclic groups are each optionally surrounded by one or more (e.g., 2, 3, 4, 5, or 6) deuterium, halogen, cyano, hydroxyl, methoxy, methylamino, dimethylamino, C 5-8 Bridged alkyl, phenyl, or 5-6-membered heteroaryl substitutions; or, any two R groups substituted on the same carbon atom. 4 Together with the carbon atoms it is attached to, they form C 3-5 Aliphatic cyclic group; or, any two R groups substituted on the same carbon atom. 4 The groups combine to form carbonyl groups;

[0046] If it exists, each R 5 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; or, any two Rs substituted on the same carbon atom. 5 Together with the carbon atoms it is attached to, they form C 3-5 aliphatic ring group;

[0047] If it exists, each R 6 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; or, any two Rs substituted on the same carbon atom. 6 Together with the carbon atoms it is attached to, they form C 3-5 Aliphatic cyclic group or 3-5 membered heterocyclic group; or, two R groups located on two adjacent or non-adjacent carbon atoms. 6 It forms C with the carbon atom it is attached to. 3-6 Cycloalkanes or 3-6 membered saturated heterocycles;

[0048] If it exists, R 6a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4Halogenated alkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino;

[0049] L m The linker segment consists of m identical, partially identical, or different L groups; L m One end is covalently connected to DIM, and the other end is covalently connected to any ring atom in the 5-8 membered ring framework structure.

[0050] Each L is independently selected from the following groups:

[0051] (1) by 0-3 R 1f Replacement C 3-12 Cycloalkylene;

[0052] (2) by 0-3 R 1f Replacement C 6-10 Alpha-aryl;

[0053] (3) by 0-3 R 1f Substituted 4-12-membered heterocyclic groups;

[0054] (4) by 0-3 R 1f Substituted 8-10 fused heterobicyclic groups;

[0055] (5) by 0-3 R 1f Substituted 5-12 heteroaryl groups;

[0056] (6) by 0-3 R 2f Replacement C 1-12 Alkylene;

[0057] (7) by 0-3 R 2f Replacement C 2-12 Vinyl;

[0058] (8) by 0-3 R 2f Replacement C 2-12 Ethyne-2-yl;

[0059] (9) 1-6 ethylene glycol or propylene glycol units;

[0060] (10)-C(=O)-, -C(=O)O-, -O-, -N(R 3f )-, -S-, -S(=O)-, -C(=S)-, -C(=S)O-, -S(=O)2-, -S(=O)N(R 3f )-、-S(=O)2N(R 3f )-、-C(=O)-N(R 3f )-、-N(R 3f)C(=O)-N(R 3f )-and-OC(=O)-N(R 3f )-;

[0061] If it exists, each R 1f Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, 5-12 heteroaryl, -OR 3f -C(=O)R 3f -C(=O)OR 3f -C(=O)N(R) 3f )2、-N(R 3f )2、-N(R 3f )C(=O)R 3f -N(R) 3f )C(=O)OR 3f -N(R) 3f )C(=O)N(R 3f )2、-OC(=O)R 3f -OC(=O)N(R) 3f )2、-SR 3f -S(=O)R 3f -S(=O)2R 3f and -S(=O)2N(R) 3f )2; The C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl or 5-12 heteroaryl groups are each optionally surrounded by 0-3 R groups. 3f Replace; or, any two non-adjacent R's 1f It forms a bridging ring with the carbon atom it is attached to; or, two R atoms on the same carbon atom... 1f Together with the carbon atoms they are attached to, they form an aliphatic ring;

[0062] If it exists, each R 2f Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl;

[0063] If it exists, each R 3f Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, and deuterated methoxy;

[0064] DIM is a small-molecule affinity ligand for E3 ubiquitin ligases.

[0065] In some implementations, DIM is selected from small molecule affinity ligands of CRBN, VHL, cIAP, MDM2, RNF4, AhR, DCAF16, RNF114, FEM1B, KEAP1, and DCAF15.

[0066] In some embodiments, the compound is a compound having the structure of formula (I'):

[0067]

[0068] in,

[0069] Ring A is a 4-6 member saturated or partially unsaturated heterocyclic group containing at least one nitrogen atom;

[0070] The C ring is selected from a naphthyl group and an 8-10 fused heterobicyclic group containing 1-3 heteroatoms, each independently selected from nitrogen, oxygen, and sulfur; the naphthyl group or the 8-10 fused heterobicyclic group is optionally surrounded by 0, 1, 2, or 3 R atoms. c replace;

[0071] R 7 Selected from hydrogen, C 1-10 Alkyl, C 4-6 Heterocyclic group, C 6-11 Spiroalkyl, C 5-8 Bridged alkyl groups, 5-12 spiroheterocyclic groups, 6-10 bridged heterobicyclic groups, and 8-10 fused heterobicyclic groups; the C 1-10 Alkyl, C 4-6 Heterocyclic group, C 6-11 Spiroalkyl, C 5-8 Bridged alkyl, 5-12 spiroheterocyclic, 6-10 bridged heterobicyclic, or 8-10 fused heterobicyclic groups are each optionally bonded by one or more deuterium, halogen, cyano, hydroxyl, methoxy, methylamino, dimethylamino, C 5-8 Bridged alkyl or 5-6-membered heteroaryl substitution;

[0072] R 1a and R 2a Each is independently selected from hydrogen, fluorine, and cyano groups, or R 1a and R 2a The groups combine to form carbonyl groups;

[0073] Y is independently selected from O or NH; when Y is O, R connected to Y is... 8 For R b When Y is NH, R connected to Y 8 For R T -(CH2) q C(=O)OR T or -CH(CH3)C(=O)OR T ;

[0074] DIM is selected from small molecule affinity ligands of CRBN, VHL, and cIAP;

[0075] X is selected from NR 6a and CHR 6a When X and L m When connecting, X is N or CR 6a ;

[0076] n, q, R 3 R 4 R 5 R 6 R 6a R c R b R T and L m As defined in equation (I).

[0077] In some preferred embodiments, the compound is a compound having the structure of formula (I'-1):

[0078]

[0079] Among them, C ring, Y, R 8 R 7 L m DIM and X are defined as in formula (I').

[0080] In some implementation schemes, R 7 Selected from hydrogen and C 1-10 Alkyl, preferably C 1-10 Alkyl; the C 1-10 The alkyl group is optionally substituted with one or more deuterium atoms; for example, the C... 1-10 Alkyl groups can be substituted with one, two, or three deuterium atoms, or the C... 1-10 All hydrogen atoms in the alkyl group are replaced by deuterium atoms.

[0081] In some implementation schemes, R 7 Selected from hydrogen and C 1-4 Alkyl, preferably C 1-4 Alkyl; the C 1-4 The alkyl group is optionally substituted with one or more deuterium atoms; for example, the C... 1-4 Alkyl groups can be substituted with one, two, or three deuterium atoms, or the C... 1-4 All hydrogen atoms in the alkyl group are replaced by deuterium atoms.

[0082] In some implementations, Y is independently selected from O or NH; when Y is O, R connected to Y... 8 For R b Each Rb Each is independently selected from hydrogen and C. 1-4 Alkylene-OC(=O)-C 1-10 Alkyl and C 1-4 Alkylene-SC(=O)-C 1-10 Alkyl group; when Y is NH, the R bonded to Y 8 Each independently as R T -(CH2) q C(=O)OR T or -CH(CH3)C(=O)OR T R T C 1-10 Alkyl group, q is selected from 0, 1, 2 and 3.

[0083] In some implementations, Y is independently selected from O or NH; when Y is O, R connected to Y... 8 For R b Each R b Each is independently selected from hydrogen and C. 1-4 Alkylene-OC(=O)-C 1-4 Alkyl and C 1-4 Alkylene-SC(=O)-C 1-4 Alkyl group; when Y is NH, the R bonded to Y 8 Each independently as R T -(CH2) q C(=O)OR T or -CH(CH3)C(=O)OR T R T C 1-4 Alkyl group, q is selected from 0, 1, 2 and 3.

[0084] In some implementations, Y is independently selected from O or NH; when Y is O, R connected to Y... 8 For R b R b Selected from hydrogen, C 1-4 Alkylene-OC(=O)-C 1-4 Alkyl and C 1-4 Alkylene-SC(=O)-C 1-4 Alkyl group; when Y is NH, the R bonded to Y 8 For R T -(CH2) q C(=O)OR T or -CH(CH3)C(=O)OR T R T Selected from C 1-4 Alkyl group, q is selected from 0, 1, 2 and 3.

[0085] In some implementations, Y represents O atoms, and each R 8 Each is independently selected from hydrogen and C. 1-4 Alkylene-OC(=O)-C 1-10 Alkyl and C 1-4 Alkylene-SC(=O)-C 1-10 alkyl.

[0086] In some preferred embodiments, Y is an O atom, and each R 8 Each is independently selected from hydrogen and C. 1-4 Alkylene-OC(=O)-C 1-4 Alkyl and C 1-4 Alkylene-SC(=O)-C 1-4 alkyl.

[0087] In some implementations, Y is NH, and each R 8 Each independently as R T -(CH2) q C(=O)OR T or -CH(CH3)C(=O)OR T R T C 1-10 Alkyl group, q is selected from 0, 1, 2 and 3.

[0088] In some preferred embodiments, Y is NH, and each R 8 Each independently as R T -(CH2) q C(=O)OR T or -CH(CH3)C(=O)OR T R T C 1-4 Alkyl group, q is selected from 0, 1, 2 and 3.

[0089] In some implementations, DIM is selected from the following fragments:

[0090] ,

[0091] Preferred More preferably ;

[0092] R 9 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, preferably hydrogen and C 1-6 Alkyl, more preferably hydrogen.

[0093] In some implementations, X and L m Connect, where X is N.

[0094] In some embodiments, the compounds of the present invention are compounds having the structure of formula (II):

[0095]

[0096] Among them, ring A, ring C, and ring R 1a R 2a Y, R 8 R 7 n, R 3 R 4 R 5 R 6 L m DIM is defined as in (I').

[0097] In some preferred embodiments, the compound is a compound having the structure of formula (II-1):

[0098]

[0099] Among them, C ring, Y, R 8 R 7 L m DIM is defined as in equation (II).

[0100] In some implementations, X does not interact with L. m Connect, X is CR 6a R 6a Selected from H and C 1-4 Alkyl group, preferably H.

[0101] In other embodiments, the compounds of the present invention are compounds having the structure of formula (III):

[0102]

[0103] Among them, ring A, ring C, and ring R 1a R 2a Y, R 8 R 7 n, R 3 R 4 R 5 R 6 L m , DIM, X are as defined in (I').

[0104] In some preferred embodiments, the compound is a compound having the structure of formula (III-1):

[0105]

[0106] Among them, C ring, Y, R 8 R7 L m DIM and X are as defined in equation (III).

[0107] In some implementations, X is CHR 6a R 6a Selected from H and C 1-4 Alkyl group, preferably H.

[0108] In some embodiments, the C ring is selected from the following groups:

[0109] ;

[0110] R c As defined in equation (I).

[0111] In some preferred embodiments, the C ring is selected from the following groups:

[0112] ;

[0113] R c As defined in equation (I).

[0114] In some preferred embodiments, the C ring is selected from the following groups:

[0115] ;

[0116] R c As defined in equation (I).

[0117] In some implementation schemes, R c It is a hydrogen atom.

[0118] In some implementations, Y is an oxygen atom, and R... 8 It is a hydrogen atom.

[0119] In some implementations, Y is an oxygen atom, and R... 8 For hydrogen atoms, DIM is selected from the following groups:

[0120] ,

[0121] Preferred More preferably ;

[0122] R 9 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, preferably hydrogen and C 1-6 Alkyl, more preferably hydrogen.

[0123] In some preferred embodiments, DIM is selected from the following groups:

[0124] ;

[0125] R 9 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl.

[0126] In some preferred embodiments, DIM is selected from the following groups:

[0127] ;

[0128] R 9 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, preferably hydrogen and C 1-6 Alkyl, more preferably hydrogen.

[0129] In some preferred embodiments, DIM is:

[0130] ;

[0131] R 9 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, preferably hydrogen and C 1-6 Alkyl, more preferably hydrogen.

[0132] In some implementations, ring A is selected from the following groups:

[0133] .

[0134] In some preferred embodiments, ring A is a group with the following composition:

[0135] .

[0136] In some implementations, L m Selected from the following groups:

[0137]

[0138]

[0139] .

[0140] In some preferred embodiments, L m Selected from the following groups:

[0141]

[0142] .

[0143] In some further preferred embodiments, L m Selected from the following groups:

[0144] .

[0145] In some implementations, X and L m When connected, or in the compounds shown in formula (II) or (II-1), L m Selected from the following groups: .

[0146] In other implementations, X is not related to L. m When connected, or in compounds represented by formula (III) or (III-1), L m Selected from the following groups: .

[0147] In some preferred embodiments, L m Selected from the following groups:

[0148] .

[0149] In some implementations, L m A ring is attached to one end of the carbonyl or oxygen group. The other end connects to DIM.

[0150] In some implementation schemes, Selected from the following groups:

[0151]

[0152]

[0153]

[0154] .

[0155] In some implementation schemes, Selected from the following groups:

[0156]

[0157]

[0158]

[0159] .

[0160] In some preferred embodiments, Selected from the following groups:

[0161] .

[0162] In some more preferred embodiments, Selected from the following groups:

[0163] .

[0164] In some further preferred embodiments, Selected from the following groups:

[0165] .

[0166] In some of the most preferred implementation schemes, Selected from the following groups:

[0167] .

[0168] In some implementation schemes, R 1a and R 2a Each is independently selected from hydrogen and fluorine, or R 1a and R 2a They combine to form carbonyl groups.

[0169] In some preferred embodiments, R 1a and R 2a It is fluorine.

[0170] In some implementation schemes, R 3 R 5 R 6 Each is independently selected from hydrogen and C. 1-4 alkyl.

[0171] In some preferred embodiments, R 3 R 5 R 6 It is hydrogen.

[0172] <Second aspect>

[0173] This invention provides the following compounds or their pharmaceutically acceptable salts, solvates, prodrugs, isotope-labeled derivatives or isomers:

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194] .

[0195] <Third aspect>

[0196] The present invention provides a pharmaceutical composition comprising a compound according to the first aspect or the second aspect, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof.

[0197] In some embodiments of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0198] <Fourth Aspect>

[0199] The present invention provides a pharmaceutical formulation comprising a compound according to the first aspect or the second aspect or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, or a pharmaceutical composition according to the third aspect, wherein the pharmaceutical formulation is any one of tablets, capsules, injections, granules, powders, suppositories, pills, gels, powders, oral solutions, inhalers, suspensions, or dry suspensions.

[0200] <Fifth Aspect>

[0201] The present invention provides a pharmaceutical combination comprising a compound according to the first aspect or the second aspect or a pharmaceutically acceptable salt, solvate, prodrug, isotope label or isomer thereof, or a pharmaceutical composition according to the third aspect, or a pharmaceutical formulation according to the fourth aspect.

[0202] <Sixth Aspect>

[0203] The use of a compound or pharmaceutically acceptable salt, solvate, prodrug, isotope label or isomer thereof as described in the first or second aspect, or a pharmaceutical composition as described in the third aspect, or a pharmaceutical preparation as described in the fourth aspect, or a combination of drugs as described in the fifth aspect, in the prevention and / or treatment of diseases and / or symptoms that are at least partially responsive to STAT6.

[0204] <Seventh Aspect>

[0205] The compound described in the first or second aspect, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, or a pharmaceutical composition described in the third aspect, or a pharmaceutical preparation described in the fourth aspect, or a combination of drugs described in the fifth aspect, is used for the prevention and / or treatment of diseases and / or conditions that are at least partially responsive to STAT6.

[0206] <Eighth Aspect>

[0207] A method for preventing and / or treating at least a partial response to STAT6 diseases and / or symptoms, comprising: administering a preventive and / or therapeutically effective amount of a compound according to the first or second aspect or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, or a pharmaceutical composition according to the third aspect, or a pharmaceutical preparation according to the fourth aspect, or a combination of pharmaceuticals according to the fifth aspect, to an individual in need.

[0208] In some embodiments of the present invention, the disease and / or symptom is type 2 inflammation.

[0209] In some embodiments of the present invention, the disease and / or symptom is a type 2 inflammation primarily mediated by Th2 cells, type 2 innate lymphoid cells, and related cytokines.

[0210] In some embodiments of the present invention, the disease and / or symptom is type 2 inflammation mediated by Th2 cells and / or type 2 innate lymphoid cells.

[0211] In some embodiments of the present invention, the diseases and / or conditions include: atopic dermatitis, chronic spontaneous urticaria, nodular prurigo, bullous pemphigoid, chronic sinusitis with or without nasal polyps, allergic rhinitis, asthma, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease, eosinophilic granulomatous polyangiitis, food allergy, and eosinophilic esophagitis.

[0212] The effects of the invention

[0213] The compounds provided by this invention have high STAT6 protein degradation activity and can be used to prevent and / or treat diseases and / or symptoms that at least partially respond to STAT6, mainly type 2 inflammation mediated by Th2 cells, type 2 innate lymphoid cells and related cytokines.

[0214] The compounds provided by this invention also have high selectivity for STAT6 protein degradation and do not cause biologically significant degradation of other proteins in the STAT family (especially STAT3 protein), thus avoiding safety risks caused by off-target STATs (especially STAT3 protein).

[0215] The compounds provided by this invention have no species diversity, have a small risk of off-target toxicity with CRBN ligands, have weak inhibition of CYP isoenzymes, have a low risk of drug-drug interactions, have no significant inhibitory effect on hERG, and have a low risk of cardiotoxicity.

[0216] The compound provided by this invention can effectively degrade STAT6 protein in lung tissue, has a long duration of efficacy, exhibits good pharmacokinetic characteristics, can selectively expose to lung tissue, can reduce systemic drug exposure, reduce safety risks to other organs, and is suitable for local treatment of respiratory and lung diseases.

[0217] The compounds provided by this invention can also be used as prodrugs for highly selective STAT6 protein degraders, which can greatly improve the degradation activity of STAT6 protein. Attached Figure Description

[0218] Figure 1 Western blot results for compound A6 targeting STAT1, STAT3, STAT5, and STAT6 in MV4-11 cells.

[0219] Figure 2 Western blot results for compounds A9 and A11 against STAT3 and STAT6 in MV4-11 cells.

[0220] Figure 3 Western blot results for compound A6 targeting STAT1-STAT6 in mouse spleen cells.

[0221] Figure 4 The results show the degradation of STAT6 by compound A14 in MV4-11 cells.

[0222] Figure 5 The degradation of Ikaros, Aiolos, and GSPT1 proteins by compounds A11, A17, and the positive control pomalidomide (denoted as poma) is shown.

[0223] Figure 6 The degradation of SALL4 protein by compounds A11, A17 and the positive control pomalidomide is shown.

[0224] Figure 7 This is a volcano plot of protein degradation of compound A11 in hPBMC; a total of 6013 proteins were detected by compound A11, and the names of proteins that showed significant degradation are marked in the corresponding volcano plot.

[0225] Figure 8 The degradation of STAT6 in mice (lungs and plasma) after intratracheal nebulization of compound A11. Detailed Implementation

[0226] In order to provide a clearer understanding of the technical features, objectives and beneficial effects of the present invention, the technical solution of the present invention will now be described in detail below, but it should not be construed as limiting the scope of implementation of the present invention.

[0227] To more clearly describe the content of this invention, the terms involved are defined as follows:

[0228] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, either alone or in combination, especially fluorine, chlorine, or bromine.

[0229] Term "C" 1-6"Alkyl" refers alone or in combination to a saturated straight-chain or branched alkyl group containing 1-6 carbon atoms (particularly 1-3 carbon atoms), including (but not limited to) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3,-dimethyl-2-butyl, etc. Preferably, "C1-6 alkyl" refers to any one of methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Similarly, the term "C1-6 alkyl" refers to... 1-3 "Alkyl" alone or in combination refers to a saturated straight-chain or branched alkyl group containing 1-3 carbon atoms, including methyl, ethyl, propyl, isopropyl, etc. The term "C"... 1-4 "Alkyl" refers to a saturated straight-chain or branched alkyl group containing 1 to 4 carbon atoms, either alone or in combination, including (but not limited to) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl.

[0230] The term "cycloalkyl" refers to a saturated cyclic alkane group. In this invention, "C" refers to a cyclic alkane group. 3-6 "Cycloalkyl" refers to cycloalkyl groups with 3-6 carbon atoms in the ring, including (but not limited to) cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

[0231] The term "alicylic cyclic group" refers to a saturated or partially unsaturated cyclic alkane group. In this invention, it can be a monovalent group or a divalent group. 3-6 "Aliphatic cyclic group" refers to aliphatic cyclic groups with 3-6 carbon atoms in the ring, including (but not limited to) cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentenyl, cyclohexenyl, etc.

[0232] The term "aryl" refers to any stable monocyclic or polycyclic aromatic group, including (but not limited to) phenyl, naphthyl, etc.

[0233] The term "heteroaryl" refers to an aromatic cyclic group whose ring atom contains at least one heteroatom selected from sulfur, oxygen, or nitrogen. This group can be a 5-7 membered monocyclic or a 7-12 membered bicyclic group. In this invention, the carbon atom or heteroatom on the heteroaryl ring may optionally be oxidized. Preferably, the number of heteroatoms in the heteroaryl group is 1, 2, 3, or 4. The heteroaryl groups of the present invention include (but are not limited to) thiophene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridine-2(1H)-keto, pyridin-4(1H)-keto, pyrroleyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxiadiazolyl, benzothiophene, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl, etc.

[0234] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic group, either alone or in combination, whose ring-forming atoms include carbon atoms and may also include heteroatoms or heteroatom groups selected from O, S, NH, N, P(=O), S(=O), and S(=O)2. The term "4-6 member saturated or partially unsaturated heterocyclic group" refers to a saturated or partially unsaturated heterocyclic group, either alone or in combination, with 4 to 6 ring atoms, including (but not limited to) azirobutyl, oxobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholinyl, piperazine, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valproic acid, butyrolactone, valproic acid, etc.

[0235] In this invention, "a cyclic group containing at least one nitrogen atom" means that the ring atom of the cyclic group contains at least one nitrogen atom. For example, "a 4-6 member saturated or partially unsaturated heterocyclic group containing at least one nitrogen atom" means that the ring atom of the heterocyclic group contains at least one nitrogen atom.

[0236] In this invention, "a cyclic group containing 1-4 heteroatoms each independently selected from nitrogen, oxygen and sulfur" means that the cyclic atom of the cyclic group contains 1-4 heteroatoms each independently selected from nitrogen, oxygen and sulfur. For example, "a 5-6 membered heteroaryl containing 1-4 heteroatoms each independently selected from nitrogen, oxygen and sulfur" means that the cyclic atom of the 5-6 membered heteroaryl contains 1-4 heteroatoms each independently selected from nitrogen, oxygen and sulfur.

[0237] The term "6-12 denoted heterocyclic group" refers, alone or in combination, to a saturated or partially unsaturated bicyclic group comprising 6-12 (particularly 7-10) carbon atoms and heteroatoms or heteroatom groups for cyclization, wherein the bicyclic group shares a single carbon-carbon bond, carbon-hetero-bond, or hetero-hetero-bond, and the heteroatom or heteroatom group is selected from O, S, NH, N, P(=O), S(=O), and S(=O)2. "6- to 12 denoted heterocyclic groups" include (but are not limited to) 3,7-diazabicyclo[3.3.0]oct-3-yl, 3,6-diazabicyclo[3.3.0]oct-3-yl, 2,7-diazabicyclo[3.3.0]oct-2-yl, etc.

[0238] The term "8-10 fused heterobicyclic group" refers to an 8- to 10-membered fused bicyclic group, either alone or in combination, consisting of one aryl group and one heteroaryl group or two heteroaryl groups, including (but not limited to) benzothiophene, indolyl, benzimidazolyl, pyridiniumimidazolyl, pyraziniumimidazolyl, pyrazolopyrimidinyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl, etc.

[0239] Term "C" 6-11 "Spiroalkyl" refers to a 6-11 member polycyclic alkyl group formed by two cycloalkanes sharing a single carbon atom, either alone or in combination.

[0240] Term "C" 5-8 "Bridged alkyl" refers to a 5-8 membered polycyclic alkyl group, either alone or in combination, that shares two or more carbon atoms.

[0241] The term "5-12 spiroheterocyclic group" refers, alone or in combination, to a saturated or partially unsaturated bicyclic group comprising 5-12 (particularly 6-9) carbon atoms and heteroatoms or heteroatom groups for cyclization, wherein the bicyclic groups are interconnected by a single carbon atom, and the heteroatoms or heteroatom groups are selected from O, S, NH, N, P(=O), S(=O), and S(=O)2. "5-12-membered spirocyclobicyclic groups" include (but are not limited to) 4,7-diazaspiro[2.5]oct-7-yl, 1-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2,5-diazaspiro[3.4]oct-2-yl, 5-oxa-2-azaspiro[3.4]oct-2-yl, 6-oxa-2-azaspiro[3.4]oct-2-yl, 1-oxa-7-azaspiro[3.5]non-7-yl, etc.

[0242] The term "6-10 bridging heterobicyclic group" refers, alone or in combination, to a saturated or partially unsaturated bridging heterobicyclic group comprising 6-10 (particularly 6-8) carbon atoms and heteroatoms or heteroatom groups for cyclization, wherein the heteroatoms or heteroatom groups are selected from O, S, NH, N, P(=O), S(=O), and S(=O)2. "6-10 bridging heterobicyclic group" includes (but is not limited to) 3,6-diazabicyclo[3.1.1]hept-1-yl, 3,6-diazabicyclo[3.1.1]hept-3-yl, 3,6-diazabicyclo[3.1.1]hept-6-yl, etc.

[0243] The term "alkenyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, either alone or in combination. 2-12 "Alkenyl" refers to a straight-chain or branched alkenyl group containing 2-12 carbon atoms, including (but not limited to) vinyl, 1-propenyl, 1-butenyl, etc., preferably "C 2-6 Alkenyl group.

[0244] The term "alkynyl" refers to an alkyl group, as defined above, which, alone or in combination, consists of at least two carbon atoms and at least one carbon-carbon triple bond. 2-12 "Alkynyl" refers to a straight-chain or branched alkenyl group containing 2-12 carbon atoms, including (but not limited to) ethynyl, 1-propynyl, 1-butynyl, etc., preferably "C". 2-6 "Alkyne group".

[0245] The term "subunit" refers to a divalent group, either alone or in combination, such as alkylene (divalent alkyl), alkenylene (divalent alkenyl), ynylene (divalent ynyl), cycloalkylene (divalent cycloalkyl), heterocyclicene (divalent heterocyclic), arylene (divalent aryl), and heteroarylene (divalent heteroaryl). The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are as defined above.

[0246] The term "amino" refers to a primary amino group (-NH2), a secondary amino group (-NH-), or a tertiary amino group, either alone or in combination. ).

[0247] The term "NH(C)" 1-6 Alkyl)", N(C) 1-6 Alkyl)2", NH(C) 3-6 cycloalkyl), N(C) 3-6 "cycloalkyl)2" refers to an amino group as defined above, either alone or in combination, in which the hydrogen atoms are separated by one or two carbon atoms. 1-6 Alkyl or C 3-6 Cycloalkyl substituted, wherein "C" 1-6 "alkyl" and "C" 3-6 "Cycloalkyl" is as defined above.

[0248] The term "ethylene glycol or propylene glycol unit" refers to the structural segment formed by the dehydration of ethylene glycol or propylene glycol, i.e., the structural segment represented by the ethylene glycol unit is... The structural segment represented by propylene glycol units is .

[0249] The term "pharmaceutically acceptable salt" indicates that the compounds of the present invention exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. Pharmaceutically acceptable salts are described in SMBerge's description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977). In the present invention, a pharmaceutically acceptable non-toxic acid addition salt refers to a salt formed by the compounds of the present invention with an organic or inorganic acid, including (but not limited to) hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, and malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of this invention with organic or inorganic bases, including (but not limited to) alkali metal salts, such as lithium, sodium, or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts or N-containing organic bases formed with N-groups. + (C) 1-6 Alkyl)4 salts, preferably salts formed by lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia, triethylamine, or tetrabutylammonium hydroxide with the compounds of the present invention. In the present invention, in pharmaceutically acceptable base addition salts of the compounds of the present invention, the compounds may be in a phosphate anion state. "Pharmaceutically acceptable salts" can be synthesized by conventional chemical methods.

[0250] The term "solvent" refers to an association formed by one or more solvent molecules with the compounds of this invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0251] The term "prodrug" refers to a chemical derivative of the compound of the present invention, which can be converted into the compound represented by general formula (I) in vivo by a chemical reaction.

[0252] The term "isotope label" refers to isotopes including (but not limited to) [the following]. 2 H, 3 H, 11 C 13 C14 C 15 N、 17 O、 18 O、 18 F, 32 P, 35 S and 36 Cl, etc.

[0253] The term "isomer" encompasses all isomeric forms, including enantiomers, diastereomers, tautomers, and geometric isomers (including cis-trans isomers). Therefore, any single stereochemical isomer of the compound designed in this invention, or a mixture of its enantiomers, diastereomers, tautomers, or geometric isomers (or cis-trans isomers), is within the scope of this invention.

[0254] The terms "independently" and "individually" refer to at least two groups (or ring systems) in a structure that have the same or similar value ranges, which may have the same or different meanings under specific circumstances. For example, if substituent X and substituent Y are independently (individually) hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl; similarly, when substituent Y is hydrogen, substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl, or aryl.

[0255] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0256] The term “prevention” refers to the complete or near-complete prevention of the occurrence of a disease or condition (e.g., infection, ischemia, or reperfusion injury) when a patient or subject is susceptible to or at risk of the disease or condition; prevention may also include suppression, i.e., preventing the development of the condition.

[0257] The term “treatment” means: 1) suppressing the disease; for example, suppressing the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom of the disease (i.e., preventing further development of the pathology and / or symptom); or 2) improving the disease; for example, improving the disease, symptoms or symptom of an individual experiencing or exhibiting the pathology or symptom (i.e., reversing the pathology and / or symptom).

[0258] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0259] In the following examples, the solvents and reagents used were all analytical grade or chemically pure.

[0260] Column chromatography silica gel (100-200 mesh) and thin-layer chromatography silica gel (GF254) are products of Leyan; unless otherwise specified, petroleum ether (60-90℃) / ethyl acetate (v / v) are used as eluents.

[0261] The colorimetric reagent is an ethanol solution of iodine or phosphomolybdic acid.

[0262] Unless otherwise specified, all extraction solvents were dried over anhydrous Na2SO4.

[0263] 1 H-NMR was performed using the Qone-WNMR-I-AS400 nuclear magnetic resonance spectrometer from Oxford Spectroscopy Technology Co., Ltd., with TMS as the internal standard.

[0264] LC-MS was performed using a Waters 2795 high-performance liquid chromatograph with a Quattro micro triple quadrupole mass spectrometer, with detection wavelengths of 220 nm and 254 nm.

[0265] This invention may use the following abbreviations: (Boc)₂O (di-tert-butyl dicarbonate); DAST (diethylaminosulfur trifluoride); DCM (dichloromethane); DIBAL-H (diisobutylaluminum hydride); DIPEA (diisopropylethylamine); DMF (N,N-dimethylformamide); EA (ethyl acetate); EtOH (ethanol); HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate); LiHMDs (lithium bis(trimethylsilyl)amino); MeO H (methanol); NaHMDs (sodium bis(trimethylsilyl)amino); NFSI (N-fluorobis(benzyl)sulfonamide); Pd2(dba)3 (tris(dibenzylacetone)dipalladium); Pd(PPh3)4 (tetraphenylphosphine palladium); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride); Pd(OAc)2 (palladium acetate); PE (petroleum ether); RuPhos (2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl); RuPhos Pd G2 ([2'-(amino)[1,1'-biphenyl]-2-yl][[2',6'-di(1-methylethoxy)[1,1'-biphenyl]-2-yl]dicyclohexylphosphine]palladium chloride); STAB (sodium triacetylborohydride); TBSCl (tert-butyldimethylchlorosilane); TBAF (tetrabutylammonium fluoride); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TMSBr (trimethylbromosilane); TsCl (p-methylbenzenesulfonyl chloride).

[0266] Example 1: Synthesis of intermediate P1

[0267]

[0268] 1) Synthesis of intermediate P1-1

[0269] 2,7-Dibromonaphthalene (25 g, 88 mmol) and dry toluene (40 mL) were added to a three-necked flask. Under nitrogen protection, the mixture was cooled to -10 °C, and n-butylmagnesium bromide (19 mL, 37 mmol) was added. The temperature was maintained at -5 °C, and n-butyllithium (30 mL, 75 mmol) was added dropwise. The mixture was then stirred at -10 °C for 1 hour. Di-tert-butyl dicarbonate (25 g, 88 mmol) was dissolved in 250 mL of dry toluene and slowly added dropwise to the reaction system at -5 °C. After the addition was complete, the mixture was stirred at -10 °C for 4 hours. After the reaction was complete, the reaction was quenched with 100 mL of 10% citric acid aqueous solution, extracted with ethyl acetate (100 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1, v / v) yielded a white solid intermediate P1-1 (17 g, 63%). 1 H NMR (300 MHz, CDCl3) δ 8.43 (s, 1H),8.10 (s, 1H), 8.07 – 7.96 (m, 1H), 7.91 – 7.77 (m, 1H), 7.73 (s, 1H), 7.67 –7.50 (m, 1H), 1.73 – 1.59 (m, 9H). LC-MS (m / z): 328.8 [M + Na] + .

[0270] 2) Synthesis of intermediate P1-2

[0271] Intermediate P1-1 (20 g, 65 mmol), methylboric acid (7.8 g, 130 mmol), anhydrous potassium phosphate (28 g, 130 mmol), SPhos (2.7 g, 6.5 mmol), and palladium acetate (0.73 g, 3.3 mmol) were dissolved in 1,4-dioxane (150 mL) and water (50 mL). The mixture was reacted at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, the mixture was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1, v / v) to obtain a pale yellow solid intermediate P1-2 (14 g, 89%). 1H NMR(300 MHz, CDCl3) δ 8.45 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.86 – 7.73 (m,2H), 7.71 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 2.53 (s, 3H), 1.65 (s, 9H).

[0272] 3) Synthesis of intermediate P1-3

[0273] Intermediate P1-2 (10 g, 41 mmol) was dissolved in dichloroethane (100 mL), and benzoyl peroxide (400 mg, 1.6 mmol) was added. The mixture was heated to 80 °C, and N-bromosuccinimide (7.7 g, 43 mmol) was slowly added in portions. After the addition was complete, the mixture was reacted at 80 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched in 200 mL of ice water. The mixture was extracted with dichloromethane (100 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1, v / v) to give intermediate P1-3 (11 g, 84%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 8.51(s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.91 – 7.81 (m, 2H), 7.60(d, J = 8.4 Hz, 1H), 4.67 (s, 2H), 1.65 (s, 9H).

[0274] 4) Synthesis of intermediate P1-4

[0275] Intermediate P1-3 (14 g, 44 mmol) was added to a round-bottom flask, and about 60 mL of triethyl phosphite was added. The mixture was heated to 120 °C and stirred for 16 hours. After the reaction was complete, the solvent was removed by rotary evaporation using an oil pump, the mixture was concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain yellow liquid intermediate P1-4 (14 g, 84%). 1H NMR (300 MHz, CDCl3)δ 8.49 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.89 – 7.82 (m, 2H), 7.81 (s, 1H),7.53 (d, J = 8.1 Hz, 1H), 4.07 – 3.94 (m, 4H), 3.32 (d, J = 21.9 Hz, 2H), 1.64 (s, 9H), 1.23 (t, J = 6.9 Hz, 6H). LC-MS (m / z): 378.9 [M + H] + .

[0276] 5) Synthesis of intermediate P1-5

[0277] Intermediate P1-4 (6.5 g, 17 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Under nitrogen protection, the mixture was cooled to -78 °C, and sodium bis(trimethylsilyl)amino (13 mL, 26 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 5 minutes. Davies oxaziridine reagent (9.0 g, 34 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and slowly added dropwise to the reaction system at -65 °C. After the addition was complete, the mixture was stirred at -78 °C for 20 minutes. After the reaction was complete, the solution was quenched in 200 mL of saturated ammonium chloride aqueous solution. After stirring for 30 minutes, the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give intermediate P1-5 (5.0 g, 74%) as a yellow solid. 1 H NMR (300 MHz, CDCl3) δ 8.53 (s, 1H), 8.10 – 7.95 (m,2H), 7.92 – 7.79 (m, 2H), 7.69 (d, J = 8.1 Hz, 1H), 5.22 (d, J = 10.2 Hz,1H), 4.19 – 3.93 (m, 4H), 3.80 (s, 1H), 1.64 (s, 9H), 1.30 – 1.15 (m, 6H).

[0278] 6) Synthesis of intermediate P1-6

[0279] Intermediate P1-5 (6.5 g, 16 mmol) was dissolved in dichloromethane (60 mL) and cooled to -78 °C under nitrogen protection. DAST (4.0 g, 25 mmol) was dissolved in dichloromethane (40 mL) and slowly added dropwise to the reaction system at -65 °C. After the addition was complete, the mixture was stirred at -78 °C for 20 minutes. After the reaction was complete, the mixture was quenched in 100 mL of saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain yellow liquid intermediate P1-6 (5.0 g, 79%). 1 H NMR (300MHz, CDCl3) δ 8.56 (s, 1H), 8.11 – 8.00 (m, 2H), 7.97 – 7.81 (m, 2H), 7.69(d, J = 8.4, 1H), 5.87 (dd, J = 44.7, 8.1 Hz, 1H), 4.23 – 3.94 (m, 4H), 1.65 (s, 9H), 1.34 – 1.18 (m, 6H). LC-MS (m / z): 396.9 [M + H] + .

[0280] 7) Synthesis of intermediate P1-7

[0281] Intermediate P1-6 (4.0 g, 11 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (10 mL) was added at room temperature. The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the solution was directly concentrated to give intermediate P1-7 (3.5 g, 94%, crude).

[0282] 8) Synthesis of intermediate P1

[0283] Intermediate P1-7 (3.5 g, 10.3 mmol, crude) was dissolved in dichloromethane (20 mL), and DMF (0.2 mL) was added. Oxaloyl chloride (3.4 g, 27 mmol) was slowly added dropwise to the reaction at room temperature. After the addition was complete, the reaction was stirred at room temperature for 20 minutes. Once the reaction was complete, the solution was directly concentrated to obtain a concentrated solution for later use.

[0284] In a separate three-necked flask, pentafluorophenol (2.5 g, 14 mmol) was dissolved in dichloromethane (20 mL). Under nitrogen protection, the mixture was cooled to 0°C, and triethylamine (3.2 g, 32 mmol) was slowly added to the reaction mixture. The mixture was kept at 0°C and stirred for about 15 minutes. The concentrated solution was then dissolved in dichloromethane (10 mL) and slowly added dropwise to the reaction mixture while maintaining the temperature at 0°C. After the addition was complete, the mixture was allowed to cool to room temperature and stirred for 30 minutes. After the reaction was complete, the solution was poured into about 100 mL of ice water and extracted with dichloromethane (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a yellow solid intermediate P1 (3.0 g, 57%). 1 H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.20 (d, J =8.7 Hz, 1H), 8.12 (s, 1H), 8.07 – 7.93 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 5.90 (dd, J = 44.7, 8.4 Hz, 1H), 4.35 – 3.91 (m, 4H), 1.37 – 1.17 (m, 6H).

[0285] Example 2: Synthesis of intermediate P2

[0286]

[0287] 1) Synthesis of intermediate P2-1

[0288] NFSI (1.3 g, 4.2 mmol) and intermediate P1-6 (500 mg, 1.4 mmol) were dissolved in anhydrous THF (10 mL). Under nitrogen protection, the mixture was cooled to -78 °C, and NaHMDS (2.1 mL, 4.2 mmol) was slowly added dropwise at -65 °C. After the addition was complete, the mixture was stirred at -78 °C for 1 hour. After the reaction was complete, the mixture was quenched in 50 mL of saturated ammonium chloride aqueous solution and extracted with ethyl acetate (30 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give yellow liquid intermediate P2-1 (500 mg, 86%).

[0289] 2) Synthesis of intermediate P2-2

[0290] Intermediate P2-1 (500 mg, 1.2 mmol) was dissolved in dichloromethane (10 mL), and then trifluoroacetic acid (3 mL) was added at room temperature. The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the solution was directly concentrated to obtain intermediate P2-2 (430 mg, crude).

[0291] 3) Synthesis of intermediate P2

[0292] Intermediate P2-2 (600 mg, crude) was dissolved in dichloromethane (10 mL), DMF (0.1 mL) was added, and oxaloyl chloride (638 mg, 5.0 mmol) was slowly added dropwise to the reaction at room temperature. After the addition was complete, the reaction was stirred at room temperature for 20 minutes. Once the reaction was complete, the solution was directly concentrated to obtain the concentrate for later use.

[0293] In a separate three-necked flask, pentafluorophenol (462 mg, 2.5 mmol) was dissolved in dichloromethane (15 mL). Under nitrogen protection, the mixture was cooled to 0°C, and triethylamine (508 mg, 5.0 mmol) was slowly added to the reaction mixture. The mixture was stirred at 0°C for approximately 15 minutes. The concentrated solution was then dissolved in dichloromethane (5 mL) and slowly added dropwise to the reaction mixture while maintaining the temperature at 0°C. After the addition was complete, the mixture was allowed to cool to room temperature and stirred for 30 minutes. After the reaction was complete, the solution was poured into approximately 50 mL of ice water and extracted with dichloromethane (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a yellow solid intermediate P2 (700 mg). LC-MS (m / z): 525.3 [M + H] + .

[0294] Example 3: Synthesis of intermediate P3

[0295]

[0296] 1) Synthesis of intermediate P3-2

[0297] The starting material P3-1 (500 mg, 1.5 mmol) and sodium bicarbonate (370 mg, 4.4 mmol) were dissolved in anhydrous dioxane (5 mL). Benzyl chloroformate (325 mg, 1.9 mmol) was slowly added dropwise at room temperature. After the addition was complete, the mixture was stirred at room temperature for 6 hours. After the reaction was complete, the mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL). The organic phase was washed once with water (10 mL) and once with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a colorless liquid intermediate P3-2 (800 mg, crude). LC-MS (m / z): 476.4 [M + H] + .

[0298] 2) Synthesis of intermediate P3-3

[0299] Intermediate P3-2 (800 mg, crude) was dissolved in a mixed solvent of tetrahydrofuran / water = 1 / 1 (v / v, 20 mL). Lithium hydroxide monohydrate (500 mg, 11 mmol) was added at room temperature, and the reaction was carried out for 6 hours. After the reaction was completed, the solution was poured into about 20 mL of ice water, and ethyl acetate (20 mL) was added for extraction. The mixture was separated, and the aqueous phase was retained. The pH was adjusted to 5 with 1N hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a white solid intermediate P3-3 (700 mg).

[0300] 3) Synthesis of intermediate P3-4

[0301] Intermediate P3-3 (700 mg, 1.5 mmol), morpholine (261 mg, 3.0 mmol), and N,N-diisopropylethylamine (387 mg, 3.0 mmol) were dissolved in dry dichloromethane (30 mL), and HATU (1.2 g, 3.0 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1) to give a white solid intermediate P3-4 (700 mg, 90% yield in three steps). LC-MS (m / z): 531.6 [M + H] + .

[0302] 4) Synthesis of intermediate P3

[0303] Intermediate P3-4 (450 mg, 1.2 mmol) and 10% Pd / C (127 mg, 1.2 mmol) were added to a round-bottom flask, dissolved in ethanol, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The solid was filtered and washed with ethanol, and the filtrate was concentrated to give intermediate P3 (350 mg, 73%). LC-MS (m / z): 397.4 [M + H] + .

[0304] Example 4: Synthesis of intermediate P4

[0305]

[0306] 1) Synthesis of intermediate P4-2

[0307] The starting material P4-1 (10 g, 39 mmol) and potassium carbonate (11 g, 78 mmol) were dissolved in dry N,N-dimethylformamide (100 mL). At room temperature, benzyl bromide (7.3 g, 43 mmol) was added, and the mixture was stirred overnight. After the reaction was complete, the reaction solution was slowly poured into approximately 350 mL of ice water, filtered, and the filter cake was washed with approximately 100 mL of ice water and 50 mL of petroleum ether. The dried filter cake yielded a pale yellow solid, P4-2 (10 g, 74%).

[0308] 2) Synthesis of intermediate P4-3

[0309] Intermediate P4-2 (7 g, 20 mmol), methylboric acid (2.4 g, 40 mmol), anhydrous potassium phosphate (8.6 g, 40 mmol), SPhos (829 mg, 2.0 mmol), and palladium acetate (227 mg, 1.0 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 mL). The mixture was reacted at 100 °C for 4 hours under nitrogen protection. After the reaction was completed, the mixture was filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1, v / v) to obtain a pale yellow solid intermediate P4-3 (4.3 g, 75%).

[0310] 3) Synthesis of intermediate P4-4

[0311] Intermediate P4-3 (6.0 g, 21 mmol) was dissolved in dichloroethane (60 mL), and benzoyl peroxide (258 mg, 1.1 mmol) was added. The mixture was heated to 80 °C, and N-bromosuccinimide (3.9 g, 22 mmol) was slowly added in portions. After the addition was complete, the mixture was reacted at 80 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched in 200 mL of ice water. The mixture was extracted with dichloromethane (100 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. The solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 1, v / v) to give intermediate P4-4 (6.0 g, 79%) as a yellow solid.

[0312] 4) Synthesis of intermediate P4-5

[0313] Intermediate P4-4 (6.0 g, 17 mmol) was added to a round-bottom flask, and about 40 mL of triethyl phosphite was added. The mixture was heated to 120 °C and stirred for 16 hours. After the reaction was complete, the solvent was removed by rotary evaporation using an oil pump, the mixture was concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain yellow liquid intermediate P4-5 (6.2 g, 87%).

[0314] 5) Synthesis of intermediate P4-6

[0315] Intermediate P4-5 (6.2 g, 15 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Under nitrogen protection, the mixture was cooled to -78 °C, and sodium bis(trimethylsilyl)amino (11 mL, 22 mmol) was added dropwise. After the addition was complete, the mixture was stirred at -78 °C for 5 minutes. Davies oxaziridine reagent (7.7 g, 30 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and slowly added dropwise to the reaction system at -65 °C. After the addition was complete, the mixture was stirred at -78 °C for 20 minutes. After the reaction was complete, the solution was quenched in 450 mL of saturated ammonium chloride aqueous solution. After stirring for 30 minutes, the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give intermediate P4-6 (2.2 g, 34%) as a yellow solid.

[0316] 6) Synthesis of intermediate P4-7

[0317] Intermediate P4-6 (1.5 g, 3.5 mmol) was dissolved in dichloromethane (20 mL) and cooled to -78 °C under nitrogen protection. DAST (0.84 g, 5.2 mmol) was dissolved in dichloromethane (10 mL) and slowly added dropwise to the reaction system at -65 °C. After the addition was complete, the mixture was stirred at -78 °C for 20 minutes. After the reaction was complete, the mixture was quenched in 100 mL of saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain yellow liquid intermediate P4-7 (0.7 g, 46%).

[0318] 7) Synthesis of intermediate P4-8

[0319] NFSI (1.1 g, 3.4 mmol) and intermediate P4-7 (500 mg, 1.2 mmol) were dissolved in anhydrous THF (10 mL). Under nitrogen protection, the mixture was cooled to -78 °C, and NaHMDS (1.7 mL, 3.4 mmol) was slowly added dropwise at -65 °C. After the addition was complete, the mixture was kept at -78 °C and stirred for 1 hour. After the reaction was completed, the mixture was quenched in a saturated ammonium chloride aqueous solution (100 mL). The mixture was extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a yellow liquid intermediate P4-8 (500 mg, 92%).

[0320] 8) Synthesis of intermediate P4-9

[0321] Intermediate P4-8 (350 mg, 0.77 mmol) was dissolved in ethanol (10 mL). Ammonium formate (490 mg, 7.7 mmol) and 10% palladium on carbon (160 mg, 1.5 mmol) were added at room temperature. The mixture was heated to 80 °C and stirred under reflux for 30 minutes. After the reaction was complete, the mixture was filtered, and the filtrate was directly concentrated. The residue was dissolved in 10 mL of ethyl acetate, washed with 5 mL of water, and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to give intermediate P4-9 (300 mg, crude).

[0322] 9) Synthesis of intermediate P4

[0323] Dissolve intermediate P4-9 (300 mg, crude) in dichloromethane (5 mL), add DMF (0.05 mL), and slowly add oxaloyl chloride (314 mg, 2.5 mmol) dropwise to the reaction at room temperature. After the addition is complete, stir the reaction at room temperature for 20 minutes. Once the reaction is complete, concentrate the solution directly to obtain the concentrate for later use.

[0324] In a separate three-necked flask, pentafluorophenol (228 mg, 1.3 mmol) was dissolved in dichloromethane (10 mL). Under nitrogen protection, the mixture was cooled to 0°C, and triethylamine (250 mg, 2.5 mmol) was slowly added to the reaction mixture. The mixture was stirred at 0°C for about 15 minutes. The concentrated solution was then dissolved in dichloromethane (5 mL) and slowly added dropwise to the reaction mixture while maintaining the temperature at 0°C. After the addition was complete, the mixture was allowed to cool to room temperature and stirred for 30 minutes. After the reaction was complete, the solution was poured into about 50 mL of ice water and extracted with dichloromethane (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a yellow solid P4 (150 mg). The two-step yield was 37%. 1 H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 8.22 (s,1H), 8.01 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 4.32 – 4.17 (m, 4H),1.38 – 1.32 (m, 6H).

[0325] Example 5: Synthesis of intermediate P5

[0326]

[0327] 1) Synthesis of intermediate P5-1

[0328] 5-((diethoxyphosphoryl)difluoromethyl)-1H-indole-2-carboxylic acid (9.3 g, 27 mmol), pentafluorophenol (6.4 g, 35 mmol), EDCI (6.6 g, 35 mmol), and DMAP (1.6 g, 13 mmol) were dissolved in 150 mL of DCM and stirred at room temperature for 2 hours. The solution was quenched with saturated sodium bicarbonate solution, separated, and the solvent was evaporated. The solution was then purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid intermediate P5-1 (4.0 g, 30%). 1 H NMR (400 MHz, CDCl3)δ 9.60 (s, 1H), 8.02 (s, 1H), 7.60 – 7.52 (m, 2H), 7.43 (d, J = 8.8 Hz, 1H), 4.31 – 4.11 (m, 4H), 1.33 (t, J = 7.2 Hz, 6H). LC-MS (m / z): 512.3 [M - H] - .

[0329] 2) Synthesis of intermediate P5-2

[0330] Add intermediate P5-1 (1.0 g, 2.0 mmol) and DCM (5 mL) to a flask. Cool the solution to 0 °C, then add TMSBr (612 mg, 4.0 mmol). Stir the reaction mixture at room temperature until the starting material disappears. Reduce the solvent by rotary evaporation, dissolve the residue in a mixture of acetonitrile and water, and purify by reverse-phase silica gel column chromatography (water / acetonitrile = 4 / 1, v / v) to give an acetonitrile-water solution of intermediate P5-2, which can be used directly in the next reaction. LC-MS (m / z): 456.1 [M-H] - .

[0331] 3) Synthesis of intermediate P5

[0332] TFA (8 mL) was added to an acetonitrile-water solution of intermediate P5-2. The mixture was heated to 52 °C for 3 days. The solvent was removed by rotary evaporation, the precipitate was collected by filtration, and washed with purified water to give intermediate P5 (400 mg, 46%, two-step yield). LC-MS (m / z): 434.0 [M - H] - .

[0333] Example 6: Synthesis of final product A1

[0334]

[0335] 1) Synthesis of intermediate A1-2

[0336] The starting material A1-1 (5 mL) and tert-butyl acrylate (5 mL) were added to a round-bottom flask, and EtOH (15 mL) was added. The mixture was stirred overnight at 90 °C. The reaction solution was concentrated to obtain crude oil intermediate A1-2 (6.0 g, 66%), which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.38 – 7.26 (m, 5H), 5.11 (s, 2H), 3.53 –3.43 (m, 4H), 2.65 (t, J = 7.2 Hz, 2H), 2.47 – 2.33 (m, 6H), 1.43 (s, 9H).

[0337] 2) Synthesis of intermediate A1-3

[0338] Intermediate A1-2 (3.0 g, 8.6 mmol) was dissolved in EtOH (30 mL), and 10% Pd / C (91 mg, 0.86 mmol) was added. The mixture was stirred overnight under hydrogen atmosphere. The solid was filtered and washed with EtOH. The filtrate was concentrated to obtain crude product intermediate A1-3 (1.8 g, 100%, crude). 1 H NMR (400 MHz, CDCl3) δ 2.93 – 2.81 (m, 4H), 2.62 (t, J = 7.4 Hz, 2H), 2.47 – 2.38 (m, 6H), 1.43 (s, 9H).

[0339] 3) Synthesis of intermediate A1-4

[0340] 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (1.0 g, 3.0 mmol), intermediate A1-3 (963 mg, 4.5 mmol, crude), RuPhos Pd G2 (466 mg, 0.6 mmol), and RuPhos (280 mg, 0.6 mmol) were added to a three-necked flask, followed by toluene (15 mL). Under nitrogen protection and an ice bath, LiHMDs (1 M, 18 mL) were slowly added. The mixture was stirred at 80 °C for 1 hour. The reaction was quenched with tert-butanol, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / EA / MeOH = 100 / 100 / 6, v / v / v) to give a yellow solid intermediate A1-4 (300 mg, 21%). 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 6.72 – 6.59 (m, 3H), 5.18 (dd, J = 12.8, 5.2 Hz, 1H), 3.40 (s, 3H), 3.20 – 3.11 (m, 4H), 2.77 (t, J = 7.6 Hz, 4H), 2.74 – 2.62 (m, 5H), 2.49 (t, J = 7.3 Hz, 2H), 2.28– 2.17 (m, 1H), 1.46 (s, 9H). LC-MS (m / z): 472.5 [M + H] + .

[0341] 4) Synthesis of intermediate A1-5

[0342] Intermediate A1-4 (300 mg, 0.64 mmol) was dissolved in ethyl acetate (5 mL), and the mixture was stirred overnight at room temperature. The mixture was concentrated to obtain crude intermediate A1-5 (287 mg, 100%, crude), which was directly added to the next step.

[0343] 5) Synthesis of intermediate A1-6

[0344] Intermediate P3 (150 mg, 0.38 mmol), intermediate A1-5 (150 mg, 0.36 mmol, crude), HATU (274 mg, 0.72 mmol), and DIPEA (186 mg, 1.44 mmol) were added to a round-bottom flask, followed by the addition of DMF (5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH = 20 / 1, v / v) to give a yellow solid intermediate A1-6 (90 mg, 31%). LC-MS (m / z): 794.9 [M + H] + .

[0345] 6) Synthesis of intermediate A1-7

[0346] Intermediate A1-6 (85 mg, 0.11 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 mL / 5 mL), and the mixture was stirred overnight at room temperature. The solution was then directly concentrated to give crude intermediate A1-7 (70 mg, 91%, crude). LC-MS (m / z): 694.9 [M + H] + .

[0347] 7) Synthesis of intermediate A1-8

[0348] Intermediate A1-7 (70 mg, 0.10 mmol, crude) and intermediate P1 (56 mg, 0.11 mmol) were dissolved in DMF (2 mL), followed by the addition of DIPEA (52 mg, 0.40 mmol). The mixture was stirred at room temperature for 30 minutes, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH=20 / 1, v / v) to give intermediate A1-8 (85 mg, 84%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 8.29 – 8.08 (m, 1H), 8.02 (s,1H), 7.92 (d, J = 9.2 Hz, 3H), 7.87 (d, J = 6.0 Hz, 1H), 7.70 (d, J = 8.8 Hz,1H), 6.83 – 6.54 (m, 3H), 5.87 (dd, J = 44.6, 8.4 Hz, 1H), 5.22 – 4.97 (m,1H), 4.95 – 4.87 (m, 1H), 4.87 – 4.76 (m, 1H), 4.44 – 3.96 (m, 7H), 3.92 –3.62 (m, 8H), 3.57 – 3.42 (m, 2H), 3.38 (s, 3H), 3.34 – 3.10 (m, 6H), 3.02 –2.58 (m, 8H), 2.40 – 1.82 (m, 8H), 1.32 – 1.27 (m, 6H). LC-MS (m / z): 1017.0[M + H] + .

[0349] 8) Synthesis of final product A1

[0350] Intermediate A1-8 (80 mg, 0.08 mmol) was dissolved in dichloromethane (5 mL), and TMSBr (0.5 mL) was added. The mixture was stirred at room temperature for 24 hours under nitrogen protection. The mixture was concentrated, and after adding a small amount of methanol, it was purified by C18 column (CH3CN / H2O=3 / 7) to obtain the final product A1 (37 mg, 48%).

[0351] Example 7: Synthesis of final product A2

[0352]

[0353]

[0354] 1) Synthesis of intermediate A2-2

[0355] Starting material A2-1 (5.0 g, 14 mmol) was dissolved in THF (50 mL), and LiOH·H2O (3.4 g, 41 mmol) was dissolved in water (40 mL) and added to the reaction solution. The mixture was stirred overnight at room temperature. The pH was adjusted to acidic by adding 2N HCl aqueous solution, and the organic phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated to obtain crude intermediate A2-2 (5.0 g, crude), which was directly added to the next step.

[0356] 2) Synthesis of intermediate A2-3

[0357] Intermediate A2-2 (9.5 g, 67 mmol, crude) was dissolved in DCM (250 mL). Oxaloyl chloride (23 g, 183 mmol) was added under ice bath conditions, followed by dropwise addition of DMF (5 mL). The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was dissolved in DCM (250 mL). DIPEA (16 g, 122 mmol) was added under ice bath conditions, followed by slow addition of tert-butanol (50 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1, v / v) to give a yellow oily intermediate A2-3 (7.0 g, 49%). 1 H NMR (400 MHz, CDCl3) δ 2.40 – 2.32 (m, 4H), 2.26 – 2.17 (m, 3H), 2.11 – 2.00 (m, 2H), 1.51 – 1.39 (m, 11H).

[0358] 3) Synthesis of intermediate A2-4

[0359] Methyltriphenylphosphine bromide (17 g, 49 mmol) was dissolved in tetrahydrofuran (180 mL), and potassium tert-butoxide (5.4 g, 49 mmol) was added under nitrogen protection at 0 °C. The mixture was stirred for 10 minutes in an ice bath, and then stirred for 2 hours at room temperature. Intermediate A2-3 (5.1 g, 24 mmol) was dissolved in tetrahydrofuran (20 mL) and added dropwise to the reaction solution in an ice bath. The mixture was stirred for 30 minutes at room temperature, and then stirred overnight at 50 °C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE / EA=50 / 1) to give intermediate A2-4 (4.5 g, 88%), a colorless, transparent oil. 1H NMR (400 MHz, CDCl3) δ4.60 (s, 2H), 2.33 – 2.24 (m, 2H), 2.12 (d, J = 7.2 Hz, 2H), 2.10 – 2.00 (m,2H), 1.95 – 1.87 (m, 1H), 1.87 – 1.78 (m, 2H), 1.45 (s, 9H), 1.13 – 1.01 (m, 2H).

[0360] 4) Synthesis of intermediate A2-5

[0361] 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (2.7 g, 7.9 mmol), intermediate A2-4 (2.5 g, 11.9 mmol), Pd2(dba)3 (724 mg, 0.79 mmol), and DIPEA (2.0 g, 15.8 mmol) were dissolved in DMF (40 mL). 10% P(t-Bu)3 (3.2 g, 1.6 mmol) was added at room temperature, and the mixture was stirred overnight at 80°C under nitrogen protection. The mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA / MeOH = 50 / 50 / 1, v / v / v) to give intermediate A2-5 (2.5 g, 67%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.13(s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.84 (s, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.27 (s, 1H), 5.20 (dd, J = 12.8, 5.2 Hz, 1H), 3.42 (s, 3H), 2.94 – 2.69 (m,4H), 2.40 – 2.18 (m, 3H), 2.14 (d, J = 6.8 Hz, 2H), 2.02 – 1.77 (m, 4H), 1.51– 1.36 (m, 11H). LC-MS (m / z): 468.5 [M + H] + .

[0362] 5) Synthesis of intermediate A2-6

[0363] Intermediate A2-5 (2.5 g, 5.3 mmol) was dissolved in ethanol (20 mL), and formic acid (2 mL) and 10% palladium on carbon (227 mg, 2.1 mmol) were added. The mixture was stirred at 80 °C for 2 hours. The solid was filtered off and washed with ethanol. The filtrate was concentrated to give crude intermediate A2-6 (2.5 g, 100%, crude), which was directly added to the next step. LC-MS (m / z): 470.5 [M + H] + .

[0364] 6) Synthesis of intermediate A2-7

[0365] Intermediate A2-6 (2.5 g, 5.3 mmol, crude) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give intermediate A2-7 (1.8 g, 82%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.92(s, 1H), 11.07 (s, 1H), 6.98 (d, J = 6.8 Hz, 1H), 6.87 – 6.73 (m, 1H), 5.32(dd, J = 12.8, 5.2 Hz, 1H), 3.31 (s, 3H), 2.96 – 2.52 (m, 6H), 2.13 (dd, J =62.8, 7.2 Hz, 2H), 2.04 – 1.95 (m, 1H), 1.95 – 1.78 (m, 1H), 1.77 – 1.59 (m,2H), 1.49 – 1.35 (m, 4H), 1.34 – 1.25 (m, 1H), 1.02 – 0.81 (m, 1H). LC-MS (m / z): 414.3 [M + H] + .

[0366] 7) Synthesis of intermediate A2-8 (024-29)

[0367] Intermediate P3 (143 mg, 0.36 mmol), intermediate A2-7 (150 mg, 0.36 mmol), HATU (274 mg, 0.72 mmol), and DIPEA (139 mg, 1.1 mmol) were added to a round-bottom flask, followed by DMF (5 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 25 / 1, v / v) to obtain a white solid intermediate A2-8 (140 mg, 49%). LC-MS (m / z): 792.9 [M + H] + .

[0368] 8) Synthesis of intermediate A2-9

[0369] Intermediate A2-8 (85 mg, 0.11 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 mL / 5 mL), and the mixture was stirred overnight at room temperature and then concentrated directly to obtain crude product intermediate A2-9 (170 mg, crude).

[0370] 9) Synthesis of intermediate A2-10

[0371] Intermediate A2-9 (70 mg, 0.10 mmol, crude) and intermediate P1 (51 mg, 0.10 mmol) were dissolved in DMF (4 mL), followed by the addition of DIPEA (39 mg, 0.30 mmol). The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give a colorless, transparent liquid intermediate A2-10 (100 mg, 99%). LC-MS (m / z): 1015.3 [M + H] + .

[0372] 10) Synthesis of final product A2

[0373] Intermediate A2-10 (100 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), and TMSBr (1 mL) was added. The mixture was stirred at room temperature for 24 hours under nitrogen protection. The mixture was concentrated, and after adding a small amount of methanol, it was purified by C18 column (CH3CN / H2O=3 / 7, v / v) to obtain final product A2 (50 mg, 52%).

[0374] Example 8: Synthesis of final product A3

[0375]

[0376] 1) Synthesis of intermediate A3-1

[0377] Intermediate A2-9 (100 mg, 0.14 mmol, crude) and intermediate P2 (73 mg, 0.14 mmol) were dissolved in DMF (2 mL), followed by the addition of DIPEA (72 mg, 0.56 mmol). The mixture was stirred at room temperature for 30 minutes, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 3, v / v) to give a white solid intermediate A3-1 (75 mg, 52%).

[0378] 2) Synthesis of final product A3

[0379] Intermediate A3-1 (70 mg, 0.070 mmol) was dissolved in dichloromethane (5 mL), and TMSBr (1 mL) was added. The mixture was stirred overnight at room temperature under nitrogen protection. The mixture was concentrated, and the reaction was quenched with water (1 mL). Acetonitrile (1 mL) was then added. The mixture was purified by C18 column (CH3CN / H2O=3 / 7, v / v) to give the final product A3 (30 mg, 44%).

[0380] Example 9: Synthesis of final product A4

[0381]

[0382] 1) Synthesis of intermediate A4-1

[0383] The starting materials 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (338 mg, 1.0 mmol), potassium ethylene trifluoroborate (402 mg, 3.0 mmol), anhydrous potassium carbonate (276 mg, 2.0 mmol), and Pd(dppf)Cl2 (73.2 mg, 0.10 mmol) were dissolved in dry dioxane (10 mL) and stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was complete, the solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a pale yellow solid intermediate A4-1 (210 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.21 –7.07 (m, 2H), 6.79 – 6.66 (m, 2H), 5.69 (d, J = 17.6 Hz, 1H), 5.26 – 5.14 (m,2H), 3.45 (s, 3H), 2.99 – 2.89 (m, 1H), 2.87 – 2.65 (m, 2H), 2.28 – 2.19 (m,1H).

[0384] 2) Synthesis of intermediate A4-2

[0385] Intermediate A4-1 (210 mg, 0.73 mmol) was dissolved in (dioxane / water = 10 mL / 5 mL). K2[OsO2(OH)4] (27 mg, 73 μmol), sodium periodate (624 mg, 2.9 mmol), and 2,6-dimethylpyridine (156 mg, 1.5 mmol) were added to the reaction system. The mixture was stirred at room temperature for 16 hours. A saturated sodium thiosulfate solution (20 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The mixture was separated, and the organic phase was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to obtain a white solid intermediate A4-2 (150 mg, 72%). 1 H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.14 (s,1H), 7.66 – 7.56 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 5.29 – 5.21 (m, 1H), 3.50(s, 3H), 3.02 – 2.94 (m, 1H), 2.92 – 2.69 (m, 2H), 2.34 – 2.22 (m, 1H).

[0386] 3) Synthesis of intermediate A4-3

[0387] Intermediate A4-2 (150 mg, 0.52 mmol) was dissolved in DCM (2 mL), followed by the addition of 2-(piperidin-1-yl)tert-butyl acetate (209 mg, 1.0 mmol), STAB (664 mg, 3.1 mmol), triethylamine (105 mg, 1.0 mmol), and one drop of acetic acid. The mixture was stirred at room temperature for 16 hours. After the solvent was evaporated, the solution was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give intermediate A4-3 (120 mg, 49%), a yellow oil.

[0388] 4) Synthesis of intermediate A4-4

[0389] Intermediate A4-3 (120 mg, 0.25 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 16 hours. After concentration, crude intermediate A4-4 (150 mg, crude) was obtained and used directly in the next reaction. LC-MS (m / z): 416.5 [M + H] + .

[0390] 5) Synthesis of intermediate A4-5

[0391] Intermediate A4-4 (150 mg, crude) was dissolved in DMF (5 mL), and intermediate P3 (100 mg, 0.25 mmol), HATU (192 mg, 0.51 mmol), and DIPEA (130 mg, 1.0 mmol) were added. The mixture was stirred at room temperature for 2 hours, and after the solvent was evaporated, it was purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a yellow oily intermediate A4-5 (100 mg, 50%, two-step yield). LC-MS (m / z): 795.0 [M + H] + .

[0392] 6) Synthesis of intermediate A4-6

[0393] Intermediate A4-5 (100 mg, 0.13 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 16 hours. After concentration, crude intermediate A4-6 (130 mg, crude) was obtained and used directly in the next reaction. LC-MS (m / z): 694.7 [M + H] + .

[0394] 7) Synthesis of intermediate A4-7

[0395] Intermediate A4-6 (130 mg, 0.19 mmol, crude), intermediate P1 (207 mg, 0.30 mmol), DIPEA (78 mg, 0.60 mmol), and DMF (2 mL) were added to a reaction flask and stirred at room temperature for 2 hours. After the solvent was evaporated, the mixture was purified by silica gel column chromatography (dichloromethane / methanol = 40 / 1) to give a yellow oily intermediate A4-7 (90 mg, 70%, two-step yield). LC-MS (m / z): 1016.8 [M + H] + .

[0396] 8) Synthesis of final product A4

[0397] Intermediate A4-7 (90 mg, 88 μmol) was dissolved in DCM (5 mL), TMSBr (1 mL) was added, and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated, and the residue was purified by reverse silica gel column chromatography (water / acetonitrile = 4 / 1, v / v) to obtain final product A4 (11 mg, 13%).

[0398] Example 10: Synthesis of final product A5

[0399]

[0400]

[0401]

[0402] 1) Synthesis of intermediate A5-1

[0403] Intermediate P1 (200 mg, 0.40 mmol) was dissolved in dichloromethane (10 mL), and TMSBr (2 mL) was added. The mixture was stirred overnight at room temperature under nitrogen protection. The mixture was concentrated and purified by C18 column (CH3CN / H2O=3 / 7, v / v) to give white solid intermediate A5-1 (110 mg, 61%). 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.20 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.13 – 8.05 (m, 2H), 7.79 (d, J = 8.4Hz, 1H), 5.79 (dd, J = 44.4, 8.8 Hz, 1H). LC-MS (m / z): 449.2 [M - H] -

[0404] 2) Synthesis of intermediate A5-3

[0405] The starting material A5-2 (50 g, 406 mmol) was dissolved in anhydrous THF (500 mL). Under nitrogen protection, the mixture was cooled to -65 °C and LDA (243 mL, 485 mmol) was added dropwise. After the addition was complete, the reaction was stirred at -65 °C for 1 hour. Dimethyl carbonate (40 g, 445 mmol) was added dropwise while maintaining the temperature at -65 °C. After the addition was complete, the mixture was stirred at -65 °C for 1 hour. After the reaction was complete, the reaction was quenched with saturated NH4Cl aqueous solution (500 mL) and extracted with ethyl acetate (500 mL × 3). The organic layers were combined, washed with brine (500 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow liquid intermediate A5-3 (34 g, 46%).

[0406] 3) Synthesis of intermediate A5-4

[0407] Intermediate A5-3 (34 g, 188 mmol) was dissolved in anhydrous THF (350 mL). Under nitrogen protection, the mixture was cooled to -65 °C and LDA (141 mL, 281 mmol) was added dropwise. After the addition was complete, the reaction was stirred at -65 °C for 1 hour. Bromoacetonitrile (27 g, 225 mmol) was added dropwise while maintaining the temperature at -65 °C. After the addition was complete, the mixture was stirred at -65 °C for 1 hour. After the reaction was complete, the reaction was quenched with saturated NH4Cl aqueous solution (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a yellow solid intermediate A5-4 (30 g, 72%).

[0408] 4) Synthesis of intermediate A5-5

[0409] Intermediate A5-4 (30 g, 136 mmol) and tetraisopropyl titanate (19 g, 68 mmol) were dissolved in anhydrous THF (500 mL). Under nitrogen protection, the mixture was cooled to 0 °C and ethyl magnesium bromide (93 mL, 313 mmol) was added dropwise. After the addition was complete, the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction was quenched with 2N hydrochloric acid aqueous solution (250 mL) and extracted with ethyl acetate (300 mL × 3). The organic layers were combined, washed with brine (300 mL), dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1, v / v) to give a pale yellow solid intermediate A5-5 (9.0 g, 30%).

[0410] 5) Synthesis of intermediate A5-6

[0411] Intermediate A5-5 (7.0 g, 32 mmol) and RhCO(PPh)3 (1.5 g, 1.6 mmol) were added to a three-necked flask, followed by 1,4-dioxane (120 mL). Then, under nitrogen protection, PhSiH3 (20.3 g, 192 mmol) was added, and the mixture was stirred overnight at 100 °C. The reaction was quenched with methanol, the mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give a pale yellow oily intermediate A5-6 (3.0 g, 46%). LC-MS (m / z): 205.3 [M + H] + .

[0412] 6) Synthesis of intermediate A5-7

[0413] Intermediate A5-6 (2.1 g, 10 mmol) was added to a round-bottom flask, followed by 10 mL of 30% HBr aqueous solution and 5 mL of 30% HBr acetic acid solution. The mixture was stirred overnight at 100 °C, concentrated, and the pH of the residue was adjusted to alkaline with saturated sodium bicarbonate aqueous solution. The residue was then concentrated again to obtain crude intermediate A5-7 (1.9 g, crude), which was directly added to the next step. LC-MS (m / z): 191.3 [M + H] + .

[0414] 7) Synthesis of intermediate A5-8

[0415] Intermediate A5-7 (1.9 g, 10 mmol, crude) was dissolved in tetrahydrofuran (40 mL), and (Boc)2O (3.5 g, 16 mmol) and triethylamine (1.9 g, 19 mmol) were added. The mixture was stirred at room temperature for 4 hours, concentrated, and the residue was subjected to silica gel column chromatography (DCM / MeOH=100 / 3, v / v) to give intermediate A5-8 (2.1 g, 72%) as a yellow solid. 1H NMR(400 MHz, CDCl3) δ 12.34 (s, 1H), 7.33 (d, J = 6.4 Hz, 1H), 6.43 (s, 1H), 6.21 (dd, J = 6.4, 1.2 Hz, 1H), 3.95 – 3.85 (m, 1H), 3.51 – 3.40 (m, 1H),3.35 – 3.22 (m, 1H), 2.20 (dd, J = 12.4, 10.0 Hz, 1H), 1.99 (dd, J = 12.0,6.4 Hz, 1H), 1.42 (s, 9H), 1.40 – 1.22 (m, 2H), 0.55 – 0.39 (m, 2H). LC-MS (m / z): 291.2 [M + H] + .

[0416] 8) Synthesis of intermediate A5-9

[0417] Intermediate A5-8 (580 mg, 2.0 mmol) was dissolved in DMF (10 mL), and cesium carbonate (2.0 g, 6.0 mmol) and iodomethane (568 mg, 4.0 mmol) were added. The mixture was stirred overnight at room temperature, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give intermediate A5-9 (300 mg, 50%), a colorless, viscous, oily substance. 1 HNMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.2 Hz, 1H), 6.45 (d, J = 1.2 Hz, 1H), 6.09 (dd, J = 6.8, 2.0 Hz, 1H), 3.96 – 3.84 (m, 1H), 3.52 (s, 3H), 3.47 –3.38 (m, 1H), 3.30 – 3.20 (m, 1H), 2.27 – 2.15 (m, 1H), 2.03 – 1.91 (m, 1H), 1.49 – 1.39 (m, 10H), 1.28 – 1.21 (m, 1H), 0.56 – 0.39 (m, 2H).

[0418] 9) Synthesis of intermediate A5-10

[0419] Intermediate A5-9 (300 mg, 1.0 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 4 hours, and the mixture was concentrated to obtain crude intermediate A5-10 (300 mg, crude), which was used directly in the next step.

[0420] 10) Synthesis of intermediate A5-11

[0421] Intermediate P3-3 (270 mg, 0.58 mmol), intermediate A5-10 (300 mg, 1.5 mmol, crude), HATU (331 mg, 0.87 mmol), and DIPEA (300 mg, 2.3 mmol) were dissolved in dichloromethane (20 mL). The mixture was stirred at room temperature for 4 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 3, v / v) to give a viscous oily intermediate A5-11 (200 mg, 53%). LC-MS (m / z): 648.7 [M + H] + .

[0422] 11) Synthesis of intermediate A5-12

[0423] Intermediate A5-11 (200 mg, 0.31 mmol) was dissolved in ethanol (5 mL), and 10% Pd / C (164 mg, 1.6 mmol) and ammonium acetate (372 mg, 3.1 mmol) were added. The mixture was stirred at 80 °C for 10 min. The solid was filtered off and washed with dichloromethane. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH=100 / 3, v / v) to give a white solid intermediate A5-12 (130 mg, 82%). LC-MS (m / z): 514.4 [M + H]+.

[0424] 12) Synthesis of intermediate A5-13

[0425] Intermediate A2-7 (130 mg, 0.31 mmol), HATU (194 mg, 0.51 mmol), and DIPEA (87 mg, 0.68 mmol) were dissolved in DMF (2 mL). The mixture was stirred at room temperature for 5 minutes, and then A5-12 (130 mg, 0.25 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give a white solid intermediate A5-13 (130 mg, 46%). LC-MS (m / z): 909.9 [M + H]+.

[0426] 13) Synthesis of intermediate A5-14

[0427] Intermediate A5-13 (50 mg, 0.055 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 mL / 3 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then directly concentrated to obtain crude intermediate A5-14 (50 mg, crude).

[0428] 14) Synthesis of final product A5

[0429] Intermediate A5-14 (45 mg, 0.055 mmol, crude) was dissolved in DMF (2 mL), and intermediate A5-1 (22 mg, 0.050 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 30 minutes. The mixture was purified by C18 column (CH3CN / H2O=3 / 7, v / v) to give final product A5 (20 mg, 37%).

[0430] Example 11: Synthesis of final product A6

[0431]

[0432] 1) Synthesis of intermediate A6-1

[0433] Intermediate P2 (195 mg, 0.37 mmol) was dissolved in dichloromethane (5 mL), and TMSBr (1 mL) was added. The mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by C18 column (CH3CN / H2O=3 / 7, v / v) to give a white solid intermediate A6-1 (120 mg, 69%). 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.45 (s, 1H), 8.29 – 8.16 (m, 3H), 7.86 (d, J = 8.8 Hz, 1H). LC-MS (m / z): 467.4[MH] - .

[0434] 2) Synthesis of final product A6

[0435] Intermediate A5-14 (30 mg, 0.037 mmol) was dissolved in DMF (1 mL), and intermediate A6-1 (16 mg, 0.034 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 30 minutes. The mixture was purified by C18 column (CH3CN / H2O=2 / 8, v / v) to give final product A6 (15 mg, 40%).

[0436] Example 12: Synthesis of final product A7

[0437]

[0438] 1) Synthesis of intermediate A7-2

[0439] 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (338 mg, 1.0 mmol), intermediate A7-1 (210 mg, 1.5 mmol), Pd(dppf)Cl2 (70 mg, 0.10 mmol), and CuI (20 mg, 0.10 mmol) were added to a three-necked flask, along with DMF (4 mL) and triethylamine (2 mL). The mixture was stirred at 80 °C for 3 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 15 / 1, v / v) to give a yellow solid intermediate A7-2 (300 mg, 76%). LC-MS (m / z): 398.4 [M + H] + .

[0440] 2) Synthesis of intermediate A7-3

[0441] Intermediate P3 (110 mg, 0.28 mmol), intermediate A7-2 (100 mg, 0.25 mmol), HATU (190 mg, 0.50 mmol), and DIPEA (129 mg, 1.0 mmol) were added to a round-bottom flask, followed by DCM (5 mL). The mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 25 / 1, v / v) to give intermediate A7-3 (100 mg, 52%) as a yellow solid. LC-MS (m / z): 776.8 [M + H] + .

[0442] 3) Synthesis of intermediate A7-4

[0443] Dissolve A6-3 (50 mg, 0.064 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), stir the mixture at room temperature for 30 minutes, concentrate the mixture to obtain crude intermediate A7-4 (43 mg, 100%, crude), and proceed directly to the next step.

[0444] 4) Synthesis of final product A7

[0445] Intermediate A7-4 (43 mg, 0.064 mmol, crude) was dissolved in DMF (1 mL), and intermediate A5-1 (29 mg, 0.064 mmol) and DIPEA (33 mg, 0.26 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was purified by C18 column (CH3CN / H2O=3 / 7) to give the final product A7 (4 mg, 6.7%).

[0446] Example 13: Synthesis of final product A8

[0447]

[0448] 1) Synthesis of intermediate A8-1

[0449] Intermediate A5-12 (40 mg, 0.080 mmol), intermediate A1-5 (33 mg, 0.080 mmol), HATU (61 mg, 0.16 mmol), and DIPEA (21 mg, 0.16 mmol) were dissolved in DMF (1.5 mL), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH=20 / 1, v / v) to give colorless and transparent intermediate A8-1 (35 mg, 48%). LC-MS (m / z): 911.9 [M + H] + .

[0450] 2) Synthesis of intermediate A8-2

[0451] Intermediate A8-1 (35 mg, 0.038 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 mL / 3 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then directly concentrated to obtain crude product intermediate A8-2 (100 mg, crude).

[0452] 3) Synthesis of final product A8

[0453] Intermediate A8-2 (31 mg, 0.038 mmol, crude) was dissolved in DMF (1 mL), and intermediate A5-1 (14 mg, 0.032 mmol) and DIPEA (12 mg, 0.091 mmol) were added. The mixture was stirred at room temperature for 4 hours. The mixture was purified by C18 column (CH3CN / H2O=2 / 8, v / v) to give final product A8 (20 mg, 49%).

[0454] Example 14: Synthesis of final product A9

[0455]

[0456] 1) Synthesis of intermediate A9-1

[0457] Intermediate A5-8 (870 mg, 3.0 mmol) was dissolved in DMF (15 mL), and cesium carbonate (2.9 g, 9.0 mmol) and deuterated iodomethane (870 mg, 6.0 mmol) were added. The mixture was stirred overnight at room temperature, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give intermediate A9-1 (500 mg, 54%), a yellow oily substance.

[0458] 2) Synthesis of intermediate A9-2

[0459] Intermediate A9-1 (500 mg, 1.6 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours, and the mixture was concentrated to obtain crude intermediate A9-2 (1.2 g, crude), which was used directly in the next step.

[0460] 3) Synthesis of intermediate A9-3

[0461] Intermediate P3-3 (379 mg, 0.82 mmol), intermediate A9-2 (170 mg, 0.82 mmol, crude), HATU (467 mg, 1.2 mmol), and DIPEA (212 mg, 1.6 mmol) were dissolved in DMF (6 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give a viscous oily intermediate A9-3 (300 mg, 56%). LC-MS (m / z): 651.6 [M + H] + .

[0462] 4) Synthesis of intermediate A9-4

[0463] Intermediate A9-3 (300 mg, 0.46 mmol) was dissolved in ethanol (15 mL), and 10% Pd / C (98 mg, 0.92 mmol) and ammonium acetate (290 mg, 4.6 mmol) were added. The mixture was stirred at 80 °C for 10 minutes. The solid was filtered and washed with ethanol. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH=20 / 1, v / v) to give intermediate A9-4 (200 mg, 84%) as a white solid.

[0464] 5) Synthesis of intermediate A9-5

[0465] Intermediate A2-7 (100 mg, 0.24 mmol), intermediate A9-4 (100 mg, 0.19 mmol), HATU (137 mg, 0.36 mmol), and DIPEA (80 mg, 0.62 mmol) were dissolved in DMF (4 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give a white solid intermediate A9-5 (170 mg, 98%).

[0466] 6) Synthesis of final product A9

[0467] Intermediate A9-5 (90 mg, 0.099 mmol) was dissolved in a mixed solvent (TFA / DCM = 2 mL / 4 mL). The mixture was stirred at room temperature for 2 hours, and then directly concentrated to obtain the crude product. The crude product was dissolved in DMF (2 mL), and intermediate A6-1 (42 mg, 0.09 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 2 hours, and then purified by C18 column chromatography (CH3CN / H2O = 2 / 8, v / v) to obtain the final product A9 (65 mg, 60%).

[0468] Example 15: Synthesis of final product A10

[0469]

[0470] 1) Synthesis of intermediate A10-1

[0471] Intermediate P3-3 (150 mg, 0.32 mmol), (R)-2-phenylmorpholine (62 mg, 0.38 mmol), HATU (182 mg, 0.48 mmol), and DIPEA (83 mg, 0.64 mmol) were dissolved in DMF (2 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to obtain intermediate A10-1 (200 mg, 100%, crude).

[0472] 2) Synthesis of intermediate A10-2

[0473] Intermediate A10-1 (200 mg, 0.33 mmol, crude) was dissolved in EtOH (10 mL), and ammonium formate (376 mg, 3.3 mmol) and palladium on carbon (140 mg, 1.3 mmol) were added. The mixture was stirred at 80 °C for 20 minutes. The solid was filtered and washed with a small amount of ethanol. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH=25 / 1, v / v) to give a white solid intermediate A10-2 (170 mg, 100%, crude). LC-MS (m / z): 473.4 [M + H] + .

[0474] 3) Synthesis of intermediate A10-3

[0475] Intermediate A2-7 (100 mg, 0.24 mmol), intermediate A10-2 (170 mg, 0.36 mmol, crude), HATU (137 mg, 0.36 mmol), and DIPEA (62 mg, 0.48 mmol) were dissolved in DMF (4 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=20 / 1, v / v) to give a white solid intermediate A10-3 (150 mg, 56%).

[0476] 4) Synthesis of final product A10

[0477] Intermediate A10-3 (50 mg, 0.058 mmol) was dissolved in a mixed solvent (TFA / DCM = 2 mL / 4 mL). The mixture was stirred at room temperature for 2 hours, and then directly concentrated to obtain the crude product. The crude product was dissolved in DMF (2 mL), and intermediate A6-1 (25 mg, 0.053 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 1 hour, and then purified by C18 column chromatography (CH3CN / H2O = 1 / 3, v / v) to obtain the final product A10 (22 mg, 36%).

[0478] Example 16: Synthesis of final product A11

[0479]

[0480] 1) Synthesis of intermediate A11-1

[0481] Intermediate P4 (160 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL), and TMSBr (1 mL) was added. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated, and the residue was purified by C18 column (CH3CN / H2O=3 / 7, v / v) to give a white solid intermediate A11-1 (55 mg, 39%). 1 H NMR (400 MHz, CDCl3) δ 8.27 – 8.10 (m, 2H),7.88 – 7.67 (m, 2H). LC-MS (m / z): 473.1 [MH] - .

[0482] 2) Synthesis of the final product A11

[0483] Intermediate A9-5 (50 mg, 0.055 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 mL / 3 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then directly concentrated to obtain the crude product. The crude product was dissolved in DMF (2 mL), and intermediate A11-1 (23 mg, 0.05 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 2 hours, and then purified by C18 column chromatography (CH3CN / H2O = 2 / 8, v / v) to obtain the final product A11 (22 mg, 40%).

[0484] Example 17: Synthesis of final product A12

[0485]

[0486] 1) Synthesis of intermediate A12-1

[0487] Intermediate A9-4 (40 mg, 0.078 mmol), intermediate A7-2 (34 mg, 0.086 mmol), HATU (59 mg, 0.16 mmol), and DIPEA (20 mg, 0.16 mmol) were added to a round-bottom flask, followed by the addition of DMF (2 mL). The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to obtain a yellow solid intermediate A12-1 (58 mg, 83%).

[0488] 2) Synthesis of the final product A12

[0489] Intermediate A12-1 (50 mg, 0.055 mmol) was dissolved in a mixed solvent (TFA / DCM = 0.2 mL / 3 mL). The mixture was stirred at room temperature for 30 minutes, and then directly concentrated to obtain the crude product. The crude product was dissolved in DMF (2 mL), and intermediate A6-1 (15 mg, 0.032 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 30 minutes, and then purified by C18 column chromatography (CH3CN / H2O = 2 / 8, v / v) to obtain the final product A12 (22 mg, 64%).

[0490] Example 18: Synthesis of final product A13

[0491]

[0492] 1) Synthesis of the final product A13

[0493] Intermediate A5-13 (50 mg, 0.055 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 mL / 3 mL). The mixture was stirred at room temperature for 3 hours, and then directly concentrated to obtain the crude product. The crude product was dissolved in DMF (2 mL), and intermediate P2 (26 mg, 0.05 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 30 minutes, and then purified by silica gel column chromatography to obtain the final product A13 (12 mg, 21%).

[0494] Example 19: Synthesis of final product A14

[0495]

[0496]

[0497] 1) Synthesis of intermediate A14-1

[0498] Intermediate A6-1 (300 mg, 0.64 mmol) was dissolved in THF / H2O (5 mL / 10 mL), and then cation exchange resin Na was added. + Type (1.8 g), the mixture was stirred at room temperature for 1 hour, the solid was filtered, silver nitrate (326 mg, 1.92 mmol) was added to the filtrate, the mixture was stirred at room temperature in the dark for 1 hour, the solid was filtered, and washed with water. The solid was dried and suspended in toluene (5 mL), methyl iodide tervastatin (620 mg, 2.6 mmol) was added, the mixture was stirred at room temperature for 2 hours, the mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA=5 / 1, v / v) to give a colorless, transparent oily intermediate A14-1 (150 mg, 34%). 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.31 (s, 1H), 8.26 (dd, J =8.8, 1.6 Hz, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.4 Hz, 1H), 5.81 –5.62 (m, 4H), 1.20 (s, 18H).

[0499] 2) Synthesis of intermediate A14-2

[0500] Intermediate A9-5 (100 mg, 0.11 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 mL / 3 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give intermediate A14-2 (70 mg, 78%) as a white solid.

[0501] 3) Synthesis of the final product A14

[0502] Intermediate A14-2 (35 mg, 0.038 mmol) was dissolved in DMF (2 mL), and intermediate A14-1 (27 mg, 0.038 mmol) and DIPEA (10 mg, 0.076 mmol) were added. The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give the final product A14 (22 mg, 44%).

[0503] Example 20: Synthesis of final product A15

[0504]

[0505] 1) Synthesis of intermediate A15-1

[0506] Intermediate A4-4 (50 mg, crude) was dissolved in DMF (1.5 mL), and intermediates A9-4 (52 mg, 0.1 mmol), HATU (76 mg, 0.2 mmol), and DIPEA (52 mg, 0.4 mmol) were added. The mixture was stirred at room temperature for 2 hours, and after the solvent was evaporated, it was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give a white solid intermediate A15-1 (52 mg, 57%), LC-MS (m / z): 914.9 [M + H]. + .

[0507] 2) Synthesis of intermediate A15-2

[0508] Intermediate A15-1 (52 mg, 0.57 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. After TLC monitoring (dichloromethane / methanol = 20 / 1, v / v) showed no intermediate A15-1 remaining, the mixture was concentrated to obtain crude intermediate A15-2 (60 mg, crude), which was used directly in the next reaction step.

[0509] 3) Synthesis of final product A15

[0510] Intermediate A15-2 (60 mg, crude), intermediate A6-1 (25 mg, 0.054 mmol), DIPEA (15 mg, 0.14 mmol), and DMF (1 mL) were added to a reaction flask and stirred at room temperature for 1 hour. The solvent was evaporated, and the residue was purified by reverse silica gel column chromatography (water / acetonitrile = 4 / 1, v / v) to give the final product A15 (14 mg, two-step yield 24%).

[0511] Example 21: Synthesis of final product A16

[0512]

[0513] 1) Synthesis of intermediate A16-1

[0514] 3-(piperidin-4-yl)propionate tert-butyl ester (447 mg, 2.1 mmol), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1-benzimidazolyl)piperidin-2,6-dione (500 mg, 1.4 mmol), Ruphos (65 mg, 0.14 mmol), Pd2(dba)3 (128 mg, 0.14 mmol), and potassium tert-butoxide (403 mg, 4.2 mmol) were dissolved in dry 1,4-dioxane (20 mL) under nitrogen protection and reacted at 80 °C for 2 hours. The reaction solution was adjusted to pH 3-4 with formic acid, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 30 / 1, v / v) to give a yellow oily intermediate A16-1 (270 mg, 41%). 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 6.70 – 6.65 (m, 3H), 5.21 – 5.15 (m, 1H), 3.59 – 3.49(m, 2H), 3.40 (s, 3H), 2.98 – 2.60 (m, 5H), 2.31 – 2.17 (m, 2H), 1.88 – 1.69(m, 6H), 1.65 – 1.56 (m, 2H), 1.46 (s, 9H). LC-MS (m / z): 471.4 [M + H] + .

[0515] 2) Synthesis of intermediate A16-2

[0516] Intermediate A16-1 (270 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (650 mg, 5.7 mmol) was added. The reaction mixture was reacted at room temperature for 5 hours. The reaction solution was evaporated to dryness and purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give intermediate A16-2 (170 mg, 72%) as a white solid. LC-MS (m / z): 415.2 [M + H] + .

[0517] 3) Synthesis of intermediate A16-3

[0518] Intermediate A16-2 (44 mg, 0.10 mmol), intermediate A9-4 (50 mg, 0.090 mmol), HATU (51 mg, 0.13 mmol), and DIPEA (23 mg, 0.18 mmol) were dissolved in DMF (2 mL) and reacted at room temperature for 2 hours. The reaction solution was diluted with water, extracted with ethyl acetate, dried over the organic phase, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1, v / v) to give intermediate A16-3 (40 mg, 48%) as a red solid. LC-MS (m / z): 913.7 [M + H] + .

[0519] 4) Synthesis of the final product A16

[0520] Intermediate A16-3 (40 mg, 0.049 mmol) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and the crude product was dissolved in DMF (2 mL). DIPEA (0.5 mmol) and intermediate A6-1 (21 mg, 0.044 mmol) were added, and the mixture was reacted at room temperature for 1 hour. The product was then separated by reverse-phase column chromatography (water / acetonitrile = 4 / 1, v / v) to give the final product A16 (38 mg, 72%).

[0521] Example 22: Synthesis of final product A17

[0522]

[0523] 1) Synthesis of intermediate A17-1

[0524] The starting materials 2-mercaptoethanol (5.0 g, 64 mmol) and triethylamine (6.5 g, 64 mmol) were added to a three-necked flask, followed by dichloromethane (50 mL) under nitrogen protection. Butyryl chloride (6.8 g, 64 mmol) dissolved in dichloromethane (10 mL) was added dropwise to the reaction mixture at -78 °C. The mixture was stirred at -78 °C for 30 minutes, followed by stirring at room temperature for 2 hours. The mixture was poured into water (100 mL), and the organic phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give a colorless, transparent oily intermediate A17-1 (7.5 g, 79%). 1H NMR (400 MHz, CDCl3) δ 3.71 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.45 (s, 1H), 1.73 – 1.59 (m, 2H) 0.92 (t, J =7.2 Hz, 3H).

[0525] 2) Synthesis of intermediate A17-2

[0526] Intermediate A17-1 (2.0 g, 14 mmol) was dissolved in tetrahydrofuran (40 mL), and triphenylphosphine (3.5 g, 14 mmol), iodine (3.4 g, 14 mmol), and imidazole (3.4 g, 14 mmol) were added. The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give a pale yellow liquid intermediate A17-2 (2.5 g, 72%).

[0527] 3) Synthesis of intermediate A17-3

[0528] Intermediate A11-1 (200 mg, 0.42 mmol) was dissolved in a mixed solvent of water / tetrahydrofuran (4 mL / 2 mL), and then added to a cation exchange resin (Amberlite IR-120 Na). + The mixture was stirred at room temperature for 1 hour, and the solid was filtered off. Silver nitrate (286 mg, 1.7 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. A white solid precipitated out. The solid was filtered off and washed with water. The solid was dried and suspended in toluene (6 mL). Intermediate A17-2 (433 mg, 1.7 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1, v / v) to give a colorless, transparent oily intermediate A17-3 (45 mg, 15%).

[0529] 4) Synthesis of the final product A17

[0530] Intermediate A14-2 (45 mg, 0.055 mmol) was dissolved in DMF (2 mL), and DIPEA (0.5 mL) and intermediate A17-3 (40 mg, 0.055 mmol) were added. The mixture was stirred at room temperature for 2 hours, and then poured into 1N hydrochloric acid aqueous solution (30 mL). The organic phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give the final product A17 (8 mg, 11%).

[0531] Example 23: Synthesis of final product A18

[0532]

[0533] Intermediate A15-2 (40 mg, 50 μmol), intermediate P5 (16 mg, 39 μmol), DIPEA (13 mg, 0.10 mmol), and DMF (1 mL) were added to a reaction flask and stirred at room temperature for 1 hour. The solvent was evaporated and the residue was purified by reverse silica gel column chromatography (water / acetonitrile = 4 / 1, v / v) to give the final product A18 (22 mg, 53%).

[0534] Example 24: Synthesis of final product A19

[0535]

[0536] Intermediate A17 (40 mg, 0.029 mmol) was dissolved in a mixed solvent of acetonitrile / water (2 mL / 2 mL) and stirred at 80 °C for 6 hours. The mixture was purified by reverse-phase C18 column (acetonitrile / water = 3 / 7, v / v) to give final product A19 (13 mg, 36%).

[0537] Example 25: Synthesis of final product A20

[0538]

[0539]

[0540] 1) Synthesis of intermediate A20-1

[0541] N-Boc-cis-4-hydroxy-L-proline methyl ester (50 g, 204 mmol) was dissolved in DMF (350 mL), and imidazole (28 g, 408 mmol) was added. After nitrogen purging, the mixture was cooled to 0 °C, and tert-butyldimethylchlorosilane (37 g, 245 mmol) was added dropwise. The mixture was stirred overnight at room temperature, quenched with 1000 mL of ice water, and extracted with EA until no product was found in the aqueous phase. The organic phases were combined, washed once with water and once with brine, and dried and concentrated to obtain a colorless liquid intermediate A20-1 (70 g, 95%).

[0542] 2) Synthesis of intermediate A20-2

[0543] Sodium periodate (36 g, 167 mmol) was dissolved in water (100 mL), and ruthenium dioxide hydrate (2.0 g) was added. Intermediate A20-1 (20 g, 56 mmol) was dissolved in 100 mL of ethyl acetate and added dropwise to the reaction system. The mixture was stirred overnight at room temperature. The solid was filtered off, and the filtrate was separated. The ethyl acetate phase was quenched with saturated sodium thiosulfate aqueous solution, washed once with water and once with brine, and dried and concentrated to obtain yellow oily intermediate A20-2 (15 g, 72%).

[0544] 3) Synthesis of intermediate A20-3

[0545] Intermediate A20-2 (20 g, 53.6 mmol) was dissolved in anhydrous THF (80 mL), purged with nitrogen, cooled to -78 °C, and 1.0 N triethyl borohydride (59 mL) was added dropwise. The mixture was stirred at -78 °C for 3 hours, quenched with saturated sodium bicarbonate aqueous solution, and extracted with ethyl acetate until no product was found in the aqueous phase. The organic phases were combined, washed once with water and once with brine, dried and concentrated to obtain colorless liquid intermediate A20-3 (12 g, 60%).

[0546] 4) Synthesis of intermediate A20-4

[0547] Intermediate A20-3 (50 g, 133 mmol) was dissolved in dichloromethane (500 mL), and triethylamine (20 g, 200 mmol) and DMAP (3.2 g, 27 mmol) were added. Acetic anhydride (20 g, 200 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane until no product was found in the aqueous phase. The product was dried and concentrated, and the residue was purified by silica gel column chromatography (PE / EA=10 / 1, v / v) to give colorless liquid intermediate A20-4 (40 g, 72%).

[0548] 5) Synthesis of intermediate A20-5

[0549] Intermediate A20-4 (40 g, 96 mmol) was dissolved in dichloromethane (500 mL), purged with nitrogen, and cooled to -78 °C. Boron trifluoride ether (34 g, 240 mmol) and allyltrimethylsilane (49 g, 432 mmol) were added. The mixture was stirred at -78 °C for 3 hours, quenched with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane until no product was found in the aqueous phase. The product was dried and concentrated, and the residue was purified by silica gel column chromatography (PE / EA=10 / 1, v / v) to give colorless liquid intermediate A20-5 (35 g, 91%). 1 H NMR (400 MHz, CDCl3)δ6.06–5.83 (m, 1H), 5.19–5.05 (m, 1H), 5.03–4.92 (m,1H), 4.35–4.09 (m, 2H), 3.99–3.77 (m, 1H), 3.71 (s, 3H), 2.55–2.43 (m, 1H), 2.42–2.25 (m, 2H), 2.04–1.87 (m, 1H), 1.41 (s, 9H), 0.87 (s, 9H), 0.05 (s, 6H).

[0550] 6) Synthesis of intermediate A20-6

[0551] Intermediate A20-5 (45 g, 113 mmol) was dissolved in a mixed solvent (TFA / DCM = 100 mL / 200 mL), the mixture was stirred at room temperature for 2 hours, concentrated, quenched with saturated sodium bicarbonate aqueous solution, and extracted with dichloromethane until no product was found in the aqueous phase. After drying and concentration, a yellow liquid intermediate A20-6 (27 g, 80%) was obtained.

[0552] 7) Synthesis of intermediate A20-7

[0553] Intermediate A20-6 (5.0 g, 17 mmol), Boc-L-allylglycine (4.1 g, 19 mmol), HATU (13 g, 33 mmol), and DIPEA (11 g, 84 mmol) were dissolved in DMF (60 mL), and the mixture was stirred overnight at room temperature. The mixture was quenched with 150 mL of ice water, and extracted with EA until no product was found in the aqueous phase. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give intermediate A20-7 (7.5 g, 90%) as a white solid.

[0554] 8) Synthesis of intermediate A20-8

[0555] Intermediate A20-7 (7.5 g, 15 mmol) was dissolved in dichloromethane (200 mL), and Grubbs catalyst (2.4 g, 2.9 mmol) was added. The mixture was stirred overnight at 55 °C, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1, v / v) to give a brown liquid intermediate A20-8 (6.1 g, 89%). LC-MS (m / z): 469.3 [M + H] + .

[0556] 9) Synthesis of intermediate A20-9

[0557] Intermediate A20-8 (6.0 g, 13 mmol) was dissolved in ethyl acetate (80 mL), 10% Pd / C (1.8 g) was added, the air was replaced with hydrogen three times, the reaction was carried out at room temperature for 40 hours, and the mixture was filtered and concentrated to obtain crude intermediate A20-9 (5 g, crude), which was used directly in the next step.

[0558] 10) Synthesis of intermediate A20-10

[0559] Intermediate A20-9 (200 mg, 0.42 mmol) was dissolved in dry THF (5 mL), and TBAF (0.84 mL, 0.84 mmol) was added. The mixture was reacted at room temperature for 1 hour. The reaction solution was added to saturated ammonium chloride (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was dried and concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give a white solid intermediate A20-10 (150 mg, 100%).

[0560] 11) Synthesis of intermediate A20-11

[0561] Intermediate A20-10 (120 mg, 0.34 mmol) was dissolved in DMF (5 mL), and NaH (40 mg, 1.0 mmol) was added at 0 °C. After stirring for 30 minutes, 7-bromohept-1-yne (70 mg, 0.40 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction mixture was quenched with formic acid, and saturated sodium chloride aqueous solution (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL × 3), dried, and concentrated to obtain crude intermediate A20-11 (100 mg, crude). LC-MS (m / z): 451.2 [M + H] + .

[0562] 12) Synthesis of intermediate A20-12

[0563] Intermediate A20-11 (100 mg, 0.20 mmol) was dissolved in THF / H2O (5 mL / 5 mL), and lithium hydroxide monohydrate (30 mg, 0.65 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was extracted with EA (10 mL × 3). The aqueous phase was adjusted to pH 3-4 with 1N HCl aqueous solution, extracted with EA (10 mL × 3), dried, and concentrated to obtain a white solid intermediate A20-12 (70 mg, 80%). 1 H NMR (400 MHz, CDCl3) δ 5.41 (d, J = 8.2 Hz, 1H), 4.67 – 4.57 (m, 1H), 4.49 (t, J = 9.1 Hz, 1H), 4.34 – 4.21 (m, 1H), 4.09 – 3.99 (m, 1H), 3.54 –3.38 (m, 2H), 2.59 – 2.45 (m, 1H), 2.21 (td, J = 6.9, 2.6 Hz, 3H), 2.07 –1.98 (m, 2H), 1.82 – 1.46 (m, 13H), 1.43 (s, 9H).LC-MS (m / z): 437.2 [M + H] + .

[0564] 13) Synthesis of intermediate A20-13

[0565] Intermediate A20-12 (80 mg, 0.18 mmol), intermediate A9-2 (56 mg, 0.27 mmol), HATU (102 mg, 0.27 mmol), and DIPEA (93 mg, 0.72 mmol) were dissolved in DMF (3 mL), and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give a pale yellow solid intermediate A20-13 (70 mg, 62%). LC-MS (m / z): 626.4 [M + H] + .

[0566] 14) Synthesis of intermediate A20-14

[0567] Intermediate A20-13 (50 mg, 0.080 mmol), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (40 mg, 0.12 mmol), cuprous iodide (2.0 mg, 0.0080 mmol), TEA (40 mg, 0.40 mmol), and tetraphenylphosphine palladium (10 mg, 0.0080 mmol) were dissolved in dry DMF (2 mL), and the mixture was reacted at 80 °C for 3 hours under nitrogen protection. The reaction solution was diluted with water (10 mL), extracted with EA (10 mL × 3), and the organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give a white solid intermediate A20-14 (40 mg, 57%). LC-MS (m / z): 883.7 [M + H] + .

[0568] 15) Synthesis of final product A20

[0569] Intermediate A20-14 (40 mg, 0.045 mmol) was dissolved in a mixed solvent (TFA / DCM = 3 mL / 0.5 mL). The mixture was stirred at room temperature for 1 hour, and then directly concentrated to obtain crude intermediate A20-15. Crude intermediate A20-15 was dissolved in DMF (2 mL), and intermediate A6-1 (17 mg, 0.036 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 1 hour, and then purified by reverse-phase C18 column chromatography (CH3CN / H2O = 2 / 8, v / v) to obtain final product A20 (6 mg, 12%).

[0570] Example 26: Synthesis of final product A21

[0571]

[0572] 1) Synthesis of intermediate A21-1

[0573] Intermediate P4-9 (1.0 g, 2.7 mmol) was dissolved in DMF (20 mL), and 3-bromopropene (484 mg, 4.0 mmol) and potassium carbonate (745 mg, 5.4 mmol) were added. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / petroleum ether = 1 / 1, v / v) to give intermediate A21-1 (1.0 g, 92%), a colorless, transparent oil.

[0574] 2) Synthesis of intermediate A21-2

[0575] Intermediate A21-1 (1.0 g, 2.5 mmol) was dissolved in dichloromethane (10 mL), and trimethylbromosilane (2 mL) was added. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated, and the residue was purified by reverse-phase C18 column chromatography (methanol / water = 3 / 7, v / v) to give intermediate A21-2 (410 mg, 47%). LC-MS (m / z): 347.0 [M - H] - .

[0576] 3) Synthesis of intermediate A21-3

[0577] Intermediate A21-2 (150 mg, 0.43 mmol) was dissolved in dichloromethane (4 mL), 1 drop of DMF was added, followed by dropwise addition of oxaloyl chloride (218 mg, 1.7 mmol). The mixture was stirred at 40 °C for 2 hours. The mixture was concentrated, and the residue was dissolved in dichloromethane (4 mL). L-alanine ethyl ester hydrochloride (200 mg, 1.3 mmol) was added in an ice bath, followed by dropwise addition of triethylamine (347 mg, 3.4 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, and the residue was purified by silica gel column chromatography to give an oily intermediate A21-3 (30 mg, 13%). LC-MS (m / z): 547.1 [M + H] + .

[0578] 4) Synthesis of intermediate A21-4

[0579] Intermediate A21-3 (30 mg, 0.060 mmol) was dissolved in dichloromethane (2 mL), and tetrahydropyrrole (4.5 mg, 0.060 mmol) and tetratetraphenylphosphine palladium (3.5 mg, 0.0030 mmol) were added. The compound was stirred for 1 hour under nitrogen protection, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1, v / v) to give an oily intermediate A21-4 (25 mg, 82%). LC-MS (m / z): 507.1 [M + H] + .

[0580] 5) Synthesis of intermediate A21-5

[0581] Intermediate A21-4 (25 mg, 0.050 mmol) was dissolved in DMF (2 mL), and triethylamine (10 mg, 0.10 mmol) was added, followed by the slow addition of perfluorophenyl 2,2,2-trifluoroacetate (56 mg, 0.20 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was poured into water, and the organic phase was extracted with EA (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to give intermediate A21-5 (20 mg, 59%), a colorless, transparent oil. LC-MS (m / z): 673.2 [M + H] + .

[0582] 6) Synthesis of final product A21

[0583] Intermediate A14-2 (18 mg, 0.022 mmol) and intermediate A21-5 (20 mg, 0.030 mmol) were dissolved in DIPEA (0.5 mL) and DMF (2 mL) and stirred at room temperature for 1 hour. The mixture was poured into water (15 mL), and the organic phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give the final product A21 (23 mg, 80%).

[0584] Example 27: Synthesis of final product A22

[0585]

[0586] 1) Synthesis of intermediate A22-1

[0587] Intermediate A21-2 (150 mg, 0.43 mmol) was dissolved in dichloromethane (4 mL), DMF (1 drop) was added, followed by oxaloyl chloride (218 mg, 1.7 mmol), and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated, and the residue was dissolved in dichloromethane (4 mL). Ethyl L-alanine hydrochloride (200 mg, 1.3 mmol) was added under ice bath conditions, followed by triethylamine (347 mg, 3.4 mmol), and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, and the residue was purified by silica gel column chromatography to give 100 mg of intermediate. Intermediate (100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), oxaloyl chloride (85 mg, 0.66 mmol) and DMF (1 drop) were added, and the mixture was stirred at 40 °C for 2 hours. The residue was concentrated and dissolved in dichloromethane (5 mL). Phenol (62 mg, 0.66 mmol) was added under ice bath conditions, followed by triethylamine (133 mg, 1.3 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / petroleum ether = 1 / 1, v / v) to give a colorless, transparent oily intermediate, A22-1 (80 mg, 36%). LC-MS (m / z): 524.1 [M + H] + .

[0588] 2) Synthesis of intermediate A22-2

[0589] Intermediate A22-1 (80 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL), and tetrahydropyrrole (12 mg, 0.17 mmol) and tetratetraphenylphosphine palladium (10 mg, 0.0090 mmol) were added. The mixture was stirred for 1 hour under nitrogen protection, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1, v / v) to give a pale yellow oily intermediate A22-2 (65 mg, 90%). LC-MS (m / z): 484.0 [M + H] + .

[0590] 3) Synthesis of intermediate A22-3

[0591] Intermediate A22-2 (65 mg, 0.13 mmol) was dissolved in DCM (2 mL), and triethylamine (39 mg, 0.39 mmol) was added, followed by the slow addition of perfluorophenyl 2,2,2-trifluoroacetate (109 mg, 0.39 mmol). The mixture was stirred at room temperature for 10 minutes. The mixture was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give intermediate A22-3 (70 mg, 83%), a colorless, transparent oil.

[0592] 4) Synthesis of final product A22

[0593] Intermediate A14-2 (97 mg, 0.12 mmol) and intermediate A22-3 (70 mg, 0.11 mmol) were dissolved in DIPEA (0.5 mL) and DMF (2 mL) and stirred at room temperature for 1 hour. The mixture was poured into 1N HCl aqueous solution (20 mL), and the organic phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give final product A22 (80 mg, 57%).

[0594] Example 28: Synthesis of final product A23

[0595]

[0596] 1) Synthesis of intermediate A23-1

[0597] Intermediate A21-2 (250 mg, 0.70 mmol) was dissolved in dichloromethane (25 mL), DMF (1 drop) was added, followed by oxaloyl chloride (265 mg, 2.1 mmol). The mixture was stirred at 40 °C for 2 hours. After concentration, the residue was dissolved in dichloromethane (25 mL), and isopropyl L-alanine hydrochloride (125 mg, 0.75 mmol) was added under ice bath conditions, followed by triethylamine (350 mg, 3.5 mmol). The mixture was stirred at room temperature for 30 minutes, and phenol (195 mg, 2.1 mmol) was added, followed by stirring for another 30 minutes. The mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / petroleum ether = 1 / 1, v / v) to give intermediate A23-1 (210 mg, 56%), a colorless, transparent oil. LC-MS (m / z): 538.2 [M + H] + .

[0598] 2) Synthesis of intermediate A23-2

[0599] Intermediate A23-1 (210 mg, 0.39 mmol) was dissolved in dichloromethane (4 mL), and tetrahydropyrrole (28 mg, 0.39 mmol) and tetratetraphenylphosphine palladium (23 mg, 0.020 mmol) were added. The mixture was stirred for 1 hour under nitrogen protection, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give an oily intermediate A23-2 (210 mg, crude). LC-MS (m / z): 498.1 [M + H] +.

[0600] 3) Synthesis of intermediate A23-3

[0601] Crude intermediate A23-2 (180 mg, 0.36 mmol, crude) was dissolved in DMF (4 mL), and triethylamine (180 mg, 1.8 mmol) was added, followed by the slow addition of perfluorophenyl 2,2,2-trifluoroacetate (504 mg, 1.8 mmol). The mixture was stirred at room temperature for 30 minutes. After concentration, the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give intermediate A23-3 (200 mg, 83%), a colorless, transparent oil.

[0602] 4) Synthesis of final product A23

[0603] Intermediate A14-2 (106 mg, 0.13 mmol) and intermediate A23-3 (80 mg, 0.12 mmol) were dissolved in DIPEA (0.5 mL) and DMF (3 mL) and stirred at room temperature for 1 hour. The mixture was poured into 1N HCl aqueous solution (15 mL), and the organic phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give final product A23 (110 mg, 71%).

[0604] Example 29: Synthesis of final product A24

[0605]

[0606] 1) Synthesis of intermediate A24-1

[0607] Mercaptoethanol (1.2 g, 15 mmol) was dissolved in DCM (20 mL) and cooled to -78 °C. Triethylamine (1.7 g, 17 mmol) and pentanoyl chloride (2.1 g, 17 mmol) were added. The mixture was stirred at -78 °C for 1 hour, then transferred to room temperature and stirred for 1 hour. The mixture was concentrated, and the residue was purified by silica gel column chromatography (Hexane / EA=20 / 1, v / v) to give a colorless oily intermediate A24-1 (2.4 g, 99%). 1 H NMR (400 MHz, CDCl3) δ 3.72 (t, J = 6.0 Hz, 2H), 3.03 (t,J = 6.0 Hz, 2H), 1.22 (s, 9H).

[0608] 2) Synthesis of intermediate A24-2

[0609] Intermediate A11-1 (50 mg, 0.10 mmol) was dissolved in DCM (2 mL), one drop of DMF was added, and oxaloyl chloride (65 mg, 0.51 mmol) was added dropwise under an ice-water bath. The mixture was stirred at 40 °C for 1 hour, then the solvent was removed by rotary evaporation. DCM (2 mL), intermediate A24-1 (51 mg, 0.32 mmol), and DIPEA (55 mg, 0.42 mmol) were added, and the mixture was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by silica gel column chromatography (Hexane / EA = 3 / 1, v / v) to give a colorless oily intermediate A24-2 (50 mg, 62%). LC-MS (m / z): 780.0 [M + H2O] + .

[0610] 3) Synthesis of final product A24

[0611] Intermediate A24-2 (50 mg, 0.066 mmol) was dissolved in DMF (2 mL), and intermediate A14-2 (64 mg, 0.080 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 30 minutes, and 1 N hydrochloric acid (5 mL) was added. Extraction was performed with EA (10 mL), the liquid was separated, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to obtain the final product A24 (3 mg, 3%).

[0612] Example 30: Synthesis of final product A25

[0613]

[0614] 1) Synthesis of intermediate A25-1

[0615] Intermediate A11-1 (70 mg, 0.15 mmol) was dissolved in DCE (5 mL), and oxalyl chloride (75 mg, 0.59 mmol) and catalytic amount DMF (0.05 mL) were added. The reaction mixture was reacted at 50 °C for 2 hours. The reaction mixture was evaporated to dryness, diluted with DCM (5 mL), and DIPEA (76 mg, 0.59 mmol) and (S)-1-(3-chlorophenyl)-1,3-propanediol (33 mg, 0.18 mmol) were added. The mixture was reacted overnight at room temperature. The reaction mixture was then diluted with water (10 mL), extracted with DCM (10 mL × 3), dried and concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1 / 1, v / v) to give a pale yellow oily intermediate A25-1 (50 mg, 54%). 1H NMR (400 MHz, CDCl3)δ 8.32 (s, 1H), 8.20 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.8 Hz,1H), 7.32 – 7.25 (m, 4H), 5.62 (d, J = 10.9 Hz, 1H), 4.74 – 4.52 (m, 2H),1.89 – 1.85 (m, 2H). LC-MS (m / z): 642.1 [M + H2O] + .

[0616] 2) Synthesis of final product A25

[0617] Intermediate A9-5 (60 mg, 0.060 mmol) was dissolved in a mixed solvent (TFA / DCM = 5 mL / 0.5 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was then directly concentrated to obtain the crude product. The crude product was dissolved in DMF (2 mL), and intermediate A25-1 (50 mg, 0.080 mmol) and DIPEA (31 mg, 0.24 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with 1N hydrochloric acid aqueous solution (5 mL), extracted with EA (10 mL × 3), washed with saturated sodium chloride aqueous solution (15 mL), dried and concentrated the organic phase, and the residue was purified by silica gel column chromatography (DCM / MeOH = 15 / 1, v / v) to obtain the final product A25 (20 mg, 27%).

[0618] Example 31: Synthesis of final product A26

[0619]

[0620]

[0621] 1) Synthesis of intermediate A26-7

[0622] Methyltriphenylphosphine bromide (19 g, 54 mmol) was dissolved in anhydrous THF (50 mL), purged with nitrogen, and cooled to -20 °C. Potassium tert-butoxide (6.1 g, 54 mmol) was added, and the mixture was stirred at -20 °C for 30 min, then heated to room temperature and stirred for 1 hour. Ethyl 4-carbonylcyclohexane (5.0 g, 27.1 mmol) was dissolved in anhydrous THF (40 mL) and added dropwise to the reaction system at -20 °C. The mixture was stirred overnight at room temperature, quenched with 200 mL of ice water, and extracted with EA until no product was found in the aqueous phase. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 50 / 1, v / v) to give a colorless liquid intermediate A26-7 (3.5 g, 71%).

[0623] 2) Synthesis of intermediate A26-8

[0624] Intermediate A26-7 (3.5 g, 19 mmol) was dissolved in anhydrous dichloromethane (40 mL), purged with nitrogen, cooled to 0 °C, and 1.0 N diisobutylaluminum hydride (58 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour, quenched with ammonia, and extracted with dichloromethane until no product was found in the aqueous phase. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 20 / 1, v / v) to give colorless liquid intermediate A26-8 (2.4 g, 90%). 1 H NMR (400 MHz, CDCl3)δ4.59 (s,2H), 3.68 (d, J = 6.6 Hz, 2H), 2.33–2.24(m, 2H), 2.09–1.97 (m, 2H), 1.88–1.78(m, 2H), 1.63–1.45 (m, 3H), 1.13–1.05 (m, 2H).

[0625] 3) Synthesis of intermediate A26-9

[0626] Intermediate A26-8 (2.4 g, 17 mmol) was dissolved in anhydrous dichloromethane (30 mL), and triethylamine (3.5 g, 34 mmol) and DMAP (209 mg, 1.7 mmol) were added. p-Toluenesulfonyl chloride (4.9 g, 26 mmol) was added in portions. The mixture was stirred overnight at room temperature, quenched with water, and extracted with dichloromethane until no product was observed in the aqueous phase. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 30 / 1, v / v) to give a yellow oily intermediate A26-9 (4.5 g, 90%).

[0627] 4) Synthesis of intermediate A26-10

[0628] Intermediate A26-9 (4.5 g, 15 mmol) was dissolved in acetone (50 mL), and a mixture of lithium bromide (2.7 g, 31 mmol) was added. The mixture was stirred overnight at room temperature, quenched with water, and extracted with petroleum ether until no product was found in the aqueous phase. The organic phases were combined, dried, and concentrated. The residue was rapidly purified by silica gel column chromatography (PE) to give a colorless liquid intermediate A26-10 (3.0 g, 97%). 1 H NMR (400 MHz, CDCl3) δ4.61 (s, 2H), 3.50–3.39 (m, 2H), 2.37–2.24 (m, 2H), 2.11–1.98 (m, 2H), 1.87–1.74 (m, 3H), 1.70–1.59 (m, 2H), 1.11–0.97 (m, 2H).

[0629] 5) Synthesis of intermediate A26-1

[0630] Intermediate A20-10 (220 mg, 0.62 mmol) was dissolved in DMF (10 mL), and potassium tert-butoxide (138 mg, 0.86 mmol) was added at 0 °C. After stirring for 30 minutes, 1-(2-bromoethyl)-4-methylenecyclohexane (intermediate A26-10, 175 mg, 0.40 mmol) was added, and the reaction was carried out at 0 °C for 2 hours. The reaction solution was adjusted to pH 4-5 with formic acid, extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated sodium chloride aqueous solution (10 mL). After drying and concentration, crude intermediate A26-1 (290 mg, crude) was obtained and used directly in the next step. LC-MS (m / z): 479.3 [M + H] + .

[0631] 6) Synthesis of intermediate A26-2

[0632] Intermediate A26-1 (290 mg, 0.62 mmol, crude) was dissolved in THF / H2O (5 mL / 5 mL), and lithium hydroxide monohydrate (78 mg, 1.8 mmol) was added. The mixture was stirred overnight at room temperature. The reaction solution was extracted with EA (10 mL × 3). The aqueous phase was adjusted to pH 3-4 with 1N HCl aqueous solution, extracted with EA (10 mL × 3), dried, and concentrated to obtain a white solid intermediate A26-2 (120 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 5.50 (dd, J = 30.7, 8.1 Hz, 1H), 4.73– 4.62 (m, 2H), 4.58 – 4.45 (m, 2H), 4.34 – 4.04 (m, 2H), 3.63 – 3.42 LC-MS (m / z): 465.2 [M + H] + .

[0633] 7) Synthesis of intermediate A26-3

[0634] Intermediate A26-2 (120 mg, 0.26 mmol), intermediate A9-2 (80 mg, 0.39 mmol), HATU (147 mg, 0.39 mmol), and DIPEA (129 mg, 1.0 mmol) were dissolved in DMF (6 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 30 / 1, v / v) to give a pale yellow solid intermediate A26-3 (70 mg, 41%). LC-MS (m / z): 654.5 [M + H] + .

[0635] 8) Synthesis of intermediate A26-4

[0636] Intermediate A26-3 (50 mg, 0.076 mmol), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidin-2,6-dione (33 mg, 0.098 mmol), tri-tert-butylphosphine (30 mg, 0.015 mmol), DIPEA (20 mg, 0.15 mmol), and Pd2(dba)3 (10 mg, 0.0076 mmol) were dissolved in dry DMF (3 mL) and reacted overnight at 80 °C under nitrogen protection. The reaction solution was diluted with water (10 mL), extracted with EA (10 mL × 3), and the organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give colorless oily intermediate A26-4 (10 mg, 14%). LC-MS (m / z): 911.8 [M + H] + .

[0637] 9) Synthesis of intermediate A26-5

[0638] Intermediate A26-4 was dissolved in methanol (2 mL), and 10% Pd / C (10 mg) was added. The mixture was purged with hydrogen three times and reacted at room temperature for 5 hours. The reaction solution was filtered and concentrated to obtain a colorless oily intermediate A26-5 (10 mg, crude), which was used directly in the next step. LC-MS (m / z): 913.7 [M + H] + .

[0639] 10) Synthesis of final product A26

[0640] Intermediate A26-5 (10 mg, 0.012 mmol) was dissolved in a mixed solvent (TFA / DCM = 2 mL / 0.2 mL). The mixture was stirred at room temperature for 2 hours, and then directly concentrated to obtain crude intermediate A26-6. Crude intermediate A26-6 was dissolved in DMF (1 mL), and intermediate A14-1 (11 mg, 0.015 mmol) and DIPEA (3.0 mg, 0.024 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with 1N hydrochloric acid aqueous solution (5 mL), extracted with EA (10 mL × 3), washed with saturated sodium chloride aqueous solution (15 mL), dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 15 / 1, v / v) to obtain final product A26 (5.0 mg, 32%).

[0641] Example 32: Synthesis of final product A27

[0642]

[0643] 1) Synthesis of intermediate A27-1

[0644] Intermediate A21-2 (100 mg, 0.29 mmol) was dissolved in dichloromethane (4 mL), DMF (1 drop) was added, followed by oxaloyl chloride (110 mg, 0.87 mmol), and the mixture was stirred at 40 °C for 2 hours. The mixture was concentrated, and the residue was dissolved in dichloromethane (4 mL). Propyl L-alanine hydrochloride (49 mg, 0.29 mmol) was added under ice bath conditions, followed by triethylamine (145 mg, 1.4 mmol), and the mixture was stirred at room temperature for 30 minutes. Phenol (82 mg, 0.87 mmol) was added, and stirring was continued for another 30 minutes. The mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / petroleum ether = 1 / 1, v / v) to give intermediate A27-1 (80 mg, 51%), a colorless, transparent oil. LC-MS (m / z): 538.1 [M + H] + .

[0645] 2) Synthesis of intermediate A27-2

[0646] Intermediate A27-1 (23 mg, 0.043 mmol) was dissolved in dichloromethane (2 mL), and tetrahydropyrrole (3.1 mg, 0.043 mmol) and tetratriphenylphosphine palladium (5.0 mg, 0.0043 mmol) were added. The mixture was stirred for 1 hour under nitrogen protection, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give intermediate A27-2 (15 mg, 70%), a colorless oil.

[0647] 3) Synthesis of intermediate A27-3

[0648] Intermediate A27-2 (15 mg, 0.030 mmol) was dissolved in DCM (2 mL), and triethylamine (6 mg, 0.060 mmol) was added, followed by the slow addition of perfluorophenyl 2,2,2-trifluoroacetate (17 mg, 0.060 mmol). The mixture was stirred at room temperature for 30 minutes. The solution was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to give intermediate A27-3 (20 mg, 100%), a colorless, transparent oil.

[0649] 4) Synthesis of final product A27

[0650] Intermediate A14-2 (27 mg, 0.033 mmol) and intermediate A27-3 (20 mg, 0.030 mmol) were dissolved in DIPEA (0.5 mL) and DMF (2 mL) and stirred at room temperature for 1 hour. The mixture was poured into 1N HCl aqueous solution (10 mL), and the organic phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give final product A27 (24 mg, 62%).

[0651] Example 33: Synthesis of final product A28

[0652]

[0653] Intermediate A26-5 (30 mg, 0.033 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was dissolved in DMF (2 mL). Triethylamine (17 mg, 0.17 mmol) and intermediate A11-1 (14 mg, 0.030 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. The mixture was purified by C18 column to obtain the final product A28 (20 mg, 60%).

[0654] Example 34: Synthesis of the final product A11-P1

[0655]

[0656]

[0657] 1) Chiral separation of intermediates A5-8-P1 / A5-8-P2:

[0658] Intermediate A5-8 (4.0 g, 13.7 mmol) was chirally resolved (column: AD-3 4.6 × 100 mm 3 μm; mobile phase: MeOH [0.2% NH3 (7 M in MeOH)]) to yield intermediates A5-8-P1 (1.8 g, t = 1.556 min) and A5-8-P2 (1.7 g, t = 2.289 min). Intermediates A5-8-P1 and A5-8-P2 are isomers, and their absolute configurations are arbitrarily identified.

[0659] 2) Synthesis of intermediate A11-P1-1

[0660] Intermediate A5-8-P1 (1.8 g, 6.4 mmol) was dissolved in DMF (30 mL), and cesium carbonate (6.2 g, 19.2 mmol) and deuterated iodomethane (1.8 g, 12.8 mmol) were added. The mixture was stirred overnight at room temperature, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give intermediate A11-P1-1 (1.8 g, 91%), a yellow oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 7.0 Hz, 1H), 6.45 (s, 1H), 6.08 (d, J = 7.0 Hz, 1H), 3.96 – 3.79 (m, 1H), 3.49 – 3.38 (m, 1H), 3.30 – 3.18(m, 1H), 2.25 – 2.13 (m, 1H), 1.99 – 1.92 (m, 1H), 1.90 – 1.73 (m, 2H), 0.55– 0.35 (m, 2H).

[0661] 3) Synthesis of intermediate A11-P1-2

[0662] Intermediate A11-1 (1.8 g, 5.8 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 2 hours, and the mixture was concentrated to obtain crude intermediate A11-P1-2, which was used directly in the next step.

[0663] 4) Synthesis of intermediate A11-P1-3

[0664] The crude intermediates A11-P1-2, P3-3 (2.8 g, 6.1 mmol), HATU (2.2 g, 7.0 mmol), and DIPEA (2.3 g, 17.5 mmol) from the previous step were dissolved in DMF (30 mL). The mixture was stirred at room temperature for 30 minutes, concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give a viscous oily intermediate, A11-P1-3 (3.1 g, 82%). LC-MS (m / z): 651.8 [M + H] + .

[0665] 5) Synthesis of intermediate A11-P1-4

[0666] Intermediate A11-P1-3 (3.1 g, 4.8 mmol) was dissolved in ethanol (30 mL), and 10% Pd / C (1.0 g, 9.5 mmol) and ammonium acetate (3.0 mg, 47.5 mmol) were added. The mixture was stirred at 80 °C for 5 minutes. The solid was filtered off and washed with ethanol. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH = 20 / 1, v / v) to give a white solid intermediate A11-P1-4 (2.1 g, 85%). LC-MS (m / z): 517.7 [M + H] + .

[0667] 6) Synthesis of intermediate A11-P1-5

[0668] Intermediate A11-P1-4 (1.1 g, 2.2 mmol), intermediate A2-7 (900 mg, 2.2 mmol), HATU (1.7 g, 4.4 mmol), and DIPEA (844 mg, 6.5 mmol) were dissolved in DMF (15 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give a white solid intermediate A11-P1-5 (1.4 g, 71%). LC-MS (m / z): 913.0 [M + H] + .

[0669] 7) Synthesis of the final product A11-P1

[0670] Intermediate A11-P1-5 (1.4 g, 1.6 mmol) was dissolved in a mixed solvent (TFA / DCM = 5 mL / 15 mL). The mixture was stirred at room temperature for 2 hours, and then directly concentrated to obtain crude intermediate A11-P1-6. Crude intermediate A11-P1-6 was dissolved in DMF (15 mL), and intermediate A11-1 (810 mg, 1.71 mmol) and DIPEA (3.0 mL) were added. The mixture was stirred at room temperature for 2 hours, and then purified by C18 column chromatography (CH3CN / H2O = 2 / 8, v / v) to obtain final product A11-P1 (900 mg, 52%). A11-P1 and A11-P2 are isomers, and their absolute configurations are arbitrarily identified.

[0671] Example 35: Synthesis of the final product A11-P2

[0672]

[0673] 1) Synthesis of intermediate A11-P2-1

[0674] Intermediate A5-8-P2 (1.6 g, 5.5 mmol) was dissolved in DMF (20 mL), and cesium carbonate (5.4 g, 16.4 mmol) and deuterated iodomethane (1.6 g, 11.0 mmol) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, it was quenched with 150 mL of ice water, and extracted with EA until no product was found in the aqueous phase. The organic phases were combined, dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50 / 1, v / v) to give a yellow oily intermediate A11-P2-1 (1.6 g, 94%).

[0675] 2) Synthesis of intermediate A11-P2-2

[0676] Intermediate A11-P2-1 (1.6 g, 5.2 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (8 mL) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed by rotary evaporation, and methanol was added to dissolve the residue. The pH of the system was adjusted to 8-9 with sodium bicarbonate. The concentrated residue was purified by silica gel column chromatography to obtain a pale yellow oily intermediate A11-P2-2 (900 mg, 84%).

[0677] 3) Synthesis of intermediate A11-P2-3

[0678] Intermediate A11-P2-2 (900 mg, 4.3 mmol), intermediate P3-3 (2.1 g, 4.5 mmol), HATU (2.0 g, 5.2 mmol), and DIPEA (1.7 g, 13.0 mmol) were dissolved in DMF (15 mL). The mixture was stirred at room temperature for 30 minutes, quenched with 50 mL of ice water, and extracted with EA until no product was observed in the aqueous phase. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 50 / 1, v / v) to give a white solid intermediate A11-P2-3 (1.7 g, 60%). LC-MS (m / z): 651.7 [M + H] + .

[0679] 4) Synthesis of intermediate A11-P2-4

[0680] Intermediate A11-P2-3 (1.7 g, 2.6 mmol) was dissolved in ethanol (50 mL), and 5% Pd / C (900 mg) and ammonium acetate (1.7 g, 26.1 mmol) were added. The mixture was stirred at 80 °C for 10 min. The solid was filtered off and washed with ethanol. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH = 20 / 1, v / v) to give a white solid intermediate A11-P2-4 (1.2 g, 89%). LC-MS (m / z): 517.6 [M + H] + .

[0681] 5) Synthesis of intermediate A11-P2-5

[0682] Intermediate A2-7 (483 mg, 1.2 mmol), intermediate A11-P2-4 (600 mg, 1.2 mmol), HATU (889 mg, 2.3 mmol), and DIPEA (453 mg, 3.5 mmol) were dissolved in DMF (8 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with 50 mL of ice water, and extracted with EA until no product was found in the aqueous phase. The organic phases were combined, dried, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give a white solid intermediate A11-P2-5 (630 mg, 58%).

[0683] 6) Synthesis of the final product A11-P2

[0684] Intermediate A11-P2-5 (630 mg, 0.69 mmol) was dissolved in a mixed solvent (TFA / DCM = 4 mL / 8 mL). The mixture was stirred at room temperature for 2 hours, and then directly concentrated to obtain the crude product. The crude product was dissolved in DMF (15 mL), and intermediate A11-1 (329 mg, 0.69 mmol) and DIPEA (3.2 mL) were added. The mixture was stirred at room temperature for 2 hours, and then purified by C18 column chromatography (CH3CN / H2O = 3 / 7, v / v) to obtain the final product A11-P2 (520 mg, 68%). A11-P2 and A11-P1 are isomers, and their absolute configurations are arbitrarily identified.

[0685] The resolved structures and spectral data of compounds A1-A28 are shown in Table 1:

[0686] Table 1. Analyzed structures and spectroscopic data of compounds A1-A18

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697] Example 1: STAT6 degradation experiment in MV4-11 cells

[0698] Experimental steps:

[0699] 1. Prepare a 6-well plate and seed the cells.

[0700] MV4-11 cells cultured to a certain cell density were centrifuged and counted, then analyzed at a concentration of 80-100 × 10⁻⁶ cells / year. 4 Plate 1.5 mL or 2.0 mL of the solution into a 6-well plate and place it in a 37°C incubator for later use.

[0701] 2. Add STAT6 PROTAC Degrader with concentration gradient

[0702] The pre-diluted analyte at concentrations of 1 μM to 3000 μM was added to a pre-laid 6-well plate at a ratio of 1:1000 to obtain a final concentration of 1 nM to 3000 nM. The 6-well plate was then shaken horizontally in a cross-shaped motion to mix the analyte.

[0703] 3. Place the well-mixed 6-well plate in a 37℃ incubator and incubate for 23-24 hours.

[0704] 4. Protein sample preparation

[0705] Transfer the cells from the 6-well plate to a 1.5 mL centrifuge tube and centrifuge at 13000 g, RT, for 1 min.

[0706] Discard the cell supernatant, add 1 mL of PBS to wash once, and centrifuge again at 13000 g, RT, for 1 min. Discard the PBS.

[0707] Lysis was performed by adding Lysis buffer containing protease inhibitors to the cell clumps at the bottom of each EP tube and then lysing on ice.

[0708] Centrifuge the cell lysis suspension at 13000 g, 4°C, for 15 min.

[0709] Add 5X loading buffer to the new EP tube at a ratio of 1:4 to the volume of the lysis buffer.

[0710] Transfer the lysate after centrifugation to the EP tube, vortex to mix, and place on a 98°C metal bath for 5 min.

[0711] 5. Protein sample gel running and transfer

[0712] Centrifuge the cooked protein sample and vortex to mix. Place the pre-prepared 7.5% SDS-PAGE gel rack in the electrophoresis tank, and load 20 μL of protein sample per well. Run at a constant voltage of 80 V until the markers separate, then adjust to a constant voltage of 150 V until the gel is finished. Perform a wet transfer on the run-through at 400 mA for 30 min.

[0713] 6. Block the transferred NC membrane with 3% milk powder for 1 hour. After blocking, rinse twice with PBS, add the pre-prepared STAT6 antibody working solution, and incubate overnight at 4°C.

[0714] 7. After rinsing on the second day, incubate with the secondary antibody working solution for 1 hour, rinse three times with PBST, and then develop.

[0715] Table 2. Degradation effect of the compounds on STAT6 in MV4-11 cells

[0716]

[0717] Note: " / " indicates no test. At the tested concentration, a degradation rate ≥50% is considered to indicate good degradation activity. AK1690 is used as a control for comparison, and its structural formula is as follows:

[0718]

[0719] The results are shown in Table 2. Table 2 reveals that compounds A5, A6, A9, A11, A12, A14, A16-A20, A24, A26, A28, A11-P1, and A11-P2 exhibit good degradation effects on STAT6. The activities of the two enantiomers, A11-P1 and A11-P2, are close to those of the racemic A11, indicating that the chirality of the resolution position has little effect on the activity.

[0720] Further tests were conducted on the degradation of STAT6 by compounds A6, A9, A11, A14, A17, A11-P1, and A11-P2. 50 The results are shown in Table 3:

[0721] Table 3. Degradation effect of the compounds on STAT6 in MV4-11 cells

[0722]

[0723] Note: A11 is the reference standard used in the A11-P1 and A11-P2 tests. The value in parentheses is the DC of A11. 50 .

[0724] Table 3 shows that compounds A6, A9, A11, A14, A17, A11-P1, and A11-P2 all exhibit high degradation activity against STAT6, DC 50 All were lower than the positive control. Among them, compounds A14 and A17 are two prodrug forms of compound A9, and their degradation activity was unexpectedly increased by 70 and 1167 times, respectively. The two enantiomers of A11, A11-P1 and A11-P2, had activities close to those of the racemic A11, indicating that the chiral center at the resolution position has little effect on the activity. The results for compound A14 are as follows... Figure 4 As shown.

[0725] Example 2: Testing the selectivity of the compound in MV4-11 cells

[0726] 1. Prepare a 6-well plate and seed the cells.

[0727] MV4-11 cells cultured to a certain cell density were centrifuged and counted, then analyzed at a concentration of 80-100 × 10⁻⁶ cells / year. 4 Plate 6-well plates with 1.5 mL or 2.0 mL of 10% FBS RPMI medium per well and place in an incubator at 37°C for later use.

[0728] 2. Add STAT6 PROTAC Degrader with concentration gradient

[0729] A6, pre-diluted to a concentration of 1 μM-3000 μM, was added to a pre-laid 6-well plate at a ratio of 1:1000 to obtain a final concentration of 1 nM-3000 nM. The 6-well plate was then shaken horizontally in a cross-shaped motion to mix the compounds in the plate.

[0730] 3. Place the well-mixed 6-well plate in a 37℃ incubator and incubate for 23-24 hours.

[0731] 4. Protein sample preparation

[0732] Transfer the cells from the 6-well plate to a 1.5 mL centrifuge tube and centrifuge at 13000 g, RT, for 1 min.

[0733] Discard the cell supernatant, add 1 mL of PBS to wash once, and centrifuge again at 13000 g, RT, for 1 min. Discard the PBS.

[0734] Lysis was performed by adding Lysis buffer containing protease inhibitors to the cell clumps at the bottom of each EP tube and then lysing on ice.

[0735] Centrifuge the cell lysis suspension at 13000 g, 4°C, for 15 min.

[0736] Add 5X loading buffer to the new EP tube at a ratio of 1:4 to the volume of the lysis buffer.

[0737] Transfer the lysate after centrifugation to the EP tube, vortex to mix, and place on a 98°C metal bath for 5 min.

[0738] 5. Protein sample gel running and transfer

[0739] Centrifuge the cooked protein sample and vortex to mix. Place the pre-prepared 7.5% SDS-PAGE gel rack in the electrophoresis tank, and load 20 μL of protein sample per well. Run at a constant voltage of 80 V until the markers separate, then adjust to a constant voltage of 150 V until the gel is finished. Perform a wet transfer on the run-through at 400 mA for 30 min.

[0740] 6. Block the transferred NC membrane with 3% milk powder for 1 hour. After blocking, rinse twice with PBS, add the pre-prepared working solutions of STAT6, STAT1, STAT3, and STAT5 antibodies, and incubate overnight at 4°C.

[0741] 7. After rinsing on the second day, incubate with the secondary antibody working solution for 1 hour, rinse three times with PBST, and then develop.

[0742] Table 4. Degradative activity of compounds against the STAT family in MV4-11 cells

[0743]

[0744] The results are as follows Figure 1-2 As shown in Table 4, compounds A6, A9, A11, and A17, at the tested concentrations, only degraded STAT6 and DC. 50The concentrations were 27 nM, 14 nM, 6 nM, and 0.012 nM, respectively. Compounds A6 and A17 did not show significant degradation effects on STAT1, STAT3, and STAT5 of the same family. Compounds A9 and A11 did not show any degradation effect on STAT3, indicating that the compounds of the present invention have good selectivity and can avoid the safety risks associated with the degradation of STAT3.

[0745] Example 3: IL-4-induced CCL17 release assay (ELISA)

[0746] Experimental steps:

[0747] 1. Prepare a 96-well plate and seed the cells.

[0748] One tube of resuscitation solution contains 500 x 10 4 PBMCs were counted at a rate of 5 × 10⁶ cells / tube. 4 Use 100 μL RPMI medium per well to lay 96-well plates and place them in an incubator at 37°C for later use.

[0749] 2. Add STAT6 PROTAC Degrader compounds in a concentration gradient sequentially.

[0750] The pre-diluted STAT6 PROTAC Degrader at concentrations of 10 μM-30 mM was added to a pre-laid 96-well plate at a ratio of 1:1000 to obtain a final concentration of 10 nM-30000 nM. The 96-well plate was then shaken horizontally in a cross-shaped motion to mix the compounds in the plate.

[0751] 3. Place the well-mixed 96-well plate in a 37°C incubator and incubate for 7 hours.

[0752] 4. Adding concentration gradients of Dupilumab monoclonal antibody

[0753] The pre-diluted 0.3 μM-1 mM Dupilumab was added to the pre-laid 96-well plate at a 1:1000 dilution to obtain a final concentration of 0.3 nM-1000 nM. The 96-well plate was then shaken horizontally in a cross-shaped motion to mix the monoclonal antibody in the plate.

[0754] 5. Place the well-mixed 96-well plate in a 37°C incubator and incubate for 1 hour.

[0755] 6. Add 100 μg / mL of IL-4 cytokine, diluted at a ratio of 1:1000 to a final concentration of 100 ng / mL, to a 96-well plate pretreated with STAT6 PROTAC Degrader or Dupilumab. Shake the 96-well plate horizontally in a crosswise motion to mix the cytokine.

[0756] 7. Place the well-mixed 96-well plate in a 37°C incubator and incubate for 24 hours.

[0757] 8. Collect 70 μL of cell culture supernatant for subsequent CCL17 ELISA testing.

[0758] Table 5. Inhibition of IL-4-induced CCL17 by the compounds

[0759]

[0760] Note: Dupilumab is a control product used for comparison. It is a marketed fully human monoclonal antibody against the α subunit of the interleukin-4 receptor (IL-4Rα), which can inhibit the IL-4-induced type 2 inflammatory signaling pathway.

[0761] The results are shown in Table 5. Compounds A6, A9, A11, A14, A17 and Dupilumab can inhibit the release of IL-4-induced CCL17. Among them, the activities of compounds A14 and A17 are about 4 and 23 times that of Dupilumab, respectively, and they are expected to play a good therapeutic role in type 2 inflammation.

[0762] Example 4: Testing the selectivity of the compound in single cells of mouse spleen and confirming whether the compound exhibits species-specific differences.

[0763] Experimental steps:

[0764] 1. Preparation of single cells from mouse spleen and placement in 6-well plates

[0765] Prepare 3 healthy mice, sacrifice them and take spleen tissue, add it to 40 mL of RPMI medium, and set aside for later use.

[0766] Prepare 2% FPBS reagent in advance. Take 10 mL of 2% FPBS into a 10 cm cell culture dish, place a 0.2 μm filter screen, and transfer mouse spleen tissue into the filter screen. Grind the cells with the handle of a 2 mL sterile syringe until no large tissue fragments remain. Transfer the cell suspension in the dish to a 50 mL centrifuge tube and centrifuge at 400 g, RT, for 3 min.

[0767] Discard the supernatant, add 2 mL of RBC Lysis buffer per spleen and lyse the red blood cells for 3-5 min. Then add 5 times the volume of 2% FPBS to terminate the lysis. Centrifuge at 400 g for 3 min at RT.

[0768] Discard the supernatant, add an appropriate volume of PBS to wash once, centrifuge at 400 g for 3 min at RT.

[0769] Discard the supernatant, add 5 mL of FBS-free RPMI medium to resuspend the cells, filter the cell suspension through a 0.2 μm filter into a new 50 mL centrifuge tube, and replenish the FBS-free RPMI medium at a volume of 2.5 mL / well for 10 wells.

[0770] After mixing the cells, plate them into 6-well plates at a rate of 2.5 mL / well and incubate them at 37°C for later use.

[0771] 2. Add STAT6 PROTAC Degrader with concentration gradient

[0772] A6, pre-diluted to a concentration of 1 μM-3000 μM, was added to a pre-laid 6-well plate at a ratio of 1:1000 to obtain a final concentration of 1 nM-3000 nM. The 6-well plate was then shaken horizontally in a cross-shaped motion to mix the compounds in the plate.

[0773] 3. Place the well-mixed 6-well plate in a 37℃ incubator and incubate for 23-24 hours.

[0774] 4. Protein sample preparation

[0775] Transfer the cells from the 6-well plate to a 1.5 mL centrifuge tube and centrifuge at 13000 g, RT, for 1 min.

[0776] Discard the cell supernatant, transfer the remaining cells in the well plate to the EP tube and centrifuge at 13000 g, RT, for 1 min.

[0777] Discard the cell supernatant, add 1 mL of PBS to wash once, and centrifuge again at 13000 g, RT, for 1 min. Discard the PBS.

[0778] Lysis was performed by adding Lysis buffer containing protease inhibitors to the cell clumps at the bottom of each EP tube and then lysing on ice.

[0779] Centrifuge the cell lysis suspension at 13000 g, 4°C, for 15 min.

[0780] Add 5X loading buffer to the new EP tube at a ratio of 1:4 to the volume of the lysis buffer.

[0781] Transfer the lysate after centrifugation to the EP tube, vortex to mix, and place on a 98°C metal bath for 5 min.

[0782] 5. Protein sample gel running and transfer

[0783] Centrifuge the cooked protein sample and vortex to mix. Place the pre-prepared 7.5% SDS-PAGE gel rack in the electrophoresis tank, and load 20 μL of protein sample per well. Run at a constant voltage of 80 V until the markers separate, then adjust to a constant voltage of 150 V until the gel is finished. Perform a wet transfer on the run-through at 400 mA for 30 min.

[0784] 6. Block the transferred NC membrane with 3% milk powder for 1 hour. After blocking, rinse twice with PBS, add the pre-prepared working solutions of STAT6, STAT1, STAT2, STAT3, STAT4, and STAT5 antibodies, and incubate overnight at 4°C.

[0785] The next day, after rinsing, the secondary antibody working solution was incubated for 1 hour, and after rinsing three times with PBST, the mixture was developed.

[0786] Table 6. Degradative activity of compounds against the STAT family in mouse spleen cells

[0787]

[0788] The results are as follows Figure 3 As shown in Table 6, compounds A6, A11, and A17 exhibited good degradation selectivity in mouse spleen cells, degrading only STAT6 at the tested concentrations, with no significant degradation effect on STAT1-5 of the same family; DC 50 The concentrations were 15 nM, 8.8 nM, and 0.13 nM, respectively, which are close to the results in MV4-11 cells, indicating that compounds A6, A11, and A17 do not show species differences.

[0789] Example 5: Testing the degradation of Ikaros, Aiolos, GSPT1, and SALL4 proteins by the compound.

[0790] Testing the degradation of Ikaros, Aiolos, GSPT1, and SALL4 proteins by the compounds in this invention can provide a preliminary assessment of potential off-target safety.

[0791] 1. Experimental steps:

[0792] (1) Degradation test methods for Ikaros, Aiolos, and GSPT1: The cell line used was human myeloid monocytic leukemia cell line MV4-11. The sterile incubator temperature was 37-38℃, pH range was 7.2-7.4, and carbon dioxide gas ratio was 5%. MV4-11 cells (9×10⁻⁶) 5 After being treated with different concentrations of compounds in 6-well plates for 24 hours, proteins were extracted using RIPA lysis buffer. Samples were then electrophoresed on 7.5% SDS-PAGE and transferred to an NC membrane. The membrane was blocked for 1 hour at room temperature with 5% skim milk (PBS + 0.05% Tween-20), and then incubated overnight at 4°C with primary antibodies (including anti-Ikaros, A3565, ABclonal; anti-Aiolos, A8614, ABclonal; anti-GSPT1, A25506, ABclonal; anti-Actin, A2066, SIGMA). The membrane was then incubated with secondary antibodies (Anti-rabbit IgG (H+L), DyLight800, CST) for 1 hour at room temperature. Finally, the samples were detected using an Odyssey CLx dual-color infrared laser imaging system.

[0793] (2) SALL4 degradation test: The cell line used was human embryonic stem cell H9. The sterile incubator temperature was 37~38℃, pH range was 7.2~7.4, and carbon dioxide gas ratio was 5%. H9 cells (2×10 5 After being treated with different concentrations of compounds in 6-well plates for 24 hours, proteins were extracted using RIPA lysis buffer. Samples were then subjected to 7.5% SDS-PAGE electrophoresis and transferred to an NC membrane. The membrane was blocked for 1 hour at room temperature with 5% skim milk (PBS + 0.05% Tween-20), and then incubated overnight at 4°C with primary antibodies (including anti-Sall4, ab29112, Abcam; anti-GAPDH, share-bio). It was then incubated at room temperature with secondary antibodies (Anti-rabbit IgG (H+L), DyLight 800, CST) for 1 hour. Finally, the samples were detected using an Odyssey CLx dual-color infrared laser imaging system.

[0794] 2. Experimental Results

[0795] Figure 5 The degradation of Ikaros, Aiolos, and GSPT1 proteins by compounds A11, A17, and the positive control pomalidomide (denoted as poma) is shown.

[0796] Figure 6 The degradation of SALL4 protein by compounds A11, A17 and the positive control pomalidomide is shown.

[0797] Conclusion: As shown in the figure, compounds A11 and A17 had no degradation effect on Ikaros, Aiolos, GSPT1, and SALL4 proteins, while the positive control pomalidomide showed dose-dependent degradation of Ikaros, Aiolos, and SALL4 proteins. These results demonstrate that the compounds of this invention have a low risk of off-target toxicity with CRBN ligands (a type of E3 ligase ligand).

[0798] Example 6: Testing the proteomics of compounds in hPBMCs

[0799] 1. Experimental steps:

[0800] (1) The cells used were human PBMCs. The sterile incubator temperature was 37-38℃, the pH range was 7.2-7.4, and the carbon dioxide gas concentration was 5%. hPBMCs (7×10⁻⁶) 5 The perforated material is laid in a 6-well plate and treated with a compound for 24 hours.

[0801] (2) Sample preparation

[0802] 2.1 Protein Extraction

[0803] a) Lysis of cells: Take a cell pellet sample, add 600 μL of lysis buffer, and vortex to mix.

[0804] b) Grinding: Transfer the sample to a grinding tube for grinding;

[0805] c) Centrifugation: Centrifuge at 14000 g for 5 min, collect the supernatant, and determine the protein concentration of the supernatant using BCA.

[0806] 2.2 Reductive Alkylation

[0807] a) Reduction: Take 200 μg of protein, add 5 μL of DTT (1 M), vortex to mix, and incubate at room temperature for 60 min;

[0808] b) Alkylation: Add 20 μL of IAM (1 M) to the sample, vortex to mix, and incubate at room temperature in the dark for 60 min;

[0809] c) Quenching: Add 10 μL DTT (1 M) to the sample, vortex mix, and incubate at room temperature for 30 min;

[0810] 2.3 SP3 digestion

[0811] a) Binding: Wash the Beads with pure water in advance and prepare a stock solution of 100 μg / μL. Mix the Beads / protein at a ratio of 10:1, add anhydrous ethanol to make the final concentration 50% (v / v), and incubate at room temperature for 15 min.

[0812] b) Rinse: Rinse three times with 500 μL of 80% ethanol and dry the Beads at room temperature;

[0813] c) Enzyme digestion: Add Trypsin at a protein:enzyme ratio of 50:1 (w / w) and incubate at 37°C for 18 h;

[0814] d) Peptide recovery: Centrifuge the enzymatically digested sample at 14000 g for 5 min at room temperature. Place the centrifuged sample on a magnetic rack and let it stand for 2 min. Take the supernatant and determine the peptide concentration in the supernatant using BCA.

[0815] 2.4 Desalination

[0816] a) Take 10 μg of each sample and desalt them using a self-made Tip column;

[0817] b) After desalting, the sample is vacuum dried and stored for testing.

[0818] (3) Chromatographic conditions

[0819] Mobile phase A was an aqueous solution containing 0.1% formic acid and 2% acetonitrile; mobile phase B was an aqueous solution containing 0.1% formic acid and 80% acetonitrile. The chromatographic column was a C18 1.9 μm 75 μm × 200 mm column, and the flow rate was 0.4 μL / min.

[0820] (4) Software Analysis

[0821] The search was performed using DIA-NN (v1.8). Search parameters were set as follows: the database was the Swissprot_human protein database (sequences); the restriction enzyme method was set to Trypsin / P, and the maximum number of missed cleavage sites was set to 2; the minimum peptide length was set to 7 amino acid residues; the mass error range for both primary and secondary mass spectrometry was 20 ppm. Fixed modification was set to Carbamidomethyl (C); variable modification was set to Oxidation (M) Acetyl (N-terminus).

[0822] (5) Volcano plot of differentially expressed proteins

[0823] This experiment used the changes in protein quantification values ​​between the experimental group and the control group to create a volcano plot of differentially expressed proteins. The horizontal axis of the volcano plot represents the fold change (relative quantitative value difference) between the two groups after log2 transformation. The vertical axis of the volcano plot represents the p-value (P-value) for the significance test after -log10 transformation.

[0824] 2. Experimental Results

[0825] The protein degradation volcano diagrams of compound A11 in hPBMCs are as follows: Figure 7 As shown, compound A11 detected a total of 6013 proteins. The names of the proteins that were significantly degraded (p<0.05) have been marked in the corresponding volcano plot (including the following proteins: STAT6, SLC37A4, MDM4, SETD2, TLRRD1, MAST3, MEPCE, TELQ2, MRTFB).

[0826] Conclusion: Compound A11 exhibits good protein degradation selectivity in hPBMCs.

[0827] Example 7: Compound CYP Enzyme Inhibition Test

[0828] 1. Experimental steps:

[0829] 1) Prepare working solutions for the test compound and positive control;

[0830] 2) Remove the human liver microparticles from the refrigerator and thaw them on ice;

[0831] 3) Transfer 20 µL of substrate working solution to the corresponding wells, and transfer 20 µL of PB buffer to the blank wells of the incubation plate.

[0832] 4) Transfer 158 µL of HLM working solution to all wells of the culture plate.

[0833] 5) Transfer 2 µL of the test compound or positive control working solution to the well, and transfer 2 µL of the solvent to the well without inhibitor control.

[0834] 6) Preheat the incubation plate to 37.0℃ for 10 min.

[0835] 7) Add 20µL of NADPH working solution to initiate the reaction, and incubate the plate at 37.0℃ for 10 min.

[0836] 8) After the reaction is complete, add 400µL of stop solution containing internal standard to terminate the reaction.

[0837] 9) Stir the reaction solution for 10 minutes and centrifuge at 3220 ×g for 20 minutes.

[0838] 10) Take 200 µL of supernatant and mix it with 100 µL of ultrapure water.

[0839] 11) After shaking for 10 min, analyze the substrate metabolites using LC-MS / MS.

[0840] 2. Experimental Results

[0841] The compounds of this invention inhibit the IC50 of CYPs. 50 The values ​​are shown in Table 7.

[0842] Table 7. IC50 of compounds inhibiting CYPs 50 value

[0843]

[0844] Conclusion: Compound A11 of this invention has an IC50 value for the tested CYP isoenzymes 1A2, 2C9, 2C19, 2D6 and CYP3A4. 50 All values ​​were greater than 40 μM, indicating that compound A11 has weak inhibition of CYP isoenzymes and a low risk of drug-drug interactions.

[0845] Example 8: hERG inhibition test of compound

[0846] 1. Experimental steps:

[0847] 1) The test sample will first be dissolved in a suitable solvent, and then diluted with ECS at a ratio of 0.3% to prepare working solutions of different concentrations: 0.3, 1, 3, 10, and 30 µM. Cisapride is a known inhibitor of hERG current and is widely used as a positive control in hERG assays (in this experiment, the inhibition rate of cisapride at 0.1 μM was greater than 50%, proving that the sensitivity of the test system meets the requirements).

[0848] 2) The cells used were Chinese hamster ovary (CHO) cell lines that stably express hERG in vitro. The complete culture medium was F12 medium supplemented with 10% fetal bovine serum and 1% geneticin. ® Selective antibiotic (G418), 89 µg / mL hygromycin B (HB). Resuscitation medium was F12 medium supplemented with 10% fetal bovine serum. CHO-hERG cells were grown in a high-humidity incubator at 37°C (±2°C) and 5% CO2 (4% to 8%).

[0849] 3) CHO-hERG cells in the exponential growth phase were collected and resuspended in ECS for later use. hERG currents were recorded using whole-cell patch-clamp technology at room temperature. The patch-clamp amplifier output signal was converted from digital to analog and then filtered with a 2.9 kHz low-pass filter. Data was acquired using Patchmaster Pro software.

[0850] 4) At the beginning of the recording of the solvent control working solution perfusion, monitor the tail current peak until more than three scan curves stabilize, then perfuse the test sample / positive control working solution until the inhibitory effect of the test sample / positive control working solution on the hERG current peak reaches a stable state. Record the inhibition rate of cell hERG current at different concentrations.

[0851] 2. Experimental Results

[0852] The hERG-inhibiting IC of the compounds of the present invention 50 The values ​​are listed in Table 8.

[0853] Table 8. IC50 of the compounds for hERG inhibition 50 value

[0854]

[0855] Conclusion: Compound A17 of this invention has no significant inhibitory effect on hERG and has a low risk of cardiotoxicity.

[0856] Example 9: Pharmacokinetics of the compound administered intratracheally in C57 mice.

[0857] 1. Experimental steps:

[0858] The pharmacokinetic characteristics of the compound after intratracheal administration were tested in rodents using a standard protocol. In the experiment, the candidate compound was prepared into a solution and administered to mice via a single intratracheal dose using a quantitative nebulizer. Physiological saline was used. Female C57 mice were used in this project. Lung and blood samples were collected from the mice at 2 h, 6 h, 24 h, and 48 h after administration. The collected samples were then analyzed by LC / MS / MS, and the data were collected.

[0859] 2. Experimental Results

[0860] The results of the pharmacokinetic assays of compound A11 in mice are shown in Table 9.

[0861] Table 9. Pharmacokinetic results of compound A11 in mice

[0862]

[0863] a: AUC Ratio = Tissue AUC 0-last / Plasma AUC 0-last

[0864] Conclusion: Compound A11 exhibited favorable pharmacokinetic characteristics in the intratracheal administration experiment in mice. The drug could be selectively exposed to lung tissue, with a lung / plasma ratio (AUC Ratio) as high as 21, which could reduce systemic drug exposure and lower the safety risk to other organs. It is suitable for the local treatment of respiratory and lung diseases.

[0865] Example 10: Degradation of STAT6 protein in C57 mice by the test compound

[0866] 1. Experimental steps:

[0867] After intratracheal administration of the drug, lung and blood samples were collected from 15 female C57 mice at 0 h, 2 h, 6 h, 24 h and 48 h to study the degradation of STAT6 protein in vivo.

[0868] PBMC cell isolation and lysis:

[0869] Blood was collected from each group of mice (n=3 per group) using EDTA-K2 crystallized anticoagulant centrifuge tubes (approximately 0.5 mL per mouse). Whole blood samples were mixed and transferred to centrifuge tubes at the same time points within the same group and centrifuged for 10 min (2000g, RT, Accel 9, Decel 9).

[0870] After centrifugation, discard the upper plasma layer and add 3 mL of PBS buffer containing 2% FBS to the centrifuge tube. Mix well and slowly add the suspension dropwise to a centrifuge tube containing 1.5 mL of human lymphocyte separation medium. Centrifuge for 25 min (400g, RT, Accel 2, Decel 2).

[0871] After centrifugation, carefully aspirate the thin, relatively dense white film layer in the middle into a centrifuge tube containing 8 mL of 2% FBS in PBS buffer and centrifuge for 5 min (400g, RT, Accel 9, Decel 9).

[0872] After centrifugation, discard the supernatant, add 100 μL of erythrocyte lysis buffer to lyse the erythrocytes, let stand at room temperature for 5 min, add 2 mL of PBS buffer containing 2% FBS, and centrifuge for 5 min (400g, RT, Accel 9, Decel 9).

[0873] Discard the supernatant, resuspend the precipitate in 1 mL PBS, transfer it to a 1.5 mL centrifuge tube, and centrifuge for 2 min (13000 g, RT).

[0874] After centrifugation, discard the supernatant, place on wet ice, resuspend the precipitate with 40 μL of cell lysis buffer (RIPA Lysisbuffer containing PMSF), quickly pipette to mix, place on ice for 15 min for lysis (during lysis, repeatedly scrape and shake to break up the nucleic acid until there are no sticky clumps in the solution), and centrifuge for 10 min (13000g, 4℃).

[0875] After centrifugation, transfer the supernatant to a 1.5 mL centrifuge tube and place it on wet ice for later use.

[0876] Tissue homogenate:

[0877] Take tissue samples of approximately the same size and place them in centrifuge tubes containing 300 μL of Western / IP lysis buffer with PMSF. Place the tubes in a wet ice box. Homogenize the tissue blocks using a PRO 200 homogenizer, then lyse them in wet ice for 30 min, followed by centrifugation for 25 min (13000g, 4℃). Transfer the supernatant to 1.5 mL centrifuge tubes and place them in wet ice for later use.

[0878] Protein sample preparation:

[0879] Protein concentration was determined using the Beyotime BCA Protein Assay Kit (catalog number: P0009). A certain volume of SDS loading buffer and Lysis buffer were added, mixed well, and 50 μL of sample with a protein concentration of 3 μg / μL or 100 μL of sample with a protein concentration of 5 μg / μL was prepared. The sample was then heated in a 98℃ metal bath for 5 min.

[0880] Western blot analysis:

[0881] Centrifuge the prepared protein samples and vortex to mix. Place the pre-prepared 10% SDS-PAGE gel in the electrophoresis tank, add the samples to the loading lanes, and perform electrophoresis at a constant voltage of 80V until the markers separate. Then adjust the voltage to 150V until electrophoresis is complete, and perform wet transfer of the PAGE gel (400 mA, 40 min). Block the NC membrane with the transferred protein samples with 3% milk powder for 1 h, wash twice with PBS, add the pre-prepared STAT6 antibody working solution (1000-fold dilution of STAT6 antibody CST5397), and incubate overnight at 4°C. The next day, after rinsing, incubation with secondary antibody working solution (1 h), rinsing with PBST, and development.

[0882] 2. Experimental Results:

[0883] The degradation of STAT6 in mice after intratracheal nebulization of compound A11 is shown in the figure. Figure 8 .Depend on Figure 8It is known that the compound A11 of the present invention can effectively degrade STAT6 protein in lung tissue, and the effect lasts for up to 48 hours.

[0884] It should be noted that although the technical solution of the present invention has been described with specific examples, those skilled in the art will understand that the present invention should not be limited thereto.

[0885] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical applications, or technological improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof: in, X is selected from NR 6a CHR 6a O, S, S(=O) and S(=O)2; when X and L m When connecting, X is N or CR 6a ; Each n is independently selected from 0, 1, 2, and 3; m is selected from 1, 2, 3, 4, 5, 6, 7, and 8; Ring A is selected from 4-6 member saturated or partially unsaturated heterocyclic groups containing at least one nitrogen atom, 5-6 member heteroaryl groups containing at least one nitrogen atom, 8-10 member fused heterobicyclic groups containing at least one nitrogen atom, and 6-12 member fused heterobicyclic groups containing at least one nitrogen atom. The B ring is absent, or is selected from 5-6 membered heteroaryl groups containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl groups; saturated or partially unsaturated 5-6 membered heterocyclic groups containing 1-2 heteroatoms independently selected from oxygen and nitrogen; and saturated or partially unsaturated C rings. 3-6 Aliphatic ring group; when ring B is absent, ring A is hydrogen-terminated; The C ring is selected from phenyl, 5-6-membered heteroaryl, naphthyl, and 8-10-membered fused heterobicyclic groups containing 1-3 heteroatoms, each independently selected from nitrogen, oxygen, and sulfur; each of the phenyl, 5-6-membered heteroaryl, naphthyl, or 8-10-membered fused heterobicyclic group is optionally surrounded by 0, 1, 2, or 3 R atoms. c replace; R 1 Selected from -C(R 1a R 2a )P(=O)(OR b )(OR b )、-C(R 1a R 2a )P(=O)[OR b [NH(CH2) q C(=O)OR T 、 -C(R 1a R 2a )P(=O)[NH(CH2) q C(=O)OR T ][NH(CH2) q C(=O)OR T ]、-C(R 1a R 2a )P(=O)[NHR T ][NHR T ]、 -C(R 1a R 2a )P(=O)[NHCH(CH3)C(=O)OR T ][NHCH(CH3)C(=O)OR T ]、 -C(R 1a R 2a )P(=O)[OR b ][NHCH(CH3)C(=O)OR T ]、-C(R 1a R 2a )P(=O)[OR b ][NHC(CH3)2C(=O)OR T ]、 -P(=O)(OR b )(OR b )、-P(=O)[OR b ][NH(CH2) q C(=O)OR T ]、 -P(=O)[NH(CH2) q C(=O)OR T ][NH(CH2) q C(=O)OR T ]、-P(=O)[NHR T ][NHR T ]、 -P(=O)[NHCH(CH3)C(=O)OR T [NHCH(CH3)C(=O)OR T and -P(=O)[OR b [NHCH(CH3)C(=O)OR T ; Preferably, R 1 is selected from -C(R 1a R 2a )P(=O)(OR b )(OR b )、-C(R 1a R 2a )P(=O)[OR b [NH(CH2) q C(=O)OR T , -C(R 1a R 2a )P(=O)[NH(CH2) q C(=O)OR T ][NH(CH2) q C(=O)OR T ]、-C(R 1a R 2a )P(=O)[NHR T ][NHR T ]、 -C(R 1a R 2a )P(=O)[NHCH(CH3)C(=O)OR T ][NHCH(CH3)C(=O)OR T ]、 -C(R 1a R 2a )P(=O)[OR b ][NHCH(CH3)C(=O)OR T ]、 -P(=O)(OR b )(OR b )、-P(=O)[OR b ][NH(CH2) q C(=O)OR T ]、 -P(=O)[NH(CH2) q C(=O)OR T ][NH(CH2) q C(=O)OR T ]、-P(=O)[NHR T ][NHR T ]、 -P(=O)[NHCH(CH3)C(=O)OR T [NHCH(CH3)C(=O)OR T and -P(=O)[OR b [NHCH(CH3)C(=O)OR T ; Each q is independently selected from 0, 1, 2, and 3; If it exists, R 1a and R 2a Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, hydroxyl and -OC 1-4 Alkyl, or R 1a and R 2a The combination forms a carbonyl group, or R 1a and R 2a Together with the carbon atom it is attached to, they form a 4-5 membered heterocycle containing oxygen atoms; If it exists, each R b Each is independently selected from hydrogen and C. 1-20 Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, naphthyl, C 1-4 Alkylene-OC 1-20 Alkyl, C 1-4 Alkylene-C(=O)OC 1-10 Alkyl, C 1-4 Alkylene-OC(=O)-C 1-10 Alkyl, C 1-4 Alkylene-OC(=O)NH-C 1-4 Alkylene-C(=O)OC 1-10 Alkyl, C 1-4 Alkylene-OC(=O)OC 1-10 Alkyl, C 1-4 alkylene-C(=O)O-5-7 membered heterocyclic group, C 1-4 alkylene-C(=O)O-phenyl, C 1-4 Alkylene-OC(=O)-5-7 membered heterocyclic group, C 1-4 alkylene-O-5-7-membered heterocyclic group, C 1-4 Alkylene-OC(=O)O-5-7-membered heterocyclic group, C 1-4 Alkylene-C(=O)SC 1-10 Alkyl, C 1-4 Alkylene-SC(=O)-C 1-10 Alkyl, C 1-4 alkylene-C(=O)S-5-7 membered heterocyclic groups and C 1-4 alkylene-SC(=O)-5-7-membered heterocyclic group; the C 1-4 Alkyl, C 1-10 Alkyl, C 1-4 Alkylene, C 1-20 Alkyl or 5-7 membered heterocyclic groups are each optionally surrounded by one or more deuterium, halogen, cyano, C 1-3 Alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino substitutions; or, two identical or different R groups. b With R 1 The phosphorus atoms in the group collectively form a 5-7 membered saturated heterocycle, which is optionally bonded by one or more deuterium, halogen, cyano, or C atoms. 1-3 The phenyl group is substituted with alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino, and the phenyl group is optionally substituted with one or more halogens. Preferably, if present, each R b Each is independently selected from hydrogen and C. 1-20 Alkyl, phenyl, benzyl, 5-6 membered heteroaryl, naphthyl, C 1-4 Alkylene-OC 1-20 Alkyl, C 1-4 Alkylene-C(=O)OC 1-10 Alkyl, C 1-4 Alkylene-OC(=O)-C 1-10 Alkyl, C 1-4 Alkylene-OC(=O)NH-C 1-4 Alkylene-C(=O)OC 1-10 Alkyl, C 1-4 Alkylene-OC(=O)OC 1-10 Alkyl, C 1-4 alkylene-C(=O)O-5-7 membered heterocyclic group, C 1-4 alkylene-C(=O)O-phenyl, C 1-4 Alkylene-OC(=O)-5-7 membered heterocyclic group, C 1-4 alkylene-O-5-7-membered heterocyclic group, C 1-4 Alkylene-OC(=O)O-5-7-membered heterocyclic group, C 1-4 Alkylene-C(=O)SC 1-10 Alkyl, C 1-4 Alkylene-SC(=O)-C 1-10 Alkyl, C 1-4 alkylene-C(=O)S-5-7 membered heterocyclic groups and C 1-4 alkylene-SC(=O)-5-7-membered heterocyclic group; the C 1-4 Alkyl, C 1-10 Alkyl, C 1-4 Alkylene, C 1-20 Alkyl or 5-7 membered heterocyclic groups are each optionally surrounded by one or more deuterium, halogen, cyano, C 1-3 Alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino substitutions; or, two identical or different R groups. b With R 1 Phosphorus atoms in the rings together form 5-7 membered saturated heterocycles; If it exists, each R T Each is independently selected from C 1-10 Alkyl, benzyl, and phenyl; the C 1-10 Alkyl, benzyl, or phenyl groups are each optionally radicalized by one or more deuterium, halogen, cyano, or C groups. 1-3 Alkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino substitutions; or, two identical or different R groups. T With R 1 Phosphorus atoms in the rings together form 5-7 membered saturated heterocycles; Or, R b With R T With R 1 Phosphorus atoms in the rings together form 5-7 membered saturated heterocycles; If it exists, each R c Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; R 2 Selected from hydrogen, phenyl and C 1-4 alkyl; If it exists, each R 3 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; or, any two Rs substituted on the same carbon atom. 3 Together with the carbon atoms it is attached to, they form C 3-5 aliphatic ring group; If it exists, each R 4 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-10 Alkyl, C 1-10 Halogenated alkyl, isopropyl, cyclopropyl, 4-6 membered heterocyclic groups, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, dimethylamino, C 6-11 Spiroalkyl, C 5-8 Bridged alkyl groups, 5-12 spiroheterocyclic groups, 6-10 bridged heterobicyclic groups, and 8-10 fused heterobicyclic groups; the C 1-10 Alkyl, 4-6 membered heterocyclic group, C 6-11 Spiroalkyl, C 5-8 Bridged alkyl, 5-12 spiroheterocyclic, 6-10 bridged heterobicyclic, or 8-10 fused heterobicyclic groups are each optionally bonded by one or more deuterium, halogen, cyano, hydroxyl, methoxy, methylamino, dimethylamino, C 5-8 Bridged alkyl, phenyl, or 5-6-membered heteroaryl substitutions; or, any two R groups substituted on the same carbon atom. 4 Together with the carbon atoms it is attached to, they form C 3-5 Aliphatic cyclic group; or, any two R groups substituted on the same carbon atom. 4 The groups combine to form carbonyl groups; If it exists, each R 5 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; or, any two Rs substituted on the same carbon atom. 5 Together with the carbon atoms it is attached to, they form C 3-5 aliphatic ring group; If it exists, each R 6 Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; or, any two Rs substituted on the same carbon atom. 6 Together with the carbon atoms it is attached to, they form C 3-5 Aliphatic cyclic group or 3-5 membered heterocyclic group; or, two R groups located on two adjacent or non-adjacent carbon atoms. 6 It forms C with the carbon atom it is attached to. 3-6 Cycloalkanes or 3-6 membered saturated heterocycles; If it exists, R 6a Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; L m The linker segment consists of m identical, partially identical, or different L groups; L m One end is covalently connected to DIM, and the other end is covalently connected to any ring atom in the 5-8 membered ring framework structure. Each L is independently selected from the following groups: (1) by 0-3 R 1f Replacement C 3-12 Cycloalkylene; (2) by 0-3 R 1f Replacement C 6-10 Alpha-aryl; (3) by 0-3 R 1f Substituted 4-12-membered heterocyclic groups; (4) by 0-3 R 1f Substituted 8-10 fused heterobicyclic groups; (5) by 0-3 R 1f Substituted 5-12 heteroaryl groups; (6) by 0-3 R 2f Replacement C 1-12 Alkylene; (7) by 0-3 R 2f Replacement C 2-12 Vinyl; (8) by 0-3 R 2f Replacement C 2-12 Ethyne-2-yl; (9) 1-6 ethylene glycol or propylene glycol units; (10)-C(=O)-, -C(=O)O-, -O-, -N(R 3f )-, -S-, -S(=O)-, -C(=S)-, -C(=S)O-, -S(=O)2-, -S(=O)N(R 3f )-, -S(=O)2N(R 3f )-, -C(=O)-N(R 3f )-, -N(R 3f )C(=O)-N(R 3f )- and -OC(=O)-N(R 3f )-; If it exists, each R 1f Each is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl, 5-12 heteroaryl, -OR 3f -C(=O)R 3f -C(=O)OR 3f -C(=O)N(R) 3f )2、-N(R 3f )2、-N(R 3f )C(=O)R 3f -N(R) 3f )C(=O)OR 3f -N(R) 3f )C(=O)N(R 3f )2、-OC(=O)R 3f -OC(=O)N(R) 3f )2、-SR 3f -S(=O)R 3f -S(=O)2R 3f and -S(=O)2N(R) 3f )2; The C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-10 Aryl or 5-12 heteroaryl groups are each optionally surrounded by 0-3 R groups. 3f Replace; or, any two non-adjacent R's 1f It forms a bridging ring with the carbon atom it is attached to; or, two R atoms on the same carbon atom... 1f Together with the carbon atoms they are attached to, they form an aliphatic ring; If it exists, each R 2f Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl; If it exists, each R 3f Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, methylamino, dimethylamino, cyano, methyl, deuterated methyl, methoxy, and deuterated methoxy; DIM is a small-molecule affinity ligand for E3 ubiquitin ligases; Preferably, DIM is selected from small molecule affinity ligands of CRBN, VHL, cIAP, MDM2, RNF4, AhR, DCAF16, RNF114, FEM1B, KEAP1, and DCAF15.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that, The compound is a compound having the structure of formula (I'): in, Ring A is a 4-6 member saturated or partially unsaturated heterocyclic group containing at least one nitrogen atom; The C ring is selected from a naphthyl group and an 8-10 fused heterobicyclic group containing 1-3 heteroatoms, each independently selected from nitrogen, oxygen, and sulfur; the naphthyl group or the 8-10 fused heterobicyclic group is optionally surrounded by 0, 1, 2, or 3 R atoms. c replace; Preferably, ring C is selected from the following segments: ； R 7 Selected from hydrogen, C 1-10 Alkyl, C 4-6 Heterocyclic group, C 6-11 Spiroalkyl, C 5-8 Bridged alkyl groups, 5-12 spiroheterocyclic groups, 6-10 bridged heterobicyclic groups, and 8-10 fused heterobicyclic groups; the C 1-10 Alkyl, C 4-6 Heterocyclic group, C 6-11 Spiroalkyl, C 5-8 Bridged alkyl, 5-12 spiroheterocyclic, 6-10 bridged heterobicyclic, or 8-10 fused heterobicyclic groups are each optionally bonded by one or more deuterium, halogen, cyano, hydroxyl, methoxy, methylamino, dimethylamino, C 5-8 Bridged alkyl or 5-6-membered heteroaryl substitution; R 1a and R 2a Each is independently selected from hydrogen, fluorine, and cyano groups, or R 1a and R 2a The groups combine to form carbonyl groups; Y is independently selected from either O atoms or NH; when Y is O, the R atoms connected to Y are... 8 For R b When Y is NH, R connected to Y 8 For R T -(CH2) q C(=O)OR T or -CH(CH3)C(=O)OR T ; DIM is selected from small molecule affinity ligands of CRBN, VHL, and cIAP; Preferably, DIM is selected from the following fragments: ； R 9 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl and C 3-6 cycloalkyl; X is selected from NR 6a and CHR 6a When X and L m When connecting, X is N or CR 6a ; n, q, R 3 R 4 R 5 R 6 R 6a R c R b R T and L m As defined in claim 1.

3. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that, The compound is a compound having the structure of formula (I'-1): Among them, C ring, Y, R 8 R 7 L m DIM and X are as defined in claim 2.

4. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that, The compound is a compound having the structure of formula (II): Among them, ring A, ring C, and ring R 1a R 2a Y, R 8 R 7 n, R 3 R 4 R 5 R 6 L m DIM is as defined in claim 2.

5. The compound according to claim 4, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that, The compound is a compound having the structure of formula (II-1): Among them, C ring, Y, R 8 R 7 L m DIM is as defined in claim 4.

6. The compound according to claim 2, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that, The compound is a compound having the structure of formula (III): Among them, ring A, ring C, and ring R 1a R 2a Y, R 8 R 7 n, R 3 R 4 R 5 R 6 L m DIM and X are as defined in claim 2.

7. The compound according to claim 6, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that, The compound is a compound having the structure of formula (III-1): Among them, C ring, Y, R 8 R 7 L m DIM and X are as defined in claim 6; Preferably, X is CHR 6a R 6a For H.

8. The compound according to any one of claims 2-7, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that: R 7 Selected from hydrogen and C 1-10 Alkyl; the C 1-10 The alkyl group may optionally be substituted with one or more deuterium groups; Preferably, R 7 Selected from hydrogen and C 1-4 Alkyl; the C 1-4 The alkyl group may optionally be substituted with one or more deuterium groups; More preferably, R 7 C 1-4 Alkyl; the C 1-4 Alkyl groups may optionally be substituted with one or more deuterium groups.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that: The C ring is selected from the following groups: Preferred ; R c Hydrogen is preferred as defined in claim 1.

10. The compound according to any one of claims 2-9, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that: Y represents an oxygen atom, and each R... 8 Each is independently selected from hydrogen atoms, C atoms 1-4 Alkylene-OC(=O)-C 1-10 Alkyl and C 1-4 Alkylene-SC(=O)-C 1-10 Alkyl; preferably, R 8 It is a hydrogen atom; DIM is selected from the following groups: Preferred More preferably ; R 9 Selected from hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl and C 3-6 Cycloalkyl, preferably hydrogen.

11. The compound according to any one of claims 1, 2, 4, 6 and 8-10, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that: Ring A is selected from the following groups: ； Preferably, ring A is .

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that: L m Selected from the following groups: ； Preferably, L m Selected from the following groups: ； More preferably, when X and L m When connected, or in the compounds shown in formula (II) or (II-1), L m Selected from the following groups: When X is not with L m When connected, or in compounds represented by formula (III) or (III-1), L m Selected from the following groups: ; More preferably, L m Selected from the following groups: 。 13. The compound according to any one of claims 2-9 and 11-12, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that: Selected from the following groups: ； Preferably, Selected from the following groups: ； More preferably, Selected from the following groups: ； More preferably, Selected from the following groups: ； Most preferably, Selected from the following groups: 。 14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that: R 1a and R 2a Each is independently selected from hydrogen and fluorine, or R 1a and R 2a The groups combine to form a carbonyl group; preferably, R 1a and R 2a It is fluorine; R 3 R 5 R 6 Each is independently selected from hydrogen and C. 1-4 Alkyl; preferably, R 3 R 5 R 6 It is hydrogen.

15. The following compounds or their pharmaceutically acceptable salts, solvates, prodrugs, isotope-labeled derivatives, or isomers: 。 16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof, characterized in that, The pharmaceutically acceptable salts of the compound are acid addition salts or base addition salts; Preferably, the acid addition salt comprises a salt formed by the compound with any one of the acids selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, and malic acid; Preferably, the alkali addition salt includes alkali metal salts, alkaline earth metal salts, and organic alkali salts, and more preferably lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, and N salts. + (C 1-6 Alkyl)4 salts; Preferably, in the alkali addition salt, the compound is in the phosphate anion state.

17. A pharmaceutical composition comprising the compound of any one of claims 1-16 or a pharmaceutically acceptable salt, solvate, prodrug, isotope label, or isomer thereof.

18. A pharmaceutical combination comprising the compound of any one of claims 1-16 or a pharmaceutically acceptable salt, solvate, prodrug, isotope label or isomer thereof, or the pharmaceutical composition of claim 17.

19. The use of the compound of any one of claims 1-16 or a pharmaceutically acceptable salt, solvate, prodrug, isotope label or isomer thereof, or the pharmaceutical composition of claim 17 or the combination of pharmaceuticals of claim 18, in a medicament for the prevention and / or treatment of diseases and / or conditions that are at least partially responsive to STAT6; Preferably, the disease and / or condition is type 2 inflammation; more preferably, the disease and / or condition is type 2 inflammation mediated by Th2 cells and / or type 2 innate lymphoid cells. Preferably, the disease and / or symptom includes: Atopic dermatitis, chronic spontaneous urticaria, nodular prurigo, bullous pemphigoid, chronic sinusitis with or without nasal polyps, allergic rhinitis, asthma, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease, eosinophilic granulomatous polyangiitis, food allergy, and eosinophilic esophagitis.

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