Compounds as STAT6 degrader, composition and application thereof

Abstract

This invention belongs to the field of medical technology, and specifically relates to a compound with STAT6 degrading activities, a pharmaceutical composition containing the same, and applications thereof. The compound has a structure represented by Formula (I), which can degrade STAT6 protein in cells, and can be used for the prevention and / or treatment of diseases and / or disorders that respond to STAT6.

Description

COMPOUNDS AS STAT6 DEGRADER, COMPOSITION AND APPLICATION THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Chinese Patent Applications 202411957446.3, filed on December 27. 2024; and 202511827255.X. filed on December 5, 2025; all of which are hereby incorporated by reference in their entirety.FIELD OF INVENTION

[0002] The present invention is in the pharmaceutical technology field and relates to compounds with STAT6 degradation activities. The present invention also relates to pharmaceutical compositions comprising the disclosed compounds, their method of making, and their applications in therapies targeting the prevention and / or treatment of diseases that respond at least partially to STAT6.BACKGROUND OF THE INVENTION

[0003] The ubiquitin-proteasome pathway (UPP), also referred to as the ubiquitin-proteasome system (UPS), plays a central role in maintaining cellular proteostasis by regulating key signaling proteins and mediating the degradation of misfolded or abnormal proteins. Dysregulation of this system is implicated in a wide range of diseases. The covalent attachment of ubiquitin to specific protein substrates is catalyzed by E3 ubiquitin ligases, which confer substrate specificity within the UPP.

[0004] The UPP enables selective protein degradation and has been exploited through strategies such as ubiquitin-target protein fusion constructs and small-molecule probes to induce proteasome-dependent protein elimination. Bifunctional small molecules, commonly referred to as targeted protein degraders, consist of a ligand that binds the target protein and a second ligand that recruits an E3 ubiquitin ligase. By bringing the target protein into proximity with the E3 ligase, these compounds promote ubiquitination and subsequent proteasomal degradation. Such drug-like molecules provide a powerful means to regulate protein overexpression. When administered to cells, animals, or humans, they can functionally inactivate disease-relevant proteins, serving both as valuable biochemical tools and as a foundation for novel therapeutic paradigms aimed at eliminating pathogenic or oncogenic proteins. See C. M. Crews, Targeting The Undruggable Proteome; The Small Molecules of My Dreams. Chem. Biol. 2010, 17(6): 551-555; J. S. Schneekloth, C. M. Crews, Chemical Approaches to Controlling Intracellular Protein Degradation. ChemBioChem 2005, 6: 40-46.

[0005] In the 1990s. distinct subtypes of T helper (Th) cells were identified, including Th2 cells, which were found to drive B-cell class switching to immunoglobulin E (IgE). This discovery' led to the concept of “Type 2 inflammation.’' Dysregulated Type 2 immune and inflammatory' responses underlie a spectrum of chronic inflammatory diseases, including atopic dermatitis (AD), chronic prurigo (CPG), chronic urticaria (CU), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic gastrointestinal diseases, and allergic rhinitis.

[0006] Signal Transducer and Activator of Transcription 6 (STAT6) is a member of the STAT family, which includes STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. STAT6 plays a critical role in cytokine signal transduction and in mediating the differentiation of Type 2 T helper (Th2) cells. See S. Goenka, M. H. Kaplan, Transcriptional Regulation by STAT6. Immunol. Res. 2011, 50(1): 87-96. STAT6 activation is primarily induced by interleukin-4 (IL-4) and interleukin- 13 (IL-13). Upon binding of IL-4 or IL-13 to the IL-4 receptor a chain (IL-4Ra), receptor-associated Janus kinases (JAKs) or other kinases phosphorylate tyrosine residues within the intracellular domain of IL-4Ra, creating docking sites for STAT6. STAT6 binds to IL-4Ra via its Src homology 2 (SH2) domain and is subsequently phosphorylated. Phosphorylated STAT6 proteins form homodimers through SH2-mediated interactions, translocate from the cytoplasm to the nucleus, and bind to target DNA sequences to regulate gene transcription. See T. Mikita, C. Daniel. P. Wu. U. Schindler, Mutational Analysis of the STAT6 SII2 Domain. J Biol. Chera 1998, 273(28): 17634-42; S. M. McCormick, N. M. Heller, Commentary: IL-4 and IL-13 Receptors and Signaling. Cytokine. 2015, 75(1): 38-50.

[0007] STAT6 is therefore a key therapeutic target in Type 2 inflammatory7diseases. IL-4 and IL- 13 are central mediators of multiple immune disorders and exert their biological effects largely through STAT6 signaling. See T. P. Vogel, et al. The Ying and Yang of STAT3 in Human Disease. J. Clin. Immunol. 2015, 35(7): 615-23. Dupilumab, a monoclonal antibody targeting IL-4Ra that simultaneously inhibits IL-4- and IL-13-mediated signaling, has been approved for the treatment of AD, asthma, CRSwNP, CPG, and eosinophilic esophagitis. Conversely, STAT6 overactivation or overexpression has been associated with severe early-onset atopic disease, eosinophilic gastrointestinal disorders, and recurrent skin and respiratory7tract infections. See K. Chen, et al. STAT6 Joins the Gain-of-Function Club. J. Allergy7Clin. Immunol. 2023,152(1): 53-55.

[0008] Genetic evidence further supports the therapeutic relevance of STAT6. STAT6-deficient (STAT6- / -) mice exhibit markedly reduced expression of Th2 cytokines, including 1L-4, IL-5, and IL-13, and are unable to mount effective Ty7pe 2 immune responses. In multiple disease models, including allergic airway inflammation, food allergy7, eosinophilic esophagitis, and atopic dermatitis, STAT6 deficiency results in significantly attenuated inflammatory7pathology. Importantly, STAT6- / - mice do not display major developmental abnormalities or safety concerns, indicating a favorable safety profile for therapeutic STAT6 inhibition. See S. Goenka, M. H. Kaplan, Transcriptional Regulation by STAT6. Immunol. Res. 2011, 50(1): 87-96.

[0009] These findings suggest that small-molecule degraders that induce targeted STAT6 degradation via E3 ligase recruitment may hold substantial promise for the treatment of Type 2 inflammatory diseases. Despite more than two decades of research, most reported STAT6 inhibitors or degraders exhibit limited selectivity. Additionally, because STAT6-mediated Type 2 inflammatory diseases are chronic and often require long-term treatment, drug safety is a critical consideration. High target selectivity is a key determinant of drug safety, making the development of highly selective STAT6 inhibitors or degraders a major therapeutic challenge.

[0010] For example, Recludix has recently disclosed several STAT3 / STAT6 degraders (See WO2024233639, WO2024238598, and WO2024238603), yet their selectivity between STAT6 and STAT3 has not been reported. This distinction is particularly important because STAT3 plays an essential biological role. Germline deletion of STAT3 in mice results in early embryonic lethality, making STAT3 the only STAT family member whose loss causes embryonic death. See T. P. Vogel, et al. The Ying and Yang of STAT3 in Human Disease. J. Clin. Immunol. 2015, 35(7): 615-23. In humans. STAT3 deficiency leads to hyper-IgE syndrome (See Y. Minegishi, et al. Dominant-Negative Mutations in the DNA-Binding Domain of STAT3 Cause Hyper-IgE Syndrome. Nature. 2007, 448(7157): 1058-62), characterized by eczema-like dermatitis, recurrent skin and pulmonary infections, and elevated IgE levels. These findings underscore the critical importance of STAT3 and highlight the necessity of achieving STAT6-selective degradation. Consequently, the development of STAT6 degraders with strong selectivity over STAT3 is of paramount importance for both therapeutic efficacy and safety. SUMMARY OF THE INVENTION

[0011] The present disclosure provides heterocycles as selective STAT6 degrader, and compositions and applications thereof. As a highly active and selective STAT6 protein degrader, the compound does not induce substantial (or biologically significant) degradation of other STAT family proteins, particularly STAT3, and is suitable for the prevention and / or treatment of diseases and / or disorders that are at least partially mediated by STAT6.

[0012] First Aspect: the present disclosure provides a compound of Formula (I):(I)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:X is (i) NR6a. CHR6a. O, S. S(=O). or S(=O)2, or (ii) N or CR6a, when X is linked to Lm; each n is independently 0, 1, 2, or 3;m is 1, 2, 3, 4, 5, 6, 7, or 8;Ring A is selected from 4-6 membered saturated or partially unsaturated heterocyclyl comprising at least one nitrogen. 5-6 membered heteroaryl comprising at least one nitrogen, 8-10 membered fused heterobicyclyl comprising at least one nitrogen, and 6-12 membered bndged heterobicyclyl comprising at least one nitrogen;Ring B is absent, or selected from 5-6 membered heteroaryl comprising 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, phenyl, saturated or partially unsaturated 5-6 membered heterocyclyl comprising 1-2 heteroatoms each independently selected from oxygen and nitrogen, and saturated or partially unsaturated C3.6 cycloalkyd; when Ring B is absent, (R4)nis H and connects with Ring A directly;Ring C is selected from phenyl, 5-6 membered heteroaryl, naphthyl, and 8-10 membered fused heterobicyclyl comprising 1-3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; each of said pheny l, 5-6 membered heteroaryl, naphthyl, or 8-10 membered fused heterobicyclyl is unsubstituted or substituted with 0, 1, 2, or 3 Rcgroups;R1is selected from -C(RlaR2a)P(=O)(ORb)(ORb), -C(RlaR2a)P(=O)[ORb][NH(CH2)qC(=O)ORT], -C(RlaR2a)P(=O)[NH(CH2)qC(=O)ORT] [NH(CH2)qC(=O)ORT], -C(RlaR2a)P(=O)[NHRT] [NHRT]. -C(RlaR2a)P(=O)[NHCH( CH3)C(=O)ORT][NHCH(CH3)C(=O)ORT], -C(RlaR2a)P(=O)[ORb][NHCH(CH3)C(=O)ORT], -C (RlaR2a)P(=O)[ORb][NHC(CH3)2C(=O)ORT], -P(=O)(ORb)(ORb), -P(=O)[ORb][NH(CH2)qC(=O)ORT], -P(=O)[NH(CH2)qC(=O)ORT][NH(CH2)qC(=O)ORT], -P(=O)[NHRT][NHRT], -P( =O)[NHCH(CH3)C(=O)ORT] [NHCH(CH3)C(=O)ORT], and-P(=O)[ORb] [NHCH(CH3)C(=O)ORT];preferably, R1is selected from -C(RlaR2a)P(=O)(ORb)(ORb),-C(RlaR2a)P(=O)[ORbJ[NH(CH2)qC(=O)ORTJ, -C(RlaR2a)P(=O)lNH(CH2)qC(=O)ORTJLNH(CH2)qC(=O)ORT], -C(RlaR2a)P(=O)[NHRT] [NHRT], -C(RlaR2a)P(=O)[NHCH(CH3)C(=O)ORT] [NH CH(CH3)C(=O)ORT], -C(RlaR2a)P(=O)[ORb][NHCH(CH3)C(=O)ORT], -P(=O)(ORb)(ORb), -P( =O)[ORb][NH(CH2)qC(=O)ORT], -P(=O)[NH(CH2)qC(=O)ORT][NH(CH2)qC(=O)ORT], -P(=0)[ NHRT][NHRT], -P(=O)[NHCH(CH3)C(=O)ORT][NHCH(CH3)C(=O)ORT], and-P(=O)[ORb] [NHCH(CH3)C(=O)ORT];each q is independently 0, 1, 2, or 3;when present, Rlaand R2aare each independently selected from hydrogen, deuterium, halogen, cyano, C alkyl, hydroxyl, and -OCM alkyl, or Rlaand R2atogether with the carbon to which they are attached form a carbonyl group, or Rlaand R2atogether with atoms to which they are attached form a 4-5 membered heterocycle comprising an oxygen atom;when present, each Rbis independently selected from hydrogen, Ci-2o alkyd, phenyl, benzyl, 5-6 membered heteroaryl, naphthyl, C alkylene-0-Ci.2o alkyl, CM alkylene-C(=O)O-Ci-io alkyl. CM alkylene-OC(=0)-Ci-io alkyl, CM alkylene-OC(=O)NH-CM alkylene-C(=O)O-Ci-io alkyl, CM alkylene-OC(=0)0-Ci-io alkyl, CM alkylene-C(=O)O-5-7 membered heterocyclyl, CM alkylene-C(=O)O-phenyl, CM alkylene-OC(=O)-5-7 membered heterocyclyl, CM alkylene-O-5-7 membered heterocyclyl, CM alkylene-OC(=O)O-5-7 membered heterocyclyl. CM alkylene-C(=0)S-Ci-io alkyl, CM alkylene-SC(=0)-Ci-io alkyl, CM alkylene-C(=O)S-5-7 membered heterocyclyl, and CM alkylene-SC(=O)-5-7 membered heterocyclyl; said CM alkyl, C O alkyl, CM alkylene, Ci-2o alkyl, or 5-7 membered heterocyclyl is each unsubstituted or substituted with one or more deuterium, halogen, cyano, Ci-3alky l, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino; alternatively, two Rbgroups together with the atoms to which they are attached form a 5-7 membered saturated heterocycle comprising a phosphorus, said heterocycle is unsubstituted or substituted with one or more deuterium, halogen, cyano, Ci-3alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino, and said phenyl is unsubstituted or substituted with one or more halogen;preferably, when present, each Rbis independently selected from hydrogen, CMO alkyl, phenyl, benzy l, 5-6 membered heteroaryl, naphthyl, CM alkylene-0-Ci.2o alkyl, CM alkylene-C(=0)0-C O alkyl, CM alkylene-OC(=0)-Ci-io alkyl, CM alkydene-OC(=O)NH-Ci.4alkylene-C(=0)0-Ci.io alkyl, CM alkylene-OC(=0)0-Ci-io alkyl, CM alkylene-C(=O)O-5-7 membered heterocyclyl, CM alkylene-C(=O)O-phenyl, CM alkylene-OC(=O)-5-7 membered heterocyclyl, CM alkylene-O-5-7 membered heterocyclyl, CM alkylene-OC(=O)O-5-7 membered heterocyclyl, CM alkylene-C(=0)S-Ci-io alkyl, CM alkylene-SC(=0)-Ci-io alkyl, CM alkylene-C(=O)S-5-7 membered heterocyclyl, and C1.4 alkylene-SC(=O)-5-7 membered heterocyclyl; said Ci-4 alkyl, CMO alkyl, C1-4 alkylene, C1.20 alkyl, or 5-7 membered heterocyclyl is each unsubstituted or substituted with one or more deuterium, halogen, cyano, C1-3 alky l, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino; alternatively, two Rbgroups together with the atoms to which they are attached form a 5-7 membered saturated heterocycle comprising a phosphorus;when present, each RTis independently selected from CMO alky l, benzyd, and phenyl; said CMO alky l, benzyl, or pheny l is each unsubstituted or substituted with one or more deuterium, halogen, cyano, C1.3 alkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino; alternatively, two RTtogether with the atoms to which they are attached form a 5-7 membered saturated heterocycle comprising a phosphorus;alternatively, Rband RTtogether with the atoms to which they are attached form a 5-7 membered saturated heterocycle comprising the phosphorus in R1;when present, each Rcis independently selected from hydrogen, deuterium, halogen, cyano, C1.4 alkyl, C1.4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino;R2is selected from hydrogen, phenyl, and C1.4 alkyl;when present, each R3is independently selected from hydrogen, deuterium, halogen, cyano, C1.4 alkyl, C1.4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; alternatively, two R3groups substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl or heterocycle;when present, each R4is independently selected from hydrogen, deuterium, halogen, cyano, CMO alkyd, C O haloalky l, isopropyl, cyclopropyl, 4-6 membered heterocyclyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, dimethy lamino, Cg-n spiroalkyl, C5.8 bridged alkyl, 5-12 membered spiroheterobicyclyl, 6-10 membered bridged heterobicyclyl, and 8-10 membered fused heterobicyclyl; said CMO alkyl, 4-6 membered heterocycly l, Ce-n spiroalkyl, C5.8 bridged alkyl, 5-12 membered spiroheterobicyclyl, 6-10 membered bridged heterobicycly l, or 8-10 membered fused heterobicycly l is each unsubstituted or substituted with one or more deuterium, halogen, cyano, hydroxy l, methoxy, methylamino, dimethyl amino, C5-8 bridged alkyl, phenyl, or 5-6 membered heteroaryl; alternatively, two R4groups substituted on the same carbon atom together with the carbon atom to which they7are attached form a 3-5 membered cycloalkyl or heterocycle; alternatively, two R4groups substituted on the same carbon atom are combined to form an oxo (=0) group;when present, each R5is independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, C1.4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; alternatively, two R5groups substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl or heterocycle;when present, each R6is independently selected from hydrogen, deuterium, halogen, cyano, C1.4 alkyl, C1.4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; alternatively, two R6groups substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl or heterocycle; alternatively, two R6groups located on adjacent or non-adjacent carbon atoms together with the carbon atoms to which they are attached form a C3.6 cycloalkane or 3-6 membered saturated heterocycle;when present, R6ais selected from hydrogen, deuterium, halogen, cyano, C1.4 alkyl, C haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino;Lmis a linking moiety of m identical, partially identical, or different L groups; one end of Lmis linked to DIM via a covalent bond, and another end of Lmis linked to any ring atom other than the bridged nitrogen in the 5-8 fused ring skeleton structure via another covalent bond; each L is independently selected from:(1) C3.12 cycloalkylene substituted with 0-3 Rlfgroups;(2) Cg-io arylene substituted with 0-3 R groups;(3) 4-12 membered heterocyclylene substituted with 0-3 R 1f groups;(4) 8-10 membered fused heterobi cyclylene substituted with 0-3 R groups;(5) 5-12 membered heteroarylene substituted with 0-3 R11groups;(6) C1.12 alky lene substituted with 0-3 R groups;(7) C2-12 alkenylene substituted with 0-3 R groups;(8) C2-12 alkynylene substituted with 0-3 R groups;(9) 1-6 ethylene glycol or propylene glycol units; and(10) -C(=O)-, -C(=O)O-, -O-, -N(R3f)-, -S-, -S(=O)-, -C(=S)-, -C(=S)O-, -S(=O)2-, -S(=O)N(R?f)-, -S(=O)2N(R3f)-, -C(=O)-N(R3f)-, -N(R3f)C(=O)-N(R3f)-, and -OC(=O)-N(R3f)-;when present, each Rlfis independently selected from hydrogen, deuterium, halogen, cyano, Ci.g alkyl, C cycloalkyl, Cg-io and, 5-12 membered heteroaryl, -OR3f, -C(=O)R3f, -C(=O)OR3f, -C(=O)N(R3f)2, -N(R3f)2, -N(R3f)C(=O)R3f, -N(R3f)C(=O)OR3f, -N(R3f)C(=O)N(R3f)2, -OC(=O)R3f, -OC(=O)N(R3f)2, -SR3f, -S(=O)R3f, -S(=O)2R3f, and - S(=O)2N(R 3f )2; said Ci-g alkyl, C3.6 cycloalkyl, Cg -io aryl, or 5-12 membered heteroaryl is eachunsubstituted or substituted with 0-3 R3fgroups; alternatively, any two Rlfgroups together with the carbon atoms to which they are attached form a bridged ring; alternatively, two R11groups on the same carbon atom together with the carbon atom to which they are attached form a cycloalkyl or heterocycle;when present, each R2fis independently selected from hydrogen, Ci.6alkyl, and C3.6cycloal kyl;when present, each R 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 ligase;preferably, DIM is selected from small-molecule affinity ligands for CRBN, VHL, cIAP, MDM2, RNF4, AhR, DCAF16, RNF114, FEM1B, KEAP1, and DCAF15.

[0013] In some embodiments, the compound is of Formula (I’):(Dor a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring A is a 4-6 membered saturated or partially unsaturated heterocyclyl comprising at least one nitrogen atom;Ring C is selected from naphthyl and 8-10 membered fused heterobi cyclyl comprising 1-3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; said naphthyl or 8-10 membered fused heterobicyclyl is each unsubstituted or substituted with 0, 1, 2, or 3 Rcgroups;preferably. Ring C is selected from the following moieties:R7is selected from hydrogen, Cuo alkyl, 4-6 membered heterocyclyl, Ce-n spiroalkyl, C5.8 bridged alkyl, 5-12 membered spiroheterobicyclyl, 6-10 membered bridged heterobicyclyl, and 8-10 membered fused heterobicyclyl; said Cno alkyl. C4.6 heterocyclyl, Ce-n spiroalkyl, C5.8 bridged alkyl, 5-12 membered spiroheterobicyclyl, 6-10 membered bridged heterobicyclyl, or 8-10 membered fused heterobicyclyl is each unsubstituted or substituted with one or more deuterium, halogen, cyano, hydroxyl, methoxy, methylamino, dimethylamino, C5.8 bridged alky l, or 5-6 membered heteroaryl;Rlaand R2aare each independently selected from hydrogen, fluorine, and cyano, or Rlaand R2aare combined to form an oxo (=0) group;each Y is independently selected from -O- or -NH-; wherein (i) when Y is -O-, R8attached to Y is Rb; (ii) when Y is -NH-, R8attached to Y is RT, -(CH2)qC(=O)ORT, or -CH(CH3)C(=O)ORT:DIM is selected from small-molecule affinity ligands for CRBN, VHL, and cIAP; preferably, DIM is selected from the following moieties:R9is selected from hydrogen, deuterium, halogen, cyano, Ci-6 alkyl, and C3.6 cycloalkyl; X is (i) NR6aand CHR6a; or (ii) N or CR6a. when X is linked to Lm; andn, q, R3, R4, R5, R6, R6a, Rc, Rb, RT, and Lmare as defined above when describing Formula (I).

[0014] In some embodiments, the compound is of Formula (F-l):(F-l)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring C, Y, R8, R7, Lm, DIM, and X are as defined above when describing Formula (F).

[0015] In some embodiments, the compound is of Formula (II):O^'Y^RSR®(II)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring A, Ring C, Rla, R2a, Y, R8, R7, n, R3, R4, R5, R6, Lm, and DIM are as defined above when describing Formula (I’).

[0016] In some embodiments, the compound is of Formula (II-l):(IM)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring C. Y, R8, R7, Lm, and DIM are as defined above when describing Formula (II).

[0017] In some embodiments, the compound is of Formula (III):or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring A, Ring C, Rla, R2a. Y, R8, R7, n, R3, R4, R5, R6, Lm, DIM, and X are as defined above when describing Formula (I’).

[0018] In some embodiments, the compound is of Formula (III- 1 ):(III-l)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring C, Y, R8, R7, Lm, DIM, and X are as defined above when describing Formula (III); preferably, X is CHR6a, and R6ais H.

[0019] In some embodiments, the compound is of Formula (IV-1):(IV-1)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Gi is O, NR22, or CR23R23;R20is hydrogen, fluoro or chloro;R21is hydrogen or C1.4 alkyl, preferably hydrogen;R22is hydrogen, C1-4alkyl, deuterated C1-4alkyl, or C3-6cycloalkyl, wherein the C1-4alkyl and C3-6cycloalkyl is unsubstituted or substituted with one or more substituents selected from fluoro, hydroxy, C1-4alkoxy, and C3-6cycloalkyl;each R23is independently hydrogen or C1-4alkyl, or both instances of R23together with the atoms to which they are attached form a 3-5 membered ring which may be optionally substituted with one or more substituents selected from fluoro, hydroxy, and C1-4alkyl;Y, R7, R8, and Lmare as defined above when describing Formula (II).

[0020] In some embodiments, the compound is of Formula (IV-2):(IV-2)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:G2is C(=O), or CR23R23;R20is hydrogen, fluoro or chloro;each R23is independently hydrogen or CM alkyl, or both instances of R23together with the atoms to which they are attached form a 3-5 membered ring which may be optionally substituted with one or more substituents selected from fluoro, hydroxy, and CM alkyl;Y, R7, R8, and Lmare as defined above when describing Formula (II).

[0021] in Formula (IV-2) is pomalidomide, thalidomide, lenalidomide, or analogs thereof.

[0022] In some embodiments, the compound of any one of Formulas (I’), (I’-l), (II). (II-l), (III), (III- 1), (IV-1), and (IV-2) described above, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:R7is selected from hydrogen and C1-10alkyl; the C1-10alkyl is unsubstituted or substituted with one or more deuteriums;preferably, R7is selected from hydrogen and C1-4alkyl; the C1-4alkyl is unsubstituted or substituted with one or more deuteriums;more preferably, R7is C1-4alkyl; the C1-4alkyl is unsubstituted or substituted with one or more deuteriums.

[0023] In some embodiments, R7is selected from hydrogen and CMO alkyl, preferably CMO alkyl; wherein said CMO alkyl is optionally substituted with one or more deuterium atoms; for example, said C1-10alkyl may be substituted with one, two or three deuterium atoms, or all hydrogen atoms of said C1-10alkyl are substituted with deuterium atoms.

[0024] In some embodiments, R7is selected from hydrogen and C1.4 alkyl, preferably C1.4 alkyl; wherein said C1.4 alkyl is optionally substituted with one or more deuterium atoms; for example, said C1-4alkyl may be substituted with one, two or three deuterium atoms, or all hydrogen atoms of said C1-4alkyl are substituted with deuterium atoms.

[0025] In some embodiments, the compound of any one of Formulas (I'), (I’-l), (II). (II-l), (III), and (III-l) described above, including those with the described R7elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:each Y is independently selected from O or NH; when Y is O, R8attached to Y is Rb, and each Rbis independently selected from hydrogen, C1-4alkylene-OC(=O)-C1-10alkyl and C1-4alkylene-SC(=O)-C1-10alkyl; when Y is NH, each R8attached to Y is independently RT, -(CH2)qC(=O)ORTor -CH(CH3)C(=O)ORT, wherein RTis selected from C1-10alkyl, and q is selected from 0, 1, 2 and 3; oreach Y is independently selected from O or NH; when Y is O, R8attached to Y is Rb, and each Rbis independently selected from hydrogen, C1-4alkylene-OC(=O)-C1-4alkyl and C1-4alkylene-SC(=O)-C1-4alkyl; when Y is NH, each R8attached to Y is independently RT, -(CH2)qC(=O)ORTor -CH(CH3)C(=O)ORT, wherein RTis selected from C1-4alkyl, and q is selected from 0, 1, 2 and 3; orY is an oxygen atom, and each R8is independently selected from hydrogen, C1-4alkylene-OC(=O)-C1-10alkyl and C1-4alkylene-SC(=O)-C1-10alkyl; orY is an oxygen atom, and each R8is independently selected from hydrogen, C1-4alkylene-OC(=O)-C1-4alkyl and C1-4alkylene-SC(=O)-C1-4alkyl; orY is NH, and each R8is independently RT. -(CH2)qC(=O)ORTor -CH(CH3)C(=O)ORT. wherein RTis selected from CMO alkyl, and q is selected from 0, 1, 2 and 3; orY is NH, and each R8is independently RT, -(CH2)qC(=O)ORTor -CH(CH3)C(=O)ORT, wherein RTis selected from C1-4alkyl, and q is selected from 0, 1, 2 and 3.

[0026] In some embodiments, Y is an oxygen atom and R8is a hydrogen atom.

[0027] In some embodiments, the compound of any one of Formulas (1), (F). (I’-l), (11), (II- 1), (III), and (III-l) described above, including those with the described R7and / or Y elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:wherein * indicates a covalent bond with R1, -C(R1a)(R1b)-, or –CF2–; andRcis as defined above when describing Formula (I), preferably hydrogen.

[0028] In some embodiments, the compound of any one of Formulas (F), (I’-l), (II), (II- 1), (III), and (III-l) described above, including those with the described R7, Y, and / or Ring C elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Y is an oxygen atom, and each R8is independently selected from hydrogen, C1-4 alkylene-OC(=O)-C1-10 alkyl, and C1-4 alkylene-SC(=O)-C1-10 alkyl: preferably, R8is hydrogen;DIM is selected from the following groups: / o opreferably, DIM is O or Omore preferably, DIM isR9is selected from hydrogen, deuterium, halogen, cyano, Ci-6 alkyl, and C3.6 cycloalkyl, preferably, R9is hydrogen and Ci-6 alkyl,more preferably, R9is hydrogen.

[0029] In some embodiments, DIM is selected from the following groups:wherein R9is selected from hydrogen, deuterium, halogen, cyano, Ci-6 alkyl and C3.6 cycloalkyl.

[0030] In some embodiments, DIM is O or O,wherein R9is selected from hydrogen, deuterium, halogen, cyano, Ci-6 alkyl and C3.6 cycloalkyl, preferably hydrogen and Ci-6 alkyl, and more preferably hydrogen.

[0031] In some embodiments, DIM is Owherein R9is selected from hydrogen, deuterium, halogen, cyano, Ci-6 alkyl and C3.6 cycloalkyl, preferably hydrogen and Ci-6 alkyl, and more preferably hydrogen.

[0032] In some embodiments, DIM is pomalidomide, thalidomide, lenalidomide, VHL-1, VH032, adamantane, l-((4,4,5,5,5-pentafluoropentyl)sulfmyl)nonane, nutlin-3a, RG7112, RG7338. AMG232, AA-115, bestatin. MV-1, LCL161, CPD36, GDC-0152, CRBN-1. CRBN-2. CRBN-3, CRBN-4, CRBN-5, CRBN-6, CRBN-7, CRBN-8, CRBN-9, CRBN-10, or CRBN-11, or analogs thereof.

[0033] In some embodiments, the compound of any one of Formulas (I), (I’), and (I’-l), described above, including those with the described R7, Ring C, Y, DIM, and / or R9elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:X is N and is linked to Lm.

[0034] In some embodiments, the compound of any one of Formulas (I), (I’), and (I'-l), described above, including those with the described R7. Ring C, Y, DIM. and / or R9elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:X is CHR6aand is not linked to Lm, wherein R6ais selected from hydrogen and C1.4 alkyl, preferably hydrogen.

[0035] In some embodiments, the compound of any one of Formulas (I), (F), (II), and (III), described above, including those with the described R7, Ring C, Y, DIM, R9, and / or X elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring A is selected from the following groups:J^ N-j XTNH JONH, andpreferably, Ring A is:

[0036] In some embodiments, Ring A is:

[0037] In some embodiments, the compound of any one of Formulas (I), (I’). (I’-l), (II), (II- 1), (III), (III- 1 ), (IV- 1), and (IV-2), described above, including those with the described R7, RingC, Y, DIM. R9. and / or Ring A elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Lmis selected from the following groups:,o pcovalent bond wi th DIM;preferably, Lmis selected from the following groups:more preferably, (i) when X is linked to Lm, or in the compound represented by Formula (II) or Formula (II- 1 ), Lmis selected from the following groups:(ii) when X is not linked to Lm, or in the compound represented by Formula (III) or Formula (III-l ), Lmis selected from the following groups:further preferably, Lmis selected from the follow ing groups:o

[0038] In some embodiments, Lmis selected from the following groups:DIM.

[0039] In some embodiments, Lmis selected from the following groups:,0wherein & indicates a covalent bond with DIM.

[0040] In some embodiments, when X is linked to Lm, or in the compounds represented by Formula (II) or Formula (II- 1 ) or Formula (IV-1) or Formula (IV -2), Lmis selected from thefollowing groups:0 and&, wherein & indicates a covalent bond with DIM.

[0041] In some embodiments, when X is not linked to Lm, or in the compounds represented by Formula (III) or Formula (I1I-1 ), Lmis selected from the following groups:0, wherein & indicates a covalent bond with DIM.

[0042] In some embodiments, Lmis selected from the following groups:pand i, wherein & indicates a covalent bond with DIM.

[0043] In some embodiments, each L in Lmis independently -C(=O)-, -O-, -NRL-. C₁₋₁₀ alkylene, –CH₂OCH₂–, 3-8 membered cycloalkylene, 3-8 membered heterocyclylene, 6-10 membered arylene, or 5-12 membered heteroarylene, where R^L is independently hydrogen or C₁₋₈ alkylene, each of C₁₋₁₀ alkylene, 3-8 membered cycloalkylene, 3-8 membered heterocyclylene, 6-10 membered arylene, and 5-12 membered heteroarylene is optionally substituted with one or more substituents selected from fluoro, hydroxy, C₁₋₄ alkoxy, and C₁₋₄ alkyl.

[0044] In some embodiments, the first L in Lmthat connects with DIM is -C(=O)-, -O-, Ci.4alkylene, –CH₂OCH₂–, phenyl, [image], –NH–,wherein & indicates a covalent bond with DIM.

[0045] In some embodiments, Lmis -L1-L2-L3-L4-L5-, wherein:L₁ is –C(=O)–, –CH₂C(=O)–, –C(=O)CH₂–, –C(=O)–C₁₋₁₀ alkylene–C(=O)–, –C(=O)–C₄₋₈ cycloalkylene–C(=O)–, –O–, –NR^L–, C₁₋₁₀ alkylene, C₃₋₈ cycloalkylene, 4-12 membered heterocyclylene, C₆₋₁₀ arylene, or 5-12 membered heteroarylene, wherein each of C₁₋₁₀ alkylene, C₄₋₈ cycloalkylene, C₃₋₈ cycloalkylene, 4-12 membered heterocyclylene, C₆₋₁₀ arylene, and 5-12 membered heteroarylene is optionally substituted with one or more substituents selected from fluoro, hydroxy, C₁₋₄ alkoxy, and C₁₋₄ alkyl;L₂ is absent, C₁₋₁₀ alkylene, –NR^M–, C₆₋₁₀ arylene, or 5-12 membered heteroarylene, wherein each of C₁₋₁₀ alkylene, C₆₋₁₀ arylene, and 5-12 membered heteroarylene is optionally substituted with one or more substituents selected from fluoro, hydroxy, C₁₋₄ alkoxy, and C₁₋₄ alkyl;L₃ is –C(=O)–, C₁₋₁₀ alkylene, C₃₋₈ cycloalkylene, C₁₋₁₀ heteroalkylene, 4-12 membered heterocyclylene, 5-12 membered heteroarylene, or –(CH₂OCH₂)_w–, wherein w is an integer of 1-10, wherein each of C₁₋₁₀ alkylene, C₃₋₈ cycloalkylene, C₁₋₁₀ heteroalkylene, 4-12 membered heterocyclylene, and 5-12 membered heteroarylene is optionally substituted with one or more substituents selected from fluoro, hydroxy, C₁₋₄ alkoxy, and C₁₋₄ alkyl;L₄ is absent, C₃₋₈ cycloalkylene, 4-12 membered heterocyclylene, C₆₋₁₀ arylene, 5-12 membered heteroarylene, or C₂₋₈ alkenylene, wherein each of C₃₋₈ cycloalkylene, 4-12 membered heterocyclylene, C₆₋₁₀ arylene, 5-12 membered heteroarylene, or C₂₋₈ alkenylene is optionally substituted with one or more substituents selected from fluoro, hydroxy, C₁₋₄ alkoxy, and C₁₋₄ alkyl;L₅ is –C(=O)–, –O–, –NR^R–, –CH₂OCH₂–, C₁₋₁₀ alkylene, C₂₋₈ alkynylene, 3-12 membered heterocyclylene, or C₆₋₁₀ arylene, wherein each of C₁₋₁₀ alkylene, C₂₋₈ alkynylene, 3-12 membered heterocyclylene, and C₆₋₁₀ arylene is optionally substituted with one or more substituents selected from fluoro, hydroxy, C₁₋₄ alkoxy, and C₁₋₄ alkyl, and L₅ is connected with DIM; andeach R^L, R^M, R^R is independently hydrogen or C₁₋₈ alkylene.

[0046] In some embodiments, L₅ in –L₁–L₂–L₃–L₄–L₅– described above is –C(=O)–, –O–, C₁₋₄ alkylene, –CH₂OCH₂–, phenyl, [image of C≡C structure], –NH–,. or ' &, wherein & indicates a covalent bond with DIM.

[0047] In some embodiments, the compound of any one of Formulas (I'), (I’-l), (II). (II-l), (III), (III- 1), (IV- 1), and (IV-2) described above, including those with the described R7, Ring C, Y, DIM, R9, Ring A, and / or Lmelements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:O^Y^RSr8is selected from the following groups:O°\Y^R8most preferably,r8is selected from the following groups:Y-R«

[0048] In some embodiments,r8is selected from the following groups:oP-°H0' OHO'^'Y-R8

[0051] In some embodiments,Ris selected from the following groups:

[0052] In some embodiments.is selected from the following groups:

[0053] In some embodiments, the compound of any one of Formulas (I’), (I’-l), (II), (II-l), (III), (III- 1), (IV- 1), and (IV-2) described above, including those with the described R7, Ring C, Y, DIM, R9, Ring A, and / or Lmelements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:<4'Y-R8 " TZ O' | ho HRis a prodrug of OHO' l OH

[0054] In some embodiments, the prodrug of OH isaphosphonate or phosphonic acid monoester prodrug.

[0055] As used herein, the term “phosphonate or phosphonic acid monoester prodrug" refers to compounds that break down chemically or enzy matically to a phosphonic acid in vivo. As employed herein the term includes, but is not limited to, the following groups and combinations of these groups:

[0056] (1) Acyloxyalkyl esters, including those having a cyclic alkyl ring. These esters can generate phosphorus-containing nucleotides inside cells through a postulated sequence of reactions beginning with deesterification and followed by a series of elimination reactions. See, Farquhar et al., J. Pharm. Sci., 72: 324-325 (1983), which is incorporated by reference in its entirety.

[0057] (2) Another class includes the esters known as alkyloxy carbonyloxymethyl esters or the like, as shown in (1) Formula (Pl) (see, Nishimura et al., J. Antibiotics, 40(1): 81-90 (1987); Ferres, H., Drugs of Today, 19: 499 (1983); Shaw et al., Pharm Res. 14(12): 1824-9 (1997)), (2) Formula (P2) (see W01990008155) and (3) Formula (P3) (see W01990010636), all of which are incorporated by reference in their entireties. For example,o RJ RJ O4 (pi)wherein Rnis alkoxy, aryloxy, alkylthio, arylthio, alkylamino, or arylamino; and each RJis independently hydrogen, alkyl, aryl, alkylaryl, or heterocyclyl;O R-L RJ OR AHO X O I jyRK(P2)wherein RHis hydrogen, alkyl, aryl, alkylaryl, alicyclic, or -NRLRM; each RLand RMis independently hydrogen or CMO alkyl; each RJis independently hydrogen or C1.3 alkyl; and RKis -OH, -O-CH3, or a monoester prodrug moiety;RK-M'Hc> O=p— Io / —dRHy — 'o}=oRH(P3)wherein R^H is alkyl, aryl, or alkylaryl; M^H is alkylene, –O–, –NR^L–, –NH=NH–, –NH–O–, or –O–NH–; R^L is hydrogen or C₁₋₁₀ alkyl; and R^K is hydrogen, alkyl, aryl, chloroalkyl, nitro, amine, benzyloxycarbonyl or t-butoxycarbonyl,

[0058] (3) Acyloxyalkyl esters comprising a cycloalkyl ring as shown in Formula (P4) and Formula (P5). See, Freed et al., Biochem. Pharm., 38: 3193-3198 (1989), which is incorporated by reference in its entirety. For example,¥vo ' (P4)wherein RHis hydrogen, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, or cycloalkyl;wherein each RHis independently hydrogen, alkyl, aryl, alkylaryl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, or cycloalkyl.

[0059] (4) Aryl esters comprising phenyl or mono and poly -substituted phenyl as show n in Formula (P6) and Formula (P7). See DeLambert et al., J. Med. Chem. 37(7): 498-511 (1994); Serafinowska et al., J. Med. Chem. 38(8): 1372-9 (1995), all of which are incorporated by reference in their entireties. For example,wherein RHis independently one or more hydrogen, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, or heterocyclyl;RhO II O I 7RK / (P7)wherein RHis independently one or more hydrogen, alkyl, aryl, alkylaryl, alkoxy, acyloxy, halogen, amino, alkoxycarbonyl, hydroxy, cyano, or heterocyclyl; and RKis hydrogen, -OH, -CH3, -OCH3 or a monoester prodrug moiety.

[0060] (5) Benzyl esters (Formula (P8) and Formula (P9)), including benzyl esters with 4-acyloxy or 4-alkyloxy groups which may generate 4-hydroxy benzyl compounds, can be digested by enzymes, e.g., oxidases or esterases, to generate the parent phosphonic acid. See Mitchell et al., J. Chem. Soc. Perkin Trans. I 2345 (1992); WO1991019721, all of which are incorporated by reference in its entireties. For example,wherein each RHand RPis independently hy drogen, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hydroxy, cyano, nitro, perhaloalkyl, halo, or alkydoxycarbonyl; and each RJis independently hydrogen, alkyl, aryl, alkylaryl, halogen, or cycloalkyl;wherein each RHand Rpis independently hydrogen, alkyl, aryl, alkylaryl, alkoxy, acyloxy, hy droxy’, cyano, nitro, perhaloalkyl, halo, or alkyloxycarbonyl; each RJis independently hydrogen, alkyl, aryl, alkylaryl, halogen, or cycloalkyl; and RKis independently hydrogen, -OH, -CH3, -OCH3or a monoester prodrug moiety’.

[0061] (6) Thio-containing phosphonate ester prodrug comprising a protected thioethyl moiety as shown in Formula (P10), Formula (Pl 1), and Formula (P12). The de-esterification of the phosphonate ester prodrug may require the generation of a free thiolate, and a variety of thiol protecting groups may be used in this case. For example, the disulfide can be reduced by a reductase-mediated process. See, Puech et al., Antiviral Res. 22: 155-174 (1993), which isincorporated by reference in its entirety. Thioesters can also generate free thiolates after esterase-mediated hydrolysis. See Benzaria, et al., J. Med. Chem., 39(25): 4958-65 (1996), which is incorporated by reference in its entirety. For example,■of'2wherein RHis independently alkylcarbonyl, alkoxycarbonyl, arylcarbonyl,aryloxycarbonyl, or alkylthio.swherein RHis alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, or alkylthio; and RKis independently hydrogen, -OH, -CH3, -OCH3 or a monoester prodrug moiety.(P12)

[0062] (7) HepDirect phosphonate prodrugs. See Erion et al., Curr. Opin. Investig. Drugs. 7(2): 109-17 (2006), which is incorporated by reference in its entirety. Preferably, a HepDirect phosphonate prodrugs as shown in Formula (P13). For example:wherein each RHis independently halogen, nitro, hydroxyl, amino, cyano, C1-C6alkyl, C3-C8cycloalkyl, C1-C6alkoxy, C3-C6alkylamino, C1-C6alkyl-OC(=O)-, C1-C6alkyl-C(=O)O- C2-C6alkyl-C(=O)-, or C2-C6alkyl-NHC(=O)-, wherein each of C1-C6alkyl, C2-C6alkyl, C3-C8cycloalkyl, C1-C6alkoxy, and C3-C6alkylamino is optionally substituted with one or more substituents selected from fluoro, hydroxy, C1-4alkoxy, and C1-4alkyl; andp is 0, 1, 2, 3, 4, or 5.

[0063] (8) Aryl phosphonamidate prodrugs. This strategy comprises a phosphorus atom having a phosphonamide bond derived from a nitrogen-linked amino acid ester and a phosphonate ester bond derived from an aryl alcohol, as shown in Formula (P14). For example,^P.N IR1wherein RHis C2-6alkyl; RJis hydrogen or methyl; and RKis phenyl, 1-naphthyl, or 2-naphthyl, each of phenyl, 1-naphthyl, and 2-naphthyl is optionally substituted with one or more substituents selected from fluoro, hydroxy, C1.4 alkoxy, and C1.4 alkyl.

[0064] (9) Phosphonodiamidate prodrugs. This strategy comprises a phosphorus atom having two phosphonamide bonds derived from nitrogen-linked amino acid esters, as shown in Formula (P15).wherein RHis C2-6alkyl, phenyl, or benzyl; and RJis hydrogen or methyl.

[0065] In some embodiments, the compound of any one of Formulas (I), (I’), (II), and (III) described above, including those with the described R7, Ring C, Y, DIM, R9, Ring A, Lm, and / orr8elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:R1aand R2aare each independently selected from hydrogen and fluorine, or R1aand R2aare combined to form an oxo (=O) group;preferably, both R1aand R2aare fluorine;R3, R\ and R6are each independently selected from hydrogen and C1.4 alkyl; preferably, R’. R5, and R6are hydrogen.

[0066] In some embodiments, the compound of any one of Formulas (I), (I’), (I’-l), (II), (II- 1), (III), (III-l), (IV- 1), and (IV-2) described above, including those with the described R7, RingC, Y, DIM, R9, Ring A, Lm,r8, Rla. R2a, R3, R5, and / or R6elements, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:the pharmaceutically acceptable salt of the compound is an acid addition salt or a base addition salt;preferably, the acid addition salt comprises a salt formed by the compound and any one acid 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 base addition salt comprises alkali metal salts, alkaline earth metal salts, and organic base salts, preferably lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, and N+(C1-8alkyl)4salts;preferably, in the base addition salt, the compound is in a phosphate anion state.

[0067] Second Aspect: the present disclosure provides a compound selected from the group consisting of:or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof.

[0068] In some embodiments, the compound according to First Aspect or Second Aspect, including any one of the hitherto described embodiments thereof, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, or isomer thereof, wherein the pharmaceutically acceptable salt of the compound is an acid addition salt or a base addition salt;preferably, the acid addition salt comprises a salt formed by the compound and any one acid 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 base addition salt comprises alkali metal salts, alkaline earth metal salts, and organic base salts, preferably lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, and N+(C1-6alkyl)4salts;preferably, in the base addition salt, the compound is in a phosphate anion state.

[0069] Third Aspect: the present disclosure provides a pharmaceutical composition comprising the compound according to First Aspect or Second Aspect, including any one of the hitherto described embodiments thereof, or a pharmaceutically acceptable salt, ester, solvate, prodrug, isotope-labeled derivative, or isomer thereof.

[0070] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0071] Fourth Aspect: the present disclosure provides a pharmaceutical preparation comprising the compound according to First Aspect or Second Aspect, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled compound, or isomer thereof, or the pharmaceutical composition according to Third Aspect, wherein the pharmaceutical preparation is any one of tablets, capsules, injections, granules, powders, suppositories, pills, gels, dusting powders, oral solutions, inhalants, suspensions, or dry suspensions.

[0072] Fifth Aspect: the present disclosure provides a pharmaceutical combination comprising (i) the compound according to First Aspect or Second Aspect, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled compound, or isomer thereof, or the pharmaceutical composition according to Third Aspect, or the pharmaceutical preparation according to Fourth Aspect; and (ii) an additional therapeutic agent.

[0073] Sixth Aspect: the present disclosure provides a use of the compound according to First Aspect or Second Aspect, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled compound, or isomer thereof, or the pharmaceutical composition according to Third Aspect, or the pharmaceutical preparation according to Fourth Aspect, or the pharmaceutical combination according to Fifth Aspect in the preparation of a medicament for preventing and / or treating diseases and / or disorders that are at least partially responsive to STAT6.

[0074] Seventh Aspect: the present disclosure provides the compound according to First Aspect or Second Aspect, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled compound, or isomer thereof, or the pharmaceutical composition according to Third Aspect, or the pharmaceutical preparation according to Fourth Aspect, or the pharmaceutical combination according to Fifth Aspect, for use in preventing and / or treating diseases and / or disorders that are at least partially responsive to STAT6.

[0075] Eighth Aspect: the present disclosure provides a method for preventing and / or treating diseases and / or disorders that are at least partially responsive to STAT6, comprising administering a prophylactically and / or therapeutically effective amount of the compound according to First Aspect or Second Aspect, or a pharmaceutically acceptable salt, solvate,prodrug, isotopically labeled compound, or isomer thereof, or the pharmaceutical composition according to Third Aspect, or the pharmaceutical preparation according to Fourth Aspect, or the pharmaceutical combination form according to Fifth Aspect to a subject in need thereof.

[0076] In some embodiments for Sixth Aspect, Seventh Aspect, or Eighth Aspect, the disease and / or disorder is type 2 inflammation. In some embodiments, the type 2 inflammation is mainly mediated by Th2 cells, group 2 innate lymphoid cells, or related cytokines, or a combination thereof. In some embodiments, the type 2 inflammation is mediated by Th2 cells and / or group 2 innate lymphoid cells. In some embodiments, the disease and / or disorder is atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, bullous pemphigoid, chronic rhinosinusitis with or without nasal polyps, allergic rhinitis, asthma, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, food allergy', or eosinophilic esophagitis.

[0077] In some embodiments for Sixth Aspect, Seventh Aspect, or Eighth Aspect, the disease and / or disorder is responsive to modulation of STAT-6. In some embodiments, the disease and / or disorder is an autoimmune disease. In some embodiments, the disease and / or disorder is Th2 -mediated inflammation. In some embodiments, the Th2-mediated inflammation is atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, urticaria, rhinitis, eosinophilic esophagitis, food allergy, diffuse cutaneous systemic sclerosis, alopecia areata and / or COPD (chronic obstructive pulmonary disease). In some embodiments, the disease and / or disorder is lymphomas, triple negative breast cancer and solid fibrous cancers. In some embodiments, the disease and / or disorder is breast cancer, colorectal cancer, lung cancer, prostate cancer, liver cancer, hematological malignancies, T-cell lymphoma, primary mediastinal large B-cell lymphoma, Hodgkin ly mphoma, acute leukemia and chronic myeloid leukemia, solitary fibrous tumor, solid tumors. When treating cancer, the compounds disclosed herein can be administered either as a stand-alone treatment or in combination with other anti cancer drugs such as check point inhibitors. In some embodiments, the disease and / or disorder is mediated by a signal transducer and activator of transcription 6 (STAT6) protein activity in a subject. In some embodiments, the disease and / or disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), lupus nephritis (LN), osteoarthritis (OA), ulcerative colitis (UC), Crohn's disease (CD), idiopathic pulmonary7fibrosis (IPF), liver fibrosis, NAH-associated fibrosis, interstitial lung disease (ILD), metabolic dysfunction-associated steatohepatitis (MASH), Diabetic kidney disease (DKD) (diabetic nephropathy), or atopic dermatitis (AD). In some embodiments, the disease and / or disorder is atopic dermatitis, contact dermatitis, vitiligo, alopecia areata, acne, psoriasis, dermatomyositis, scleroderma, or morphea.

[0078] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.BRIEF DESCRIPTION OF THE DRAWINGS

[0079] FIG. 1A depicts the Western Blot experimental results of Compound A6 against STAT1, STAT3, STAT5, and STAT6 in MV4-11 cells, and FIG. IB depicts the same Western Blot data of Compound A6 against STAT6;

[0080] FIG. 2A depicts the Western Blot experimental results of Compounds A9 and Al 1 against STAT3 and STAT6 in MV4-11 cells, FIG. 2B depicts the same Western Blot data of Compound A9 against STAT6, and FIG. 2B depicts the same Western Blot data of Compound Al 1 against STAT6;

[0081] FIG. 3A depicts the Western Blot experimental results of Compound A6 against STAT1-STAT6 in mouse splenocytes, and FIG. 3B depicts the same Western Blot data of Compound A6 against STAT6 in mouse splenocytes;

[0082] FIG. 4A depicts the degradation results of Compound A14 against STAT6 in MV4-11 cells, FIG. 4B depicts the same degradation data of Compound A14 against STAT6 in MV4-11 cells;

[0083] FIG. 5 A depicts the degradation of Ikaros, Aiolos, and GSPT1 proteins by Compound All, and the positive control Pomalidomide (denoted as Poma), and FIG. 5B depicts the degradation of Ikaros, Aiolos, and GSPT1 proteins by Compound Al 7, and the positive control Pomalidomide (denoted as Poma);

[0084] FIG. 6 depicts the degradation of SALL4 protein by Compounds All, A17, and the positive control Pomalidomide (denoted as Poma);

[0085] FIG. 7 depicts a protein degradation volcano plot of Compound Al 1 in hPBMCs; a total of 6013 proteins were detected for Compound Al 1, and the names of significantly degraded proteins are labeled in the corresponding volcano plot; and

[0086] FIG. 8A depicts the STAT6 degradation in mice (lung) after intratracheal nebulization administration of Compound Al l; and FIG. 8B depicts the STAT6 degradation in mice (plasma) after intratracheal nebulization administration of Compound All.

[0087] Before proceeding with the detailed description, it is to be appreciated that the following detailed description is merely exemplary in nature and is not intended to limit theinvention or the application and uses thereof. Hence, although the present disclosure is, for convenience of explanation, depicted and described as shown in certain illustrative embodiments, it will be appreciated that it can be implemented in various other types of embodiments and equivalents, and in various other systems and environments. Furthermore, there is no intention to be bound by any theory presented in the preceding background or the following detailed description.INCORPORATION BY REFERENCE

[0088] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTION

[0089] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.DEFINITIONS

[0090] Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.

[0091] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a molecule” includes a plurality of such molecules, and the like.

[0092] The term “about” or “nearly” as used herein generally refers to within + / - 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the designated amount.

[0093] The term “halogen” or “halide” as used herein generally refers to fluorine, chlorine, bromine, and iodine. The term “haloalkyl” or ’halo-alkyl” as used herein generally refers to an alkyl group that is substituted with one or more independently chosen halogens (e.g., “Ci-Ce haloalkyl” groups have from 1 to 6 carbon atoms and at least one halogen). Examples of haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or trichloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta-chloroethyl; and 1.2.2.2-tetralluoro-l-trilluoromethyl-ethyl. The term “haloalkoxy” or “haloalkoxy” as used herein generally refers to an alkoxy group that is substituted with one or more independently chosen halogens (e.g., “Ci-Cg haloalkoxy” or “Ci-Cg halo-alkoxy” groups have from 1 to 6 carbon atoms and at least one halogen attached to one of the carbon atoms).Examples of haloalkoxy groups include, but are not limited to, mono- or di -fluoromethoxy; mono- or di-chloromethoxy; mono-, di-, tri-, or tetra-fluoroethoxy; and mono-, di-, tri-, or tetrachloroethoxy.

[0094] The term “alkyl” as used herein generally refers to a straight or branched chain saturated aliphatic hydrocarbon. Alkyl groups include groups having from 1 to 8 carbon atoms (Ci-8 alkyl), from 1 to 6 carbon atoms (Ci-6 alkyl) and from 1 to 4 carbon atoms (CM alkyl), including, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2 -butyl, 3-methyl-l -butyl, 2-methyl-l-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. In some embodiments, “CM alkyl” is, preferably, methyl, ethyl, n-propyl, isopropyl or tert-butyl.Similarly, C1.3 alkyl refers to an alky l group having from 1 to 3 carbon atoms in a straight or branched chain, including, for example, methyl, ethyl, propyl, and isopropyl. C alkyl refers to an alkyl group having from 1 to 4 carbon atoms in a straight or branched chain, including, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. In some instances, a substituent of an alkyl group is specifically indicated. For example, “cyanoalkyl” refers to an alky l group substituted with at least one cyano substituent.

[0095] The term “alkenyl” as used herein generally refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C2-8 alkeny l, C2-6 alkenyl and C2-4 alkenyl groups, which have from 2 to 8, 2 to 6, or 2 to 4 carbon atoms, respectively, including, for example, ethenyl, allyl and isopropenyl. “C2-12 alkenyl” as used herein generally refers to a straight-chain or branched-chain alkenyl group containing 2 to 12 carbon atoms, including but not limited to vinyl, 1 -propenyl, and 1-butenyl. preferably “C2-6 alkenyl”.

[0096] The term “alkynyl” as used herein generally refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C2-8 alkynyl, C2-6 alky nyl and C2.4alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, including, for example, ethynyl and propargyl. “C2-12 alkynyl” as used herein generally refers to a straight-chain or branched-chain alkynyl group containing 2 to 12 carbon atoms, including but not limited to ethynyl, 1-propyny 1, and 1-butynyl, preferably “C2.6 alkynyl”.

[0097] The term “alkoxy” as used herein generally refers to an alkyl group as described above attached via an oxygen bridge to another chemical moiety. Alkoxy groups include different length of the alkyl groups, such as, for example, C g alkoxy and C1.4 alkoxy groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively. The term “OCi-6 alkyd” as used herein generally refers to alkoxy groups include an alkyl group (with 1 to 6 carbon atoms) attached to an oxygen atom. Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy. isobutoxy, / e / 7-butoxy. n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3 -methylpentoxy are representative alkoxy groups.

[0098] The term “cycloalkyl” as used herein generally refers to a group that comprises one or more saturated rings in which all ring members are carbon. For example, certain cycloalkyl groups are C3.8 cycloalkyl, in which the cycloalkyd group contains one or more rings having from 3 to 8 ring members, all of which are carbon, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Other example of cycloalkyl group include adamantyl. Cycloalkyl groups do not comprise an aromatic ring or a heterocyclic ring. The term “cycloalkenyl” as used herein generally refers to a group that comprises one or more unsaturated rings in which all ring members are carbon.

[0099] The term “alicyclic alkyd” as used herein generally refers to a saturated or partially unsaturated cyclic alkane group. For example, it can be a monovalent group or a divalent group.“C3.6 alicyclic alkyl” as used herein generally refers to an alicyclic alkyl group with 3 to 6 carbon atoms as ring atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl.

[0100] The terms “heterocyclic” or “heterocycle” or “heterocyclyl” or “cycloheteroalkyl” as used herein generally refer to a ring structure (monocycle or poly cycle) containing 3-12 ring atoms (3-12 membered heterocycle), 3-8 ring atoms (3-8 membered heterocycle or 3-8 membered cycloheteroalkyd), 3-6 ring atoms (3-6 membered heterocycle or 3-6 membered cycloheteroalkyl), or 5-6 ring atoms (5-6 membered heterocycle or 5-6 membered cycloheteroalkyl), in which at least one ring atom is carbon, and at least one ring atom is heteroatom selected from N, O, and S or at least one heteroatom group is selected from P(=O), S(=O), and S(=O)2. A heterocyclic group may be aromatic or non-aromatic. Piperidine and oxetane are non-limiting examples of non-aromatic heterocycles. Thiazole and pyridine are nonlimiting examples of aromatic heterocycles. Other examples of heterocycle include: aziridinyl. azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactam, valerolactam, caprolactam, butyrolactone, valerolactone and caprolactone. Similarly, the term “cycloheteroalkenyl” refers to a monocycle or poly cycle ring structure comprising carbonatom(s) and heteroatom(s) / heteroatom group! s). wherein the cycloheteroalkenyl comprises at least one C=C double bond, at least one ring atom that is carbon and at least one ring atom that is heteroatom selected from N, O, and S or a heteroatom group selected from P(=O), S(=O), and S(=O)2.

[0101] The term “4-6 membered saturated or partially unsaturated heterocyclyf’ as used herein generally refers to a saturated or partially unsaturated heterocyclyl group with 4 to 6 ring atoms, including but not limited to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactamyl, butyrolactonyl. and valerolactonyl.

[0102] The term “6-12 membered fused heterobi cyclyl” as used herein generally refers to a saturated or partially unsaturated bicyclic group containing 6 to 12 (especially 7 to 10) ring atoms comprising one or more heteroatoms or heteroatom groups selected independently from O, S, N, P(=O), S(=O), and S(=O)2. The two rings share a carbon-carbon bond, a carbonheteroatom bond, or a heteroatom-heteroatom bond. The term “6- to 12-membered fused heterobicyclyf’ includes but is not limited to 3,7-diazabicyclo[3.3.0]oct-3-yl, 3,6-diazabicyclo[3.3.0]oct-3-yl, and 2,7-diazabicyclo[3.3.0]oct-2-yl.

[0103] The term “8-10 membered fused heterobicyclyf’ as used herein generally refers to an 8- to 10-membered fused bicyclic group formed by fusing one aryl group with one heteroaryl group or fusing two heteroaryl groups, including but not limited to benzothienyl, indolyl, benzimidazolyl, pyridoimidazolyl, pyridazinoimidazolyl, pyrazolopyrimidinyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl.

[0104] The term “Cg-n spiroalkyf ’ as used herein generally refers to a 6- to 11 -membered poly cycloalkyl group formed by two cycloalkanes sharing one carbon atom.

[0105] The term “C5.8 bridged alkyl” as used herein generally refers to a 5- to 8-membered polycycloalkyl group sharing more than two carbon atoms.

[0106] The term “5-12 membered spiroheterobicyclyl” as used herein generally refers to a saturated or partially unsaturated bicyclic group containing 5 to 12 (especially 6 to 9) ring atoms comprising one or more heteroatoms or heteroatom groups selected independently from O, S, NH, N, P(=O), S(=O), and S(=O)2. The two rings are connected through one carbon atom. The "5 to 12-membered spiroheterobicyclyl" includes but is not limited to 4,7-diazaspiro[2.5]oct-7-yl, l-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, and l-oxa-7-azaspiro[3.5]non-7-yl.

[0107] The term “6-10 membered bridged heterobicyclyf’ as used herein generally refers to a saturated or partially unsaturated bridged heterobicyclyl group containing 6 to 10 (especially 6 to 8) ring atoms comprising one or more heteroatoms or heteroatom groups selectedindependently from O, S, NH, N, P(=0), S(=0), and S(=0)2. The “6-10 membered bridged heterobicyclyl” includes but is not limited to 3,6-diazabicyclo[3.1.1]hept-l-yl, 3,6-diazabicyclo[3.1.1]hept-3-yl, and 3,6-diazabicyclo[3.1.1]hept-6-yl.

[0108] The term “aryl” as used herein generally refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 (C6-i2aryl) or 6 to 10 carbon atoms (C6-io aryl) having a completely conjugated pi-electron system. Examples, without limitation, of aryl groups are phenyl, naphthalenyl, tetrahydronaphthyl, indanyl, biphenyl, and anthracenyl. The aryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alky l, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, ary l th i o. cyano, nitro, carbonyl, thiocarbonyl. C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and -NRXR wherein Rxand Rxare independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, ary l, carbonyl, acetyl, sulfonyl, trifluoromethanesulfonyl and, combined, a five- or six-membered heteroalicyclic ring.Illustrative substituted alkyl group include, but are not limited to. fluoromethyl, difluoromethyl, trifluoromethyl, aminomethyl, aminoethyl, hydoxymethyl, methoxy methyl, 2-fluoroethyl, and 2-methoxyethyl, etc.

[0109] The term “heteroaryl” as used herein generally refers to an aromatic group in which at least one aromatic ring comprises at least one heteroatom selected from N, O and S. Heteroaryls include, for example, 5-12 membered heteroaryls, 5-10 membered heteroaryls, 5-7 membered monocyclic structures or 7-12 membered bicyclic structures. The number of heteroatoms in a heteroaryl can be 1, 2, 3, 4, or more. Examples included but are not limited to thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridine-2(lH)-keto, pyridine-4(lH)-keto, pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-oxadiazolyl, imidazolyl, furanyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, and quinazolinyl. The heteroaryl group may be substituted or unsubstituted. Typical substituents include halo, trihalomethyl, alkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, amino and -NRXR with Rxand RYas defined above.

[0110] The term “ylene group” as used herein generally refers to a divalent group. For example, alkylene refers to a divalent alkyl group, alkenylene refers to a divalent alkenyl group, alkynylene refers to a divalent alkynyl group, cycloalkydene refers to a divalent cycloalkyl group, heterocyclylene refers to a divalent heterocyclyl group, arylene refers to a divalent aryl group, and heteroarylene refers to a divalent heteroaryl group.

[0111] The term '‘amino’’ as used herein generally refers to a primary amino group (-NH2), asecondary amino group (-NH-), or a tertiary amino group ().

[0112] The term “alkylamino’’ as used herein generally refers to a secondary or tertiary' amine that has the general structure -NH-R1or -N^XR2). respectively, wherein R1and R2are selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups. Such groups include, but are not limited to, for example, “-NH(CI-6 alkyl)” and “-N(Ci^ alkyl)2” comprising mono- and di- (Ci-6 alkyl) groups, respectively, in which each Ci-6 alkyl may be the same or different. It will be apparent that the definition of “alkyl” as used in the term “alkylamino” differs from the definition of '‘alkyl” used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups.

[0113] The term “ethylene gly col or propylene glycol unit” as used herein generally refers to the unit structure of and the polymeric structure formed by the dehydration of ethylene glycol or propylene glycol, respectively. Specifically, the structural fragment represented by the ethylene |-o^glycol unit is ( • '), and the structural fragment represented by the propylene glycol unit is

[0114] The terms “substituent” and “substituted”, as used herein, generally denotes that a molecular moiety is covalently bonded to an atom within a molecule of interest. The atom attached to can be carbon or nitrogen. The molecule can be alky l, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. For example, a ring substituent may be a moiety such as a halogen, an alkyl group, a haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member. Substituents of aromatic groups are generally covalently bonded to a ring carbon atom or a ring nitrogen atom. A straight chain substituent may be a moiety such as a halogen, an alkyl group, a haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a member of a straight chain.

[0115] The term “pharmaceutically acceptable” as used herein generally refers to a form of the compound that is safe for administration to a subject. For example, a free base, a salt form, a solvate, a hydrate, a prodrug or derivative form of a compound described herein, which has been approved for mammalian use, via oral ingestion or any other route of administration, by a governing authority' or regulatory' agency, such as the Food and Drug Administration (FDA) of the United States, is pharmaceutically acceptable.

[0116] Included in the compounds of Formulas (I), (F), (I’-l) (II), (II-l), (III), (III-l ), (IV-1), and (IV -2) are the pharmaceutically acceptable salt forms of the free-base compounds. The term “pharmaceutically acceptable salt” as used herein generally refers to salts, commonly used to form alkali metal salts and to form addition salts of free acids or free bases, which have been approved by a regulatory agency. Salts are formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. For example, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. For example, Berge et al. describes pharmaceutically acceptable salts in detail in Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Inorganic acids from which salts can be derived include, but are not limited to. hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, but are not limited to, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laur l sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate. undecanoate, valerate salts, and the like. In some embodiments, organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0117] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and other amine salt. Inorganic bases from which salts can be derived include, but are not limited to. sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, but are not limited to, primary, secondary, and tertiary' amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, examples include, but are not limited to, isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is ammonium, potassium, sodium, calcium, or magnesium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary' ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alky l sulfonate and aryl sulfonate. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. Bis salts (i.e., two counterions) and higher salts (e.g., three or more counterions) are encompassed within the meaning of pharmaceutically acceptable salts.

[0118] Pharmaceutically' acceptable non-toxic base addition salts may refer to the salts formed by the compounds of the present disclosure with organic or inorganic bases, including but not limited to alkali metal salts (e.g.. lithium, sodium, or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and organic base salts (e.g., ammonium salts or N+(CI-6 alkyl)4 salts formed with N-containing organic bases). Preferred examples in the present disclosure include salts formed by the compounds of the present disclosure with lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, aqueous ammonia, tri ethylamine, or tetrabutylammomum hydroxide. For the pharmaceutically acceptable base addition salts of the compounds of the present disclosure, the compounds may exist in the form of phosphate anions. Pharmaceutically acceptable salts can be synthesized by conventional chemical methods.

[0119] As used herein, the term "solvate” refers to compounds that further include a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate can be of a disclosed compound or a pharmaceutically acceptable salt thereof. Where the solvent is water, the solvate is a "hydrate". Other solvates include, but are not limited to, methanol, ethanol, isopropanol, EA, tetrahydrofuran, dimethyl sulfoxide, and / VA-dimethylformamide. Pharmaceutically acceptable solvates and hydrates are complexes that, for example, can include 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

[0120] As used herein, and unless otherwise specified, "prodrug” refers to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug can be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. A discussion of prodrugs is provided in Higuchi, T., et al. " Pro-drugs as Novel Delivery Systems,” A. C. S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: " Prodrugs and Drug delivery Systems” pp. 352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; all of which are incorporated in full by reference herein. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compounds according to Formulas (I), (!’), (I’-l) (II), (II-l), (III), (III- 1), (IV-1), and (IV-2) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, can be prepared by modifying functional groups present in the active compounds according to Formulas (I), (!’), (!’-1) (II), (II- 1), (III), (III-l), (IV-1), and (IV-2) in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, mercapto, or phosphonate group is bonded to any group that, when the prodrug of the active compounds according to Formulas (I), (F), (I’-l) (II), (II- 1), (III), (III- 1), (IV-1), and (IV-2) is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, free mercapto, or free phosphonate group, respectively.

[0121] The terms “isotope-labeled”, “isotope label”, “isotope-labeled derivative” and “isotopically labeled” refer to unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. For example, the compounds can be radio labeled with radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125I), carbon-14 (14C). The compounds can also be isotope-labeled with2H,nC,13C,15N,17O,18O,18F,32P,35S, and36C1.Certain isotope-labeled disclosed compounds (e.g., those labeled with H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon-14 (i.e.,14C) isotopes can allow for ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half -life or reduced dosage requirements). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, provided herein are compounds that can also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds. All isotopic variations of compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0122] The term “isomers'’ as used herein generally refers to different compounds that have the same molecular formula, including any and all geometric isomers, tautomers and stereoisomers. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. For example, “isomers” include geometric double bond cis- and trans-isomers, also termed E- and Z- isomers; R- and S-enantiomers; diastereomers, (d)-isomers and (l)-isomers, racemic mixtures thereof; and other mixtures thereof, as falling within the scope of this disclosure, unless specified otherwise. As used herein, the term “tautomer” is a type of isomer that includes two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa).

[0123] The terms “each independently” or “each”, as used herein, mean that at least two groups (or ring systems) present in a structure with the same or similar value ranges may have the same or different meanings under certain circumstances. For example, if substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alky l or aryl, then when substituent X is hydrogen, substituent Y can be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. Similarly, when the substituent Y is hydrogen, the substituent X can be hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.

[0124] The terms “optional”, “optionally” or “optionally substituted”, as used herein, mean that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the non-occurrence of the subsequent event or circumstance.

[0125] In some embodiments, the compound(s) of Formulas (I), (I’), (I’-l) (II), (II-l), (III), (III-l), (IV-1), and (IV-2) is used to treat a subject by administering the compound(s) as a pharmaceutical composition. To this end, the compound(s), in one embodiment, is combinedwith one or more pharmaceutically acceptable excipients, including earners, diluents or adjuvants, to form a suitable composition, which is described in more detail herein.

[0126] The term “excipient"’ as used herein generally refers to any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is ty pically included for formulation and / or administration purposes.

[0127] The term “diluent” as used herein generally refers to an agent used as filler in order to achieve the desired composition volume or weight. The diluent may be present in the pharmaceutical composition within granules in the form of a single compound or in the form of a mixture of compounds. Non-limiting examples of diluent include lactose, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose acetate, dextrose, mannitol, sodium phosphate, potassium phosphate, calcium phosphate, fructose, maltose, sorbitol, or sucrose.

[0128] The term “adjuvant,” as used herein generally refers to any substance or mixture of substances that increases the efficacy or potency of a compound disclosed herein on a target where the adjuvant is used together with the compound disclosed herein. However, when the adjuvant is used alone, no pharmacological effect is observed on the same target.

[0129] The terms “treat”, “treating,” “treatment,” and “therapy” as used herein generally refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy. Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals. Treatment includes the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

[0130] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advanceaction. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0131] The term “effective amount” or “therapeutically effective amount”, as used herein, refers to a sufficient amount of an agent or a compound being administered which will relieve one or more of the symptoms of the disease or condition being treated to some extent; achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, the result thereof can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system; while avoiding adverse side effects typically associated with alternative therapies. For example, an “effective amount” for therapeutic uses is the amount of the composition as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. The effective amount, in one embodiment, is administered in a single dosage form or in multiple dosage forms.

[0132] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms or by other conventional methods known to those of skill in the art.

[0133] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0134] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular hedgehog inhibitor employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0135] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0136] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such aneffective dose will generally depend upon the factors described above. Generally, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. The mode of administration can have a large effect on dosage. Higher doses may be used for localized routes of delivery.

[0137] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Dosages for a given compound disclosed herein are readily determinable by those of skill in the art by a variety of means.PHARMACEUTICAL COMPOSITIONS / FORMULATIONS

[0138] One embodiment provides a pharmaceutical composition comprising a compound of Formulas (I). (I’), (I’-l) (II). (II- 1), (III). (III-l). (IV- 1 ). and (IV-2). or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0139] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington:Science and Practice of Pharmacy, Nineteenth Ed., Easton, Pa.: Mack Publishing Company (1995); Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975); Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y. (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed., Lippincott Williams & Wilkins (1999), herein incorporated by reference for such disclosure.

[0140] A pharmaceutical composition, as used herein, refers to a mixture of a compound of Formulas (I), (!’), (I’-l) (II), (II-l), (III), (III-l ), (IV-1), and (IV-2) with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof. The pharmaceuticalcomposition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0141] The pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0142] All formulations for oral administration are in dosages suitable for such administration. Examples of such dosage units are tablets or capsules. In some embodiments, these contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and ty pically from about 5 to 150 mg. A suitable daily dose for a human or other mammal varies widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods and practices.

[0143] Conventional formulation techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.

[0144] ADDITIONAL THERAPEUTIC AGENTS

[0145] Additional therapeutic agents can be used in combination with the compounds (STAT6 degrader) disclosed herein. In some embodiments, the additional therapeutic agent is for cytokine blockade, including lL-4Ra antagonists comprising dupilumab, IL- 13 neutralizing antibodies comprising tralokinumab or lebrikizumab, TSLP inhibitors comprising tezepelumab, thereby treating severe asthma, atopic dermatitis, or eosinophilic disorders. In some embodiments, the additional therapeutic agent is JAK-STAT pathway inhibitors, includingJAK1 / 2 inhibitors comprising ruxolitinib or baricitinib, JAK1 -selective inhibitors comprising upadacitinib or abrocitinib, thereby treating inflammatory skin disease, steroid-refractory allergic disease, or lymphomas having STAT6 redundancy. In some embodiments, the additional therapeutic agent is corticosteroids, including systemic corticosteroids comprising prednisone or methylprednisolone, inhaled corticosteroids comprising budesonide or fluticasone, thereby treating acute asthma exacerbation or severe allergic inflammation. In some embodiments, the additional therapeutic agent is anti-eosinophil therapies, including IL-5 antibodies comprising mepolizumab or reslizumab, IL-5Ra antibodies comprising benralizumab, thereby treating hypereosinophilic syndrome, eosinophilic asthma, or eosinophilic GI disease. In some embodiments, the additional therapeutic agent is anti-fibrotic agents, including TGF-p / tyrosine kinase antifibrotics comprising nintedanib or pirfenidone, PPAR agonists comprising lanifibranor, thereby treating pulmonary' fibrosis, liver fibrosis, or systemic sclerosis. In some embodiments, the additional therapeutic agent is anti-cancer agents, including epigenetic modifiers comprising HD AC inhibitors (vorinostat or panobinostat) or BET inhibitors (molibresib), cytotoxic agents comprising DNA-damaging agent (doxorubicin or cyclophosphamide) or B-cell targeting antibodies (rituximab), thereby treating STAT6-mutant lymphomas or solitary fibrous tumor. In some embodiments, the additional therapeutic agent is checkpoint inhibitors, including PD-1 inhibitors comprising nivolumab or pembrolizumab. PD-L1 inhibitors comprising atezolizumab, thereby treating lymphomas or solid tumors with Th2-skewed microenvironment. In some embodiments, the additional therapeutic agent is mast cell / histamine modulators, including Hl antihistamines comprising cetirizine or fexofenadine, and mast cell stabilizers comprising cromolyn sodium, thereby treating allergic rhinitis or food allergy.SYNTHETIC METHODS

[0146] The examples and preparations provided below illustrate and exemplify the compounds described herein and methods of preparing such compounds. In general, the compounds described herein may be prepared by processes known in the general chemical arts. Unless otherwise specified, the experimental methods described in the following examples are conventional methods; and the reagents and materials, unless otherwise specified, are commercially available.

[0147] The compounds of the present disclosure can be prepared using various synthetic routes, including those described below, starting from commercially available materials. Starting materials of the disclosure are either known, commercially available, or can be synthesized in analogy' to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and can be prepared using processes described in theexamples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary. Functional groups may be removed according to known procedures in the art.

[0148] The protection of functional groups by protecting groups, the protecting groups themselves, and their removal reactions (commonly referred to as “deprotection”) are described, for example, in standard reference works, such as J. F. W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, London and New York (1973), in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E. Gross and J.Meienhofer editors, Academic Press, London and New York (1981).

[0149] All synthetic procedures described herein can be conducted under known reaction conditions, advantageously under those described herein, either in the absence or in the presence (usually) of solvents or diluents. In the following examples, all solvents and reagents used are of analytical grade or chemical grade.

[0150] The invention further encompasses “intermediate” compounds, including structures produced from the synthetic procedures described, whether isolated or not, prior to obtaining the finally desired compound. Structures resulting from conducting steps from a transient starting material, structures resulting from divergence from the described method(s) at any stage, and structures forming starting materials under the reaction conditions are all “intermediates” included in the invention. Further, structures produced by using starting materials in the form of a reactive derivative or salt or produced by a compound obtainable by means of the process according to the invention and structures resulting from processing the compounds of the invention in situ are also within the scope of the invention.

[0151] New starting materials and / or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention. In select embodiments, such starting materials are used and reaction conditions so selected as to obtain the desired compound(s).

[0152] Starting materials of the invention are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and can be prepared using processes described in the examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary. Protecting groups, their introduction and removal are described above.

[0153] All reagents and solvents were obtained commercially unless stated otherwise. All commercial reagents and solvent were used without purification unless stated otherw ise. When required, some reagents and solvents were purified by standard techniques. For example, tetrahydrofuran may be purified by distillation from sodium. Column chromatography silica gel(100 - 200 mesh) and thin-layer chromatography silica gel (GF254) are products of Leyan Technology, using PE (b.p. 60-90 °C) / EA (v / v) as eluent unless otherwise specified; and spots revealed by UV visualization at 254 nm and E vapor or phosphomolybdic acid. All organic layers after extraction are dried over anhydrous NazSCL unless stated otherwise. All nuclear magnetic resonance spectra (1H NMR) are recorded using a Qone-WNMR-I-AS400 nuclear magnetic resonance spectrometer from Zhongke Oxford Spectroscopy Technology Co., Ltd., with TMS as the internal standard. LC-MS is run using a Waters 2795 high-performance liquid chromatograph coupled with a Quattro Micro triple quadrupole mass spectrometer, with detection wavelengths at 220 nm and 254 nm. The HPLC column is an AgelaDurashell Cl 83.5 pm 4.6x50 mm column. Gradients are run using 0.1 NH4HCO3 aqueous solution and acetonitrile with gradient 5 / 95 to 95 / 5 in the run time indicated (for example, 5 min), flow rate at 1.8 mL / min.

[0154] The size and scale of the synthetic methods will vary depending on the desired amount of end product. It is understood that while specific reactants and amounts are provided in the Examples, one of skill in the art knows other alternative and equally feasible sets of reactants that will also yield the same compounds. Thus, where general oxidizers, reducers, solvents of various nature (aprotic, apolar, polar, etc.) are utilized, equivalents will be known in the art and are herein contemplated for use in the present methods.

[0155] Many of the steps below indicate various work-ups following termination of the reaction. A work-up involves quenching of a reaction to terminate any remaining catalytic activity and starting reagents. This is followed by addition of an organic solvent and separation of the aqueous layer from the organic layer. The product is typically obtained from the organic layer and unused reactants, and other spurious side products and unwanted chemicals are trapped in the aqueous layer and discarded. The work-up in standard organic synthetic procedures found throughout the literature is followed by dry ing the product by exposure to a drying agent, such as anhydrous NazSCfi. to remove any excess water or aqueous byproducts remaining partially dissolved in the organic layer and concentration of the remaining organic layer. Concentration of product dissolved in solvent may be achieved by any known means, such as evaporation under pressure, evaporation under increased temperature and pressure, and the like. Such concentrating may be achieved by use of standard laboratory equipment such as rotary-evaporator distillation, and the like. This is optionally followed by one or more purification steps which may include, but is not limited to, flash column chromatography, filtration through various media and / or other preparative methods known in the art and / or crystallization / recrystallization. (See, for instance, Addison Ault, “Techniques and Experimentsfor Organic Chemistry,” 6th Ed., University Science Books, Sausalito, Calif., 1998, Ann B. McGuire, Ed., pp. 45-59).

[0156] Abbreviations:

[0157] (BOC)2O means di-tert-butyl dicarbonate.DAST means diethylaminosulfur trifluoride.DCM means dichloromethane.DIBAL-H means diisobutylaluminum hydride.DIPEA (N, N-diisopropylethylamine.DMF means A. A-dimethylformamide.EA means ethyl acetate.EDCI means l-ethyl-3-(3-dimethylaminopropyl)carbodiimideEtOH means ethanol.HATU means 2-(7-azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate.LiHMDS means lithium bis(trimethylsilyl)amide.MeOH means methanol.NaHMDS means sodium bis(trimethylsilyl)amide.NFSI means N-fluorobenzenesulfonimide.Pd2(dba)s means tris(dibenzylideneacetone)dipalladium.Pd(PPh3)4means tetrakis(triphenylphosphine)palladium.Pd(dppf)C12 meansfl, l'-bis(diphenylphosphino)ferrocene]dichloropalladium).Pd(OAc)2 means palladium(II) acetate.PE means petroleum ether.PFPOH means pentafluorophenol.RuPhos means 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl.RuPhos Pd G2 means [2'-(amino)[l,r-biphenyl]-2-yl][[2',6'-bis(l-methylethoxy)[l,r- biphenyl]-2-yl]dicyclohexylphosphine]palladium(II) chloride.STAB means sodium triacetoxyborohydride.TBSC1 means tert-butyldimethylsilyl chloride.TBAF means tetrabuty lammonium fluoride.TFA means trifluoroacetic acid.THF means tetrahydrofuran.TMSBr means trimethyl silyl bromide.TsCl means p-toluenesulfonyl chloride.TLC means thin layer chromatography.HPLC means high-performance liquid chromatography.LC-MS means liquid chromatography-mass spectrometry.NMR means nuclear magnetic resonance.Examples

[0158] Example 1: perfluorophenyl 7-((diethoxyphosphoryl)fluoromethyl)-2-naphthoate (Pl)P(OEt)3step 4

[0159] Step 1. tert-butyl 7-bromo-2-naphthoate: 2,7-Dibromonaphthalene (25 g, 88 mmol) and dry toluene (40 mL) were added into a three-necked flask. Under nitrogen protection, the mixture was cooled to -10 °C, and n-butylmagnesium bromide (19 mL. 37 mmol) was then added. The temperature of the system was maintained at -5 °C, and n-butyllithium (30 mL, 75 mmol) was added dropwise; after the addition, the reaction mixture was stirred at -10 °C for 1 hour while the temperature was kept constant. Di-tert-butyl dicarbonate (25 g, 88 mmol) was dissolved in 250 mL of dry’ toluene, and this prepared solution was slowly added dropwise into the reaction system with the temperature controlled at -5 °C. Upon completion of the dropwise addition, the reaction mixture was stirred at -10 °C for 4 hours. After the reaction was finished, it was quenched with 100 mL of 10% aqueous citric acid solution, and the resulting mixture was extracted with EA (100 mL x 3). The obtained organic phase was dried with anhydrous sodium sulfate and then concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 100: 1), yielding intermediate Pl-1 as a white solid (17 g, 63% yield).¹H 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]+.

[0160] Step 2. tert-butyl 7-methyl-2-naphthoate: Intermediate Pl-1 (20 g, 65 mmol), methylboronic 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). Under nitrogen protection, the mixture was reacted at 100 °C for 4 hours. After the reaction was completed, the mixture was filtered and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 100:1) and then concentrated to obtain intermediate Pl-2 as a pale-yellow solid (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).

[0161] Step 3. tert-butyl 7-(bromomethyl)-2-naphthoate: Intermediate Pl-2 (10 g, 41 mmol) was dissolved in dichloroethane (100 mL). and benzoyl peroxide (400 mg, 1.6 mmol) was added. The temperature was raised to 80°C, and N-bromosuccinimide (7.7 g, 43 mmol) was slowly added to the reaction in batches. After the addition was completed, the reaction was conducted at 80°C for 3 hours. When the reaction finished, the temperature was cooled to room temperature, and the mixture was poured into 200 mL of ice water to quench the reaction. The mixture was extracted with DCM (100 mL x 2). and the organic phase was dried with anhydrous sodium sulfate and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 80:1) to obtain intermediate Pl -3 as a yellow solid (11 g, 84%). ¹H 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).

[0162] Step 4. tert-butyl 7-((diethoxyphosphoryl)methyl)-2-naphthoate: Intermediate Pl -3 (14 g, 44 mmol) was added to a round-bottomed flask, and approximately 60 mL of triethyl phosphite was added. The mixture was heated to 120 °C, and the temperature was maintained while stirring for 16 hours. After the reaction was completed, the solvent was removed by rotary evaporation using an oil pump, and the residue was concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 5: 1) to obtain intermediate Pl -4 as a yellow liquid (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]+.

[0163] Step 5. tert-butyl 7-((diethoxyphosphoryl)(hydroxy)methyl)-2-naphthoate:Intermediate Pl-4 (6.5 g, 17 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Under nitrogen protection, the temperature was cooled to -78 °C, and sodium bis(trimethylsilyl)amide (13 mL, 26 mmol) was added dropwise. After the dropwise additionwas completed, the temperature was maintained at -78 °C while stirring for 5 minutes. Davies oxaziridine reagent (9.0 g, 34 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and the solution was slowly added dropwise to the reaction system with the temperature controlled at -65 °C. After the dropwise addition, the reaction was stirred at -78 °C for 20 minutes. When the reaction finished, the mixture was poured into 200 mL of saturated aqueous ammonium chloride solution to quench the reaction. After stirring for 30 minutes, the mixture was extracted with EA (100 mL x 2). The organic phase was dried with anhydrous sodium sulfate and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 2: 1) to obtain intermediate Pl-5 as a yellow solid (5.0 g, 74%). ¹H 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).

[0164] Step 6. tert-butyl 7-((diethoxyphosphoryl)fluoromethyl)-2-naphthoate:Intermediate Pl-5 (6.5 g, 16 mmol) was dissolved in DCM (60 mL). Under nitrogen protection, the temperature was cooled to -78 °C. DAST (4.0 g. 25 mmol) was dissolved in DCM (40 mL), and the solution was slowly added dropwise to the reaction system with the temperature controlled at -65 °C. After the dropwise addition, the reaction was stirred at -78 °C for 20 minutes. When the reaction completed, the mixture was poured into 100 mL of saturated aqueous sodium bicarbonate solution to quench the reaction. The mixture was extracted with DCM (50 mL x 2), and the organic phase was dried with anhydrous sodium sulfate and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 5: 1) to obtain intermediate Pl -6 as a yellow liquid (5.0 g, 79%). ¹H NMR (300 MHz, CDCl₃) δ 8.56 (s, 1H), 8.11 – 8.00 (m, 2H), 7.97 – 7.81 (m, 2H), 7.69 (d, J = 8.4 Hz, 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]+.

[0165] Step 7.7-((diethoxyphosphoryl)fluoromethyl)-2-naphthoic acid: Intermediate Pl-6 (4.0 g, 11 mmol) was dissolved in DCM (20 mL). Trifluoroacetic acid (10 mL) was added at room temperature, and the reaction was conducted at room temperature for 6 hours. After the reaction was completed, the mixture was directly concentrated to obtain crude intermediate Pl -7 (3.5 g, 94%).

[0166] Step 8. perfluorophenyl 7-((diethoxyphosphoryl)fluoromethyl)-2-naphthoate: Crude intermediate Pl-7 (3.5 g, 10.3 mmol) was dissolved in DCM (20 mL), and DMF (0.2 mL) was added. Oxalyl chloride (3.4 g, 27 mmol) was slowly added dropwise to the reaction at room temperature. After the dropwise addition, the reaction was stirred at room temperature for 20 minutes. When the reaction finished, the mixture was directly concentrated for later use. In a separate three-necked flask, pentafluorophenol (2.5 g, 14 mmol) was dissolved in DCM (20mL). Under nitrogen protection, the temperature was cooled to 0 °C, and triethylamine (3.2 g, 32 mmol) was slowly added to the reaction. The temperature was maintained at 0 °C while stirring for approximately 15 minutes. The aforementioned concentrated solution was dissolved in DCM (10 mL), and the solution was slowly added dropwise to the reaction with the temperature controlled at 0 °C. After the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred for 30 minutes. When the reaction completed, the mixture was poured into approximately 100 mL of ice water. The mixture was extracted with DCM (50 mL x 2), and the organic phase was dried with anhydrous sodium sulfate and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 5:1) to obtain intermediate Pl as a yellow solid (3.0 g, 57%). ¹H 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).

[0167] Example 2: perfluorophenyl 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate (P2)P1-6 step 1 P2-1 step 2 P2-2 step 3 P2

[0168] Step 1. tert-butyl 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate: NFSI (1.3 g, 4.2 mmol) and intermediate Pl-6 (500 mg, 1.4 mmol) were dissolved in anhydrous THF (10 mL). Under nitrogen protection, the temperature was cooled to - 78°C, and NaHMDS (2.1 mL, 4.2 mmol) was slowly added dropwise while controlling the temperature at - 65 °C. After the dropwise addition, the reaction was stirred at - 78 °C for 1 hour under heat preservation. Upon completion of the reaction, the mixture was poured into 50 mL of saturated aqueous ammonium chloride solution to quench the reaction, extracted with EA (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 5:1) to obtain intermediate P2-1 as a yellow liquid (500 mg, 86%).

[0169] Step 2. 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoic acid: Intermediate P2-1 (500 mg, 1.2 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (3 mL) was added at room temperature. The reaction was conducted at room temperature for 6 hours. After the reaction was completed, the mixture was directly concentrated to obtain intermediate P2-2 (430 mg, crude product).

[0170] Step 3. perfluorophenyl 7-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate:Crude intermediate P2-2 (600 mg) was dissolved in DCM (10 mL), DMF (0.1 mL) was added, and oxalyl chloride (638 mg, 5.0 mmol) was slowly added dropwise to the reaction at room temperature. After the dropwise addition, the reaction was stirred at room temperature for 20 minutes, and upon completion, the mixture was directly concentrated. In a separate three-necked flask, pentafluorophenol (462 mg, 2.5 mmol) was dissolved in DCM (15 mL). Under nitrogen protection, the temperature was cooled to 0 °C, and triethylamine (508 mg, 5.0 mmol) was slowly added to the reaction. The mixture was stirred at 0 °C for approximately 15 minutes under heat preservation. The concentrated solution was dissolved in DCM (5 mL) and slowly added dropwise to the reaction while controlling the temperature at 0 °C. After the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred for 30 minutes. Upon completion, the mixture was poured into approximately 50 mL of ice water, extracted with DCM (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 5: 1) to obtain intermediate P2 as a yellow solid (700 mg). LC-MS (m / z): 525.3 [M + H]+.

[0171] Example 3: tert-butyl ((5S,8S,10aR)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate (P3)

[0172] Step 1.3-benzyl 8-methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocine-3,8(4H)-dicarboxylate: 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 dropwise addition, the reaction was stirred at room temperature for 6 hours. Upon completion of the reaction, the mixture was concentrated, and the residue was dissolved in EA (10 mL). The organic phase was washed with water (10 mL) and saturated brine(10 mL) successively, then dried over anhydrous sodium sulfate and concentrated to obtain intermediate P3-2 as a colorless liquid (800 mg, crude product). LC-MS (m / z): 476.4 [M + H]+.

[0173] Step 2. (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocine-8-carboxylic acid: Crude intermediate P3-2 (800 mg) was dissolved in a mixed solvent of tetrahydrofuran / water = 1: 1 (20 mL). Lithium hydroxide monohydrate (500 mg, 11 mmol) was added at room temperature, and the reaction was conducted for 6 hours. After the reaction was completed, the mixture was poured into approximately 20 mL of ice water, and EA (20 mL) was added for extraction. The layers were separated, and the aqueous phase was retained. The pH of the aqueous phase was adjusted to 5 with IN aqueous hydrochloric acid solution, then extracted with EA (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain intermediate P3-3 as a white solid (700 mg).

[0174] Step 3. benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(morpholine-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a] [l,5]diazocine-3(4H)-carboxylate: 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 DCM (30 mL). HATU (1.2 g, 3.0 mmol) was added, and 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 (DCM / methanol = 30: 1) to obtain intermediate P3-4 as a white solid (700 mg, 90% yield over three steps). LC-MS (m / z): 531.6 [M + H]+.

[0175] Step 4. tert-butyl ((5S,8S,10aR)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate P3 -4 (450 mg, 1.2 mmol) and 10% Pd / C (127 mg, 1.2 mmol) were added to a round-bottomed flask. Ethanol was added to dissolve the mixture, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The solid was filtered off and washed with ethanol, and the filtrate was concentrated to obtain intermediate P3 (350 mg, 73% yield). LC-MS (m / z): 397.4 [M + H]+.

[0176] Example 4: perfluorophenyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]-thiophene-2-carboxylate (P4),0,0 0 HO BnO BnO BnBr MeB(OH)2K2CO3, DMF Pd(OAc)2, SPhos, K3PO4, dioxane Br Br P4-1 step 1 P4.2 step 2 P4.3P(OEt)31 NaHMDS, THF 2. Davies oxaziridinestep 4 step 5DAST NFSIP4-6Pd / Cstep 8

[0177] Step 1. benzyl 5-bromobenzo[b]thiophene-2-carboxylate: P4-1 (10 g, 39 mmol) and potassium carbonate (11 g, 78 mmol) were dissolved in dry N, N-dimethylformamide (100 mL). Benzyl bromide (7.3 g, 43 mmol) was added at room temperature, and the reaction was stirred overnight. After the reaction was completed, the reaction solution was slowly poured into approximately 350 mL of ice water and filtered. The filter cake was washed with approximately 100 mL of ice water and 50 mL of PE, then dried to obtain intermediate P4-2 as a pale-yellow solid (10 g, 74%).

[0178] Step 2. benzyl 5-methylbenzo[b]thiophene-2-carboxylate: Intermediate P4-2 (7 g, 20 mmol), methylboronic 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 in1,4-dioxane (100 mL) and water (25 mL). Under nitrogen protection, the mixture was reacted at 100 °C for 4 hours. After the reaction was completed, the mixture was filtered and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 100: 1) and then concentrated to obtain intermediate P4-3 as a pale-yellow solid (4.3 g, 75%).

[0179] Step 3. benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate: 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 temperature was raised to 80 °C, and N-bromosuccinimide (3.9 g, 22 mmol) was slowly added to the reaction in batches. After the addition was completed, the reaction was conducted at 80 °C for 3 hours. When the reaction finished, the temperature was cooled to room temperature, and the mixture was poured into 200 mL of ice water to quench the reaction. The mixture was extracted with DCM (100 mL x 2), and the organic phase was dried with anhydrous sodium sulfate and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 80: 1) to obtain intermediate P4-4 as a yellow solid (6.0 g, 79%).

[0180] Step 4. benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate: Intermediate: P4-4 (6.0 g, 17 mmol) was added to a round-bottomed flask, and approximately 40 mL of triethyl phosphite was added. The mixture was heated to 120 °C, and the temperature was maintained while stirring for 16 hours. After the reaction was completed, the solvent was removed by rotary evaporation using an oil pump, and the residue was concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 5:1) to obtain intermediate P4-5 as a yellow liquid (6.2 g, 87%).

[0181] Step 5. benzyl 5-((diethoxyphosphoryl)(hydroxy)methyl)benzo[b]thiophene-2-carboxylate: Intermediate: P4-5 (6.2 g, 15 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). Under nitrogen protection, the temperature was cooled to -78 °C, and sodium bis(trimethylsilyl)amide (11 mL, 22 mmol) was added dropwise. After the dropwise addition was completed, the temperature was maintained at -78 °C while stirring for 5 minutes. Davies oxaziridine reagent (7.7 g, 30 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). and the solution was slowly added dropwise to the reaction system with the temperature controlled at -65 °C. After the dropwise addition, the reaction was stirred at -78 °C for 20 minutes. When the reaction finished, the mixture was poured into 450 mL of saturated aqueous ammonium chloride solution to quench the reaction. After stirring for 30 minutes, the mixture was extracted with EA (100 mL x 2). The organic phase was dried with anhydrous sodium sulfate and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 2: 1) to obtain intermediate P4-6 as a yellow solid (2.2 g, 34%).

[0182] Step 6. benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate: Intermediate: P4-6 (1.5 g, 3.5 mmol) was dissolved in DCM (20 mL). Under nitrogen protection, the temperature was cooled to -78 °C. DAST (0.84 g, 5.2 mmol) was dissolved in DCM (10 mL), and the solution was slowly added dropwise to the reaction system with the temperature controlled at -65 °C. After the dropwise addition, the reaction was stirred at -78 °C for 20 minutes. When the reaction completed, the mixture was poured into 100 mL of saturated aqueous sodium bicarbonate solution to quench the reaction. The mixture was extracted with DCM (50 mL x 2), and the organic phase was dried with anhydrous sodium sulfate and concentrated. The concentrated product was purified by silica gel column chromatography (PE / EA = 5:1) to obtain intermediate P4-7 as a yellow liquid (0.7 g, 46%).

[0183] Step 7. benzyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate: 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 temperature was cooled to -78 °C, and NaHMDS (1.7 mL, 3.4 mmol) was slowly added dropwise while controlling the temperature at -65 °C. After the dropwise addition, the reaction was stirred at -78 °C for 1 hour under heat preservation. Upon completion of the reaction, the mixture was poured into 100 mL of saturated aqueous ammonium chloride solution to quench the reaction, extracted with EA (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 5:1) to obtain intermediate P4-8 as a yellow liquid (500 mg, 92%).

[0184] Step 8.5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid: 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 temperature was raised to 80 °C, and the mixture was refluxed with stirring for 30 minutes. After the reaction was completed, the mixture was filtered, and the filtrate was directly concentrated. The residue was dissolved in 10 mL of EA, washed with 5 mL of water, and the layers were separated. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain intermediate P4-9 (300 mg, crude product).

[0185] Step 9. perfluorophenyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate: Crude intermediate P4-9 (300 mg) was dissolved in DCM (5 mL). DMF (0.05 mL) was added, and oxalyl chloride (314 mg, 2.5 mmol) was slowly added dropwise to the reaction at room temperature. After the dropwise addition, the reaction was stirred at room temperature for 20 minutes, and upon completion, the mixture was directly concentrated. In a separate three-necked flask, pentafluorophenol (228 mg, 1.3 mmol) was dissolved in DCM (10 mL). Under nitrogenprotection, the temperature was cooled to 0 °C, and triethylamine (250 mg, 2.5 mmol) was slowly added to the reaction. The mixture was stirred at 0 °C for approximately 15 minutes under heat preservation. The concentrated solution was dissolved in DCM (5 mL) and slowly added dropwise to the reaction while controlling the temperature at 0 °C. After the dropwise addition, the temperature was raised to room temperature, and the reaction was stirred for 30 minutes. Upon completion, the mixture was poured into approximately 50 mL of ice water. extracted with DCM (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain P4 as a yellow solid (150 mg) with a two-step yield of 37%. ¹H 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).

[0186] Example 5: (2-((perfluorophenoxy (carbonyl)- lH-indole-5-carbonyl)phosphonic acid (P5)

[0187] Step 1. perfluorophenyl 5-((diethoxyphosphoryl)difluoromethyl)-lH-indole-2-carboxylate: 5-((Diethoxyphosphoryl)difluoromethyl)-lH-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. Saturated sodium bicarbonate solution was added to quench the reaction, the layers were separated, and the solvent was evaporated to dryness. The residue was purified by silica gel column chromatography (DCM / methanol = 20: 1) to obtain intermediate P5-1 as a white solid (4.0 g, 30%). ¹H 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].

[0188] Step 2: (difluoro(2-((perfluorophenoxy)carbonyl)-lH-indol-5-yl)methyl)phos phonic acid: Compound P5-1 (1.0 g, 2.0 mmol) and DCM (5 mL) were added to the flask. The solution was cooled to 0°C, and then TMSBr (612 mg, 4.0 mmol) was added.The reaction mixture was stirred at room temperature until the starting material disappeared. The solvent was evaporated to dryness, and the residue was dissolved in a mixture of acetonitrile and water, then purified by reverse-phase silica gel column chromatography (water / acetonitrile = 4: 1) to obtain an acetonitrile-water solution of P5-2. which was used directly in the next step. LC-MS (m / z): 456.1 [M - H]-.

[0189] Step 3: (2-((perfluorophenoxy)carbonyl)-1H-indole-5-carbonyl)phosphonic acid:TFA (8 mL) was added to the acetonitrile-water solution of compound P5-2. The mixture was heated to 52 °C for 3 days. The solvent was evaporated, and the resulting precipitate was collected by filtration and washed with purified water to obtain compound P5 (400 mg, 46% yield over two steps). LC-MS (m / z): 434.0 [M - H].

[0190] Example 6: ((7-(((5S,8S,10aR)-3-(3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yl)propanoyl)-8-(morpholine-4-carbonyl)-6-oxodecahy dropy rrolo[ 1,2-a] [ 1, 5] diazocin-5 -y l)carbamoy l)naphthalen-2-yl)fluoromethyl)phosphonic acid (Al)

[0191] Step 1. benzyl 4-(3-(tert-butoxy)-3-oxopropyl)piperazine-l-carboxylate: Starting material Al-1 (5 mL) and tert-butyl acrylate (5 mL) were added to a round-bottomed flask, followed by the addition of EtOH (15 mL). The mixture was stirred at 90 °C overnight, and the reaction solution was concentrated to obtain crude oily intermediate Al -2 (6.0 g, 66%), which was used directly in the next step.1H 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).

[0192] Step 2. tert-butyl 3-(piperazin-l-yl)propanoate: Intermediate Al-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 a hydrogen atmosphere. The solid was filtered off and washed with EtOH, and the filtrate was concentrated to obtain crude product Al -3 (1.8 g, 100%).1H 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).

[0193] Step 3. tert-butyl 3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yl)propanoate: 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (1.0 g, 3.0 mmol), intermediate Al-3 (963 mg, 4.5 mmol), RuPhos Pd G2 (466 mg, 0.6 mmol), and RuPhos (280 mg, 0.6 mmol) were added to a three-necked flask. Toluene (15 mL) was added, and LiHMDS (1 M, 18 mL) was slowly added under nitrogen protection and ice bath conditions. The mixture was stirred at 80 °C for 1 hour, then tert-butanol was added to quench the reaction. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / EA / MeOH = 100:100:6) to obtain intermediate Al-4 as ayellow solid (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]+.

[0194] Step 4.3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yl)propanoic acid: Intermediate Al-4 (300 mg, 0.64 mmol) was dissolved in EA hydrochloride (5 mL). The mixture w as stirred at room temperature overnight and then concentrated to obtain crude Al -5 hydrochloride (287 mg, 100%), which was directly used in the next step.

[0195] Step 5. tert-butyl ((5S,8S,10aR)-3-(3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]iinidazol-5-yl)piperazin-l-yl)propanoyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate P3 (150 mg, 0.38 mmol), Al-5 (150 mg, 0.36 mmol), HATU (274 mg, 0.72 mmol), and DIPEA (186 mg, 1.44 mmol) were added to a round-bottomed flask, followed by the addition of DMF (5 mL). The mixture was stirred at room temperature for 2 hours, then concentrated. The residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH = 20:1) to obtain intermediate Al-6 as a yellow solid (90 mg, 31%). LC-MS (m / z): 794.9 [M + H]+.

[0196] Step 6.3-(5-(4-(3-((5S,8S,10aR)-5-amino-8-(morpholine-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-yl)-3-oxopropyl)piperazin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione: Intermediate Al-6 (85 mg, 0.11 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 / 5 mL). The mixture was stirred at room temperature overnight and then directly concentrated to obtain the crude product (70 mg, 91%). LC-MS (m / z): 694.9 [M + H]+.

[0197] Step 7. diethyl ((7-(((5S,8S,10aR)-3-(3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yl)propanoyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonate: Al-7 (70 mg. 0.10 mmol) and intermediate Pl (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, then the reaction solution was concentrated. The residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH = 20:1) to obtain intermediate Al-8 as a yellow solid (85 mg, 84%). 'H NMR (400 MHz, CDCL) 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]+.

[0198] Step 8. ((7-(((5S,8S,10aR)-3-(3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yl)propanoyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid: Intermediate Al-8 (80 mg, 0.08 mmol) was dissolved in DCM (5 mL), and TMSBr (0.5 mL) was added. The mixture was stirred at room temperature for 24 hours under nitrogen protection, then concentrated. A small amount of methanol was added, and the mixture was purified by C18 column chromatography (CH3CN / H2O = 3:7) to obtain final product A1 (37 mg, 48%).

[0199] Example 7: ((7-(((5S,8S.10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopipendin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahy dropyrrolo[ 1,2-a] [ 1, 5] diazocin-5 -yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid (A2)A2-7 step 7 A2-8step 8 A2-9 step 9step 10 A2

[0200] Step 1.4-oxocyclohexane-l-carboxylic acid: Starting material A2-1 (5.0 g, 14 mmol) was dissolved in THF (50 mL). LiOH•H2O (3.4 g, 41 mmol) was dissolved in water (40 mL), and this aqueous solution was added to the reaction mixture. The mixture was stirred at room temperature overnight. A 2N aqueous HC1 solution was added to adjust the pH to acidic, and the organic phase was extracted with DCM (50 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain crude product A2-2 (5.0 g, crude), which was directly used in the next step.

[0201] Step 2. tert-butyl 2-(4-oxocyclohexyl)acetate: Intermediate A2-2 (9.5 g, 67 mmol) was dissolved in DCM (250 mL). Under ice bath conditions, oxalyl chloride (23 g, 183 mmol) was added, followed by the dropwise addition of DMF (5 mL). The mixture was stirred at room temperature for 2 hours, then concentrated. The residue was dissolved in DCM (250 mL), and DIPEA (16 g, 122 mmol) was added under ice bath conditions, followed by the slow addition of tert-butanol (50 mL). The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 10:1) to obtain A2-3 as a yellow oil (7.0 g, 49%). 'H NMR (400 MHz, CDC13) 52.40 - 2.32 (m, 4H), 2.26 - 2.17 (m, 3H), 2.11 - 2.00 (m, 2H), 1.51 - 1.39 (m, 11H).

[0202] Step 3. tert-butyl 2-(4-methylenecyclohexyl)acetate: Methyltriphenylphosphonium bromide (17 g, 49 mmol) was dissolved in tetrahydrofuran (180 mL). Under nitrogen protection at 0 °C, potassium tert-butoxide (5.4 g, 49 mmol) was added. The mixture was further stirred under ice bath conditions for 10 minutes, then w armed to room temperature and stirred for 2 hours. A2-3 (5.1 g, 24 mmol) was dissolved in tetrahydrofuran (20 mL), and this solution was added dropwise to the reaction mixture under ice bath conditions. The mixture was w armed to room temperature and stirred for another 30 minutes, then heated to 50 °C and stirred overnight. The reaction solution was concentrated, and the residue w as purified by silica gel column chromatography (PE / EA = 50:1) to obtain A2-4 as a colorless transparent oil (4.5 g, 88%).1H NMR (400 MHz, CDCl3) δ 4.60 (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).

[0203] Step 4. tert-butyl 2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methylene)cyclohexyl)acetate: 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (2.7 g, 7.9 mmol), A2-4 (2.5 g, 11.9 mmol), Pd2(dba)s (724 mg, 0.79 mmol), and DIPEA (2.0 g, 15.8 mmol) were dissolved in DMF (40 mL). A 10% solution of P(t-Bu)3(3.2 g, 1.6 mmol) was added at room temperature, and the mixture was stirred at 80°C overnight under nitrogen protection. The mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA / MeOH = 50:50: 1) to obtain A2-5 as a yellow solid (2.5 g, 67%).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]+.

[0204] Step 5. tert-butyl 2-((ls,4s)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetate: Intermediate A2-5 (2.5 g, 5.3 mmol) was dissolved in ethanol (20 mL). Formic acid (2 mL) and 10% Pd / C (227 mg, 2.1 mmol) were added, and the mixture was stirred at 80 °C for 2 hours. The solid was filtered off and washed with ethanol, and the filtrate was concentrated to obtain crude product A2-6 (2.5 g, 100%), which was directly used in the next step. LC-MS (m / z): 470.5 [M + H]+.

[0205] Step 6.2-((ls,4s)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetic acid: Intermediate A2-6 (2.5 g, 5.3 mmol) was dissolved in DCM (15 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 2 hours, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 50: 1) to obtain A2-7 as a white solid (1.8 g, 82%).1H 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]+.

[0206] Step 7. tert-butyl ((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cycIohexyl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2- a] [ 1,5] diazocin-5-yl)carbamate: Intermediate P3 (143 mg, 0.36 mmol), 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-bottomed flask, followed by the addition of DMF (5 mL). The mixture was stirred at room temperature overnight, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 25: 1) to obtain A2-8 as a white solid (140 mg, 49%). LC-MS (m / z): 792.9 [M + H]+.

[0207] Step 8.3-(5-(((lR,4s)-4-(2-((5S,8S,10aR)-5-amino-8-(morpholine-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-yl)-2-oxoethyl)cyclohexyl)methyl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione: Intermediate A2- 8 (85 mg, 0.11 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 / 5 mL). The mixture was stirred at room temperature overnight and then directly concentrated to obtain crude product A2- 9 (170 mg, crude).

[0208] Step 9. diethyl ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2- a] [ 1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonate: Crude A2-9 (70 mg, 0.10 mmol) and intermediate Pl (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, then the reaction solution was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20: 1) to obtain A2-10 as a colorless transparent liquid (100 mg, 99%). LC-MS (m / z): 1015.3 [M + H]+.

[0209] Step 10. ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid: Intermediate A2-10 (100 mg, 0.10 mmol) was dissolved in DCM (5 mL), and TMSBr (1 mL) was added. The mixture was stirred at room temperature for 24 hours under nitrogen protection, then concentrated. A small amount of methanol was added, and the mixture was purified by C18 column chromatography (CH3CN / H2O = 3 / 7) to obtain final product A2 (50 mg, 52%).

[0210] Example 8: ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (A3)TMSBrDCMstep 2

[0211] Step 1. diethyl ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H- benzo [d] imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2- a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonate: Crude intermediate A2-9 (100 mg, 0.14 mmol) and 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, then the reaction solution was concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 50:3) to obtain intermediate A3-1 as a white solid (75 mg, 52%).

[0212] Step 2. ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyI-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid: Intermediate A3-1 (70 mg, 0.070 mmol) was dissolved in DCM (5 mL), and TMSBr (1 mL) was added. The mixture was stirred overnight at room temperature under nitrogen protection, then concentrated. Water (1 mL) was added to quench the reaction, followed by the addition of acetonitrile (1 mL). The mixture was purified by Cl 8 column chromatography (CH3CN / H2O = 3:7) to obtain final product A3 (30 mg, 44%).

[0213] Example 9: ((7-(((5S,8S.10aR)-3-(2-(4-((l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid (A4)K2[OsO2(OH)4] NalO4Pd(dppf)CI2K2C03dioxanedioxane / H20step 1 step 2Istep 4 A4-4A4-6 step 7

[0214] Step 1.3-(3-methyl-2-oxo-5-vinyl-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione: Starting material 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (338 mg, 1.0 mmol), potassium vinyltrifluoroborate (402 mg, 3.0 mmol), anhydrous potassium carbonate (276 mg, 2.0 mmol), and Pd(dppf)C12 (73.2 mg, 0.10 mmol) were dissolved in dry dioxane (10 mL). The mixture was stirred at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the mixture was concentrated and purified by silica gel column chromatography (PE / EA = 1: 1) to obtain intermediate A4-1 as a pale-yellow solid (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).

[0215] Step 2. l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazole-5-carbaldehyde: Intermediate A4-1 (210 mg, 0.73 mmol) was dissolved in a mixture of dioxane / water = 10 mL / 5 mL. K2[OsO2(OH)4] (27 mg, 73 pmol), sodium periodate (624 mg. 2.9 mmol), and 2,6-lutidine (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 DCM (20 mL x 3). The layers were separated, the organic phase was concentrated and then purified by silica gel column chromatography (PE / EA = 1:1) to obtain intermediate A4-2 as a white solid (150 mg, 72%).1H 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).

[0216] Step 3. tert-butyl 2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetate: A4-2 (150 mg, 0.52 mmol) was dissolved in DCM (2 mL), followed by the addition of tert-butyl 2-(piperidin-l-yl)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 to dryness, the residue was purified by silica gel column chromatography (DCM / methanol = 20: 1) to obtain A4-3 as a yellow oil (120 mg, 49%).

[0217] Step 4.2-(4-((l-(2,6-dioxopiperidin-3-yI)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetic acid: Intermediate A4-3 (120 mg, 0.25 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was stirred at room temperature for 16 hours. After concentration, crude A4-4 (150 mg) was obtained, which was directly used in the next step. LC-MS (m / z): 416.5 [M + H]+

[0218] Step 5. tert-butyl ((5S,8S,10aR)-3-(2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Crude A4-4 (150 mg) was dissolved in DMF (5 mL). 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. After the solvent was evaporated to dryness, the residue was purified by silica gel column chromatography (DCM / methanol = 30: 1) to obtain A4-5 as a yellow oil (100 mg, 50% yield over two steps). LC-MS (m / z): 795.0 [M + H]+.

[0219] Step 6.3-(5-((4-(2-((5S,8S,10aR)-5-amino-8-(morpholine-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-yl)-2-oxoethyl)piperazin-l-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione: Intermediate A4- 5 (100 mg, 0.13 mmol) was dissolved in DCM (4 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 16 hours. After concentration, crude A4- 6 (130 mg) was obtained, which was directly used in the next step. LC-MS (m / z): 694.7 [M + H]+.

[0220] Step 7. diethyl ((7-(((5S,8S,10aR)-3-(2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonate: Crude intermediate A4-6 (130 mg, 0.19 mmol), intermediate Pl (207 mg. 0.30 mmol), DIPEA (78 mg. 0.60 mmol), and DMF (2 mL) were added to a reaction flask. The mixture was stirred at room temperature for 2 hours. After the solvent was evaporated to dryness, the residue was purified by silica gel column chromatography (DCM / methanol = 40:1) to obtain A4-7 as a yellow oil (90 mg, 70% yield over two steps). LC-MS (m / z): 1016.8 [M + H]+.

[0221] Step 8. ((7-(((5S,8S,10aR)-3-(2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid: A4-7 (90 mg, 88 pmol) was dissolved in DCM (5 mL), and TMSBr (1 mL) was added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated to dryness, and the residue was purified by reverse-phase silica gel column chromatography (water / acetonitrile = 4:1) to obtain final product A4 (11 mg, 13%).

[0222] Example 10: ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropy rrolo| 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid (A5)(BocfeO CHjI, CS2CO3 TFA O. ^ A A ~Boc O^ / ^ A^N-BOC DMF TEA, THF DCM step 7 A5-8 step S A5-9 step 9 A5-10HO-P=OOH

[0223] Step 1. 7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid:Intermediate Pl (200 mg, 0.40 mmol) was dissolved in DCM (10 mL), and TMSBr (2 mL) was added. The mixture was stirred overnight at room temperature under nitrogen protection, then concentrated. The mixture was purified by C18 column chromatography (CH3CN / H2O = 3:7) to obtain A5-1 as a white solid (110 mg, 61%). 'H NMR (400 MHz, DMSO-d6) 88.93 (s, 1H), 8.20 (s, 1H), 8.15 (d, J= 8.8 Hz, 1H), 8.13 - 8.05 (m, 2H), 7.79 (d, J= 8.4 Hz, 1H), 5.79 (dd, J = 44.4. 8.8 Hz, 1H). LC-MS (m / z): 449.2 [M - H].

[0224] Step 2. methyl 2-(2-methoxypyridin-4-yl)acetate: A5-2 (50 g, 406 mmol) was dissolved in anhydrous THF (500 mL). After nitrogen protection, the temperature was cooled to-65 °C, and LDA (243 mL, 485 mmol) was added dropwise. After the dropwise addition, the reaction was stirred at -65 °C for 1 hour. While controlling the temperature at -65 °C, dimethyl carbonate (40 g, 445 mmol) was added dropwise, and the mixture was stirred at -65 °C for 1 hour after the addition. Upon completion of the reaction, the reaction was quenched with saturated aqueous NH4Cl solution (500 mL) and extracted with EA (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2: 1) to obtain A5-3 as a yellow liquid (34 g, 46%).

[0225] Step 3. methyl 3-cyano-2-(2-methoxypyridin-4-yl)propanoate: Intermediate A5-3 (34 g, 188 mmol) was dissolved in anhydrous THF (350 mL). After nitrogen protection, the temperature was cooled to -65 °C, and LDA (141 mL, 281 mmol) was added dropwise. After the dropwise addition, the reaction was stirred at -65 °C for 1 hour. While controlling the temperature at -65 °C, bromoacetonitrile (27 g, 225 mmol) was added dropwise, and the mixture was stirred at -65 °C for 1 hour after the addition. Upon completion of the reaction, the reaction was quenched with saturated aqueous NH4Cl solution (300 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 2: 1) to obtain A5-4 as a yellow solid (30 g, 72%).

[0226] Step 4.6-(2-methoxypyridin-4-yl)-4-azaspiro[2.4]heptan-5-one: Intermediate A5-4 (30 g, 136 mmol) and tetraisopropyl titanate (19 g, 68 mmol) were dissolved in anhydrous THF (500 mL). After nitrogen protection, the temperature was cooled to 0 °C, and ethylmagnesium bromide (93 mL, 313 mmol) was added dropwise. After the dropwise addition, the mixture was stirred at 0 °C for 1 hour. Upon completion of the reaction, the reaction was quenched with 2N aqueous hydrochloric acid solution (250 mL) and extracted with EA (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1: 1) to obtain A5-5 as a pale-yellow solid (9.0 g, 30%).

[0227] Step 5.6-(2-methoxypyridin-4-yl)-4-azaspiro[2.4]heptane: Intermediate A5-5 (7.0 g, 32 mmol) and RhCO(PPh3)3(1.5 g, 1.6 mmol) were added to a three-necked flask. 1,4-Dioxane (120 mL) was added, followed by the addition of PhSiH3(20.3 g, 192 mmol) under nitrogen protection. The mixture was stirred at 100 °C overnight. The reaction was quenched with methanol, the mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to obtain a pale-yellow oil (3.0 g, 46%). LC-MS (m / z): 205.3 [M + H]+.

[0228] Step 6.4-(4-azaspiro[2.4]heptan-6-yl)pyridin-2(lH)-one: Intermediate A5-6 (2.1 g, 10 mmol) was added to a round-bottomed flask. A 30% aqueous HBr solution (10 mL) and a 30% HBr acetic acid solution (5 mL) were added, and the mixture was stirred at 100 °C overnight. After concentration, the pH of the residue was adjusted to alkaline with saturated aqueous sodium bicarbonate solution, and further concentration gave crude A5-7, which was directly used in the next step. LC-MS (m / z): 191.3 [M + H]+.

[0229] Step 7. tert-butyl 6-(2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carboxylate: Crude intermediate A5-7 (1.9 g, 10 mmol) was dissolved in tetrahydrofuran (40 mL). (Boc)2O (3.5 g. 16 mmol) and triethylamine (1.9 g, 19 mmol) were added, and 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) to obtain A5-8 as a yellow solid (2.1 g, 72%). *HNMR (400 MHz, CDC13) 5 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]+.

[0230] Step 8. tert-butyl 6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carboxylate: Intermediate A5-8 (580 mg, 2.0 mmol) was dissolved in DMF (10 mL). Cesium carbonate (2.0 g, 6.0 mmol) and methyl iodide (568 mg, 4.0 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50: 1) to obtain A5-9 as a colorless viscous oil (300 mg, 50%). 'H NMR (400 MHz, CDCl₃) 5 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).

[0231] Step 9. l-methyl-4-(4-azaspiro[2.4]heptan-6-yl)pyridin-2(lH)-one: Intermediate A5-9 (300 mg, 1.0 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 4 hours, then concentrated to obtain crude A5-10 (300 mg, crude), which was directly used in the next step.

[0232] Step 10. benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(6-(l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-4- azaspiro [2.4] heptane-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocine-3(4H)-carboxylate: Intermediate P3-3 (270 mg, 0.58 mmol), crude A5-10 (300 mg, 1.5 mmol), HATU (331 mg, 0.87 mmol), and DIPEA (300 mg, 2.3 mmol) were dissolved in DCM (20 mL). The mixture was stirred at room temperature for 4 hours, then concentrated. The residue was purified by silica gel column chromatography(DCM / MeOH = 100:3) to obtain A5-11 as a viscous oil (200 mg. 53%). LC-MS (m / z): 648.7 [M + H]+.

[0233] Step 11. tert-butyl ((5S,8S,10aR)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate A5-11 (200 mg, 0.31 mmol) was dissolved in ethanol (5 mL). 10% Pd / C (164 mg, 1.6 mmol) and ammonium formate (372 mg, 3.1 mmol) were added, and the mixture was stirred at 80 °C for 10 minutes. The solid was filtered off and washed with DCM, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM / 7N NH3·MeOH = 100:3) to obtain A5-12 as a white solid (130 mg, 82%). LC-MS (m / z): 514.4 [M + H]+.

[0234] Step 12. tert-butyl ((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-methyl-2-oxo- l,2-dihydropyridin-4-yl)-4-azas piro [2.4] heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: 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, then A5-12 (130 mg, 0.25 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to obtain A5-13 as a white solid (130 mg, 46%). LC-MS (m / z): 909.9 [M + H]+.

[0235] Step 13.3-(5-(((lR,4s)-4-(2-((5S,8S,10aR)-5-amino-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-yl)-2-oxoethyl)cyclohexyl)methyl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazoI-l-yl)piperidine-2, 6-dione: Intermediate A5-13 (50 mg, 0.055 mmol) was dissolved in a mixed solvent (TFA / DCM = lmL / 3 mL). The mixture was stirred at room temperature for 1 hour, then directly concentrated to obtain crude A5-14 (50 mg, crude).

[0236] Step 14. ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyI)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid: Intermediate A5-14 (45 mg, 0.055 mmol) was dissolved in DMF (2 mL). A5-1 (22 mg, 0.050 mmol) and DIPEA (0.5 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The mixture was purified by Cl 8 column chromatography (CH3CN / H2O = 3:7) to obtain final product A5 (20 mg, 37%).

[0237] Example 11: ((7-(((5S.8S,10aR)-3-(2-((ls.4R)-4-((l-(2.6-dioxopipendin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahy dropy rrolo[ 1,2-a] [ 1, 5] diazocin-5 -y l)carbamoy l)naphthalen-2-yl)difluoromethyl)phosphonic acid (A6)step 2

[0238] Step 1. (difluoro(7-(((l-fluoro-2Il-diphosphaneyI)oxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid: Intermediate P2 (195 mg, 0.37 mmol) was dissolved in DCM (5 mL), and TMSBr (1 mL) was added. The mixture was stirred overnight at room temperature, then concentrated. The residue was purified by C18 column chromatography (CH3CN / H2O = 3:7) to obtain intermediate A6-1 as a white solid (120 mg, 69%).NMR (400 MHz, DMSO-d6) 59.12 (s, 1H), 8.45 (s, 1H), 8.29 - 8.16 (m, 3H), 7.86 (d, J= 8.8 Hz, 1H).

[0239] LC-MS (m / z): 467.4 [M - H].

[0240] Step 2. ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid:Intermediate A5-14 (30 mg, 0.037 mmol) was dissolved in DMF (1 mL). A6-1 (16 mg, 0.034 mmol) and DIPEA (0.5 mL) were added, and the mixture was stirred at room temperature for 30 minutes. The mixture was purified by C18 column chromatography (CH3CN / H2O = 2:8) to obtain final product A6 (15 mg, 40%).

[0241] Example 12: ((7-(((5S,8S,10aR)-3-(8-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)oct-7-ynoyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[ 1,2-aJ [ l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid (A7)

[0242] Step 1.8-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazoI-5-yl)oct-7-ynoic acid: 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (338 mg, 1.0 mmol), A7-1 (210 mg, 1.5 mmol), Pd(dppf)C12 (70 mg, 0.10 mmol), and Cui (20 mg, 0.10 mmol) were added to a three-necked flask. DMF (4 mL) and triethylamine (2 mL) were added, and 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) to obtain intermediate A7-2 as a yellow solid (300 mg, 76%). LC-MS (m / z): 398.4 [M + H]+.

[0243] Step 2. tert-butyl ((5S,8S,10aR)-3-(8-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)oct-7-ynoyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate P3 (110 mg, 0.28 mmol), 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-bottomed flask, followed by the addition of DCM (5 mL). The mixture was stirred at room temperature overnight, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 25: 1) to obtain intermediate A7-3 as a yellow solid (100 mg, 52%). LC-MS (m / z): 776.8 [M + H]+.

[0244] Step 3.3-(5-(8-((5S,8S,10aR)-5-amino-8-(morpholine-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-yl)-8-oxooct-l-yn-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione: A7-3 (50 mg, 0.064 mmol) was dissolved in DCM (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 30 minutes, then concentrated to obtain crude A7-4 (43 mg, 100%. crude), which was directly used in the next step.

[0245] Step 4. ((7-(((5S,8S,10aR)-3-(8-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)oct-7-ynoyl)-8-(morpholine-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid: Intermediate A7-4 (43 mg, 0.064 mmol) was dissolved in DMF (1 mL). A5-1 (29 mg, 0.064 mmol) and DIPEA (33 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was purified by Cl 8 column chromatography (CH3CN / H2O = 3:7) to obtain final product A7 (4 mg, 6.7%).

[0246] Example 13: ((7-(((5S.8S,10aR)-3-(3-(4-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yl)propanoyl)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a] [l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid (A8)oA8-2 step 3o

[0247] Step 1. tert-butyl ((5S,8S,10aR)-3-(3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yI)propanoyI)-8-(6-(l-methyl-2-oxo-1, 2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate A5-12 (40 mg, 0.080 mmol). Al-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) to obtain intermediate A8-1 as a colorless transparent substance (35 mg, 48%). LC-MS (m / z): 911.9 [M + H]+.

[0248] Step 2.3-(5-(4-(3-((5S,8S,10aR)-5-amino-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-yl)-3-oxopropyl)piperazin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione: Intermediate A8-1 (35 mg, 0.038 mmol) was dissolved in a mixed solvent (TFA / DCM = lmL / 3 mL). The mixture was stirred at room temperature for 2 hours, then directly concentrated to obtain crude product A8-2 (100 mg, crude).

[0249] Step 3. ((7-(((5S,8S,10aR)-3-(3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperazin-l-yl)propanoyl)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)fluoromethyl)phosphonic acid:Intermediate A8-2 (31 mg, 0.038 mmol) was dissolved in DMF (1 mL). A5-1 (14 mg, 0.032 mmol) and DIPEA (12 mg, 0.091 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The mixture was purified by C18 column chromatography (CH3CN / H2O = 2:8) to obtain final product A8 (20 mg, 49%).

[0250] Example 14: ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolof 1,2-a] [ l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (A9)HATU, DIPEA DCMstep 3step 5 D3C A9-51) TFA, DCMDIPEA, DMFstep 6

[0251] Step 1. tert-butyl 6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carboxylate: Intermediate A5-8 (870 mg, 3.0 mmol) was dissolved in DMF (15 mL). Cesium carbonate (2.9 g, 9.0 mmol) and deuterated methyl iodide (870 mg, 6.0 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50: 1) to obtain A9-1 as a yellow oil (500 mg, 54%).

[0252] Step 2. l-(methyl-d3)-4-(4-azaspiro[2.4]heptan-6-yl)pyridin-2(lH)-one:Intermediate A9-1 (500 mg, 1.6 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (2 mL) was added. The mixture was stirred at room temperature for 2 hours, then concentrated to obtain crude A9-2 (1.2 g, crude), which was directly used in the next step.

[0253] Step 3. benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(6-(l-(methyl-d3)-2-oxo- 1,2-dihy d ropyridin-4-yl)-4-azas pi ro [2.4] heptane-4-carbony l)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocine-3(4H)-carboxylate: Intermediate P3-3 (379 mg,0.82 mmol), A9-2 (170 mg, 0.82 mmol), 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, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 50:1) to obtain A9-3 as a viscous oil (300 mg, 56%). LC-MS (m / z): 651.6 [M + H]+.

[0254] Step 4. tert-butyl ((5S,8S,10aR)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate A9-3 (300 mg, 0.46 mmol) was dissolved in ethanol (15 mL). 10% Pd / C (98 mg, 0.92 mmol) and ammonium formate (290 mg, 4.6 mmol) were added, and the mixture was stirred at 80 °C for 10 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) to obtain A9-4 as a white solid (200 mg, 84%).

[0255] Step 5. tert-butyl ((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate A2-7 (100 mg, 0.24 mmol), 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). 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) to obtain A9-5 as a white solid (170 mg, 98%).

[0256] Step 6. ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid: Intermediate A9-5 (90 mg, 0.099 mmol) was dissolved in a mixed solvent (TFA / DCM = 2mL / 4 mL). The mixture was stirred at room temperature for 2 hours, then directly concentrated to obtain a crude product. The crude product was dissolved in DMF (2 mL), and A6-1 (42 mg, 0.09 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 2 hours, then purified by C18 column chromatography (CH3CN / H2O = 2:8) to obtain final product A9 (65 mg, 60%).

[0257] Example 15: ((7-(((5S,8S,10aR)-3-(2-((ls.4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (Al 0)P3-3 step 1 step 2 A10-2

[0258] Step 1. benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxo-8-((R)-2-phenylmorphoIine-4-carbonyI)octahydropyrrolo[l,2-a][l,5]diazocine-3(4H)-carboxylate: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, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 50: 1) to obtain A10-1 (200 mg, 100%, crude).

[0259] Step 2. tert-butyl ((5S,8S,10aR)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Crude A10-1 (200 mg, 0.33 mmol) was dissolved in EtOH (10 mL). Ammonium formate (376 mg, 3.3 mmol) and Pd / C (140 mg, 1.3 mmol) were added, and the mixture was stirred at 80 °C for 20 minutes. The solid was filtered off 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) to obtain intermediate A10-2 as a white solid (170 mg. 100%, crude). LC-MS (m / z): 473.4 [M + H]+.

[0260] Step 3. tert-butyl ((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H- benzo [d] imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: A2-7 (100 mg, 0.24 mmol), crude A10-2 (170 mg, 0.36 mmol), 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, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20: 1) to obtain intermediate A10-3 as a white solid (150 mg, 56%).

[0261] Step 4. ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxo-8-((R)-2-phenylmorpholine-4-carbonyl)decahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid: Intermediate Al 0-4 (50 mg, 0.058 mmol) was dissolved in a mixed solvent (TFA / DCM = 2mL / 4 mL). The mixture was stirred at room temperature for 2 hours, then directly concentrated to obtain a crude product. The crude product was dissolved in DMF (2 mL), and A6-1 (25 mg. 0.053 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 1 hour, then purified by C18 column chromatography (CH3CN / H2O = 1:3) to obtain final product A10 (22 mg, 36%).

[0262] Example 16: ((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][L5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (All)P4 step 1 A11-1

[0263] Step 1. (difluoro(2-(((l-fluoro-211-diphosphaneyl)oxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid: Intermediate P4 (160 mg, 0.3 mmol) was dissolved in DCM (5 mL), and TMSBr (1 mL) was added. The mixture was stirred at room temperature for 24 hours, then concentrated. The residue was purified by C18 column chromatography (CH3CN / H2O =3:7) to obtain intermediate All-1 as a white solid (55 mg, 39%).1H NMR (400 MHz, CDCl3) δ 8.27 – 8.10 (m, 2H), 7.88 – 7.67 (m, 2H). LC-MS (m / z): 473.1 [M - H].

[0264] Step 2. ((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cydohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)benzo [b] thiophen-5-yl)difluoromethyl)phosphonic acid: Intermediate A9-5 (50 mg, 0.055 mmol) was dissolved in a mixed solvent (TFA / DCM = lmL / 3 mL). The mixture was stirred at room temperature for 2 hours, then directly concentrated to obtain a crude product. The crude product was dissolved in DMF (2 mL), and All-1 (23 mg, 0.05 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 2 hours, then purified by C18 column chromatography (CH3CN / H2O = 2:8) to obtain final product Al 1 (22 mg, 40%).

[0265] Example 17: ((2-(((5S,8S,10aR)-3-(2-((ls.4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolof 1,2-a] [1, 5]diazocin-5-yl)carbamoyl)benzo [b] thi ophen-5 -yl)difluoromethyl)phosphonic acid (Al 2)

[0266] Step 1. tert-butyl ((5S,8S,10aR)-3-(8-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazoI-5-yl)oct-7-ynoyI)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: A9-4 (40 mg, 0.078 mmol), 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-bottomed flask, followed by the addition of DMF (2 mL). The mixture was stirred at room temperature for2 hours, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20:1) to obtain intermediate Al 2-1 as a yellow solid (58 mg, 83%).

[0267] Step 2. ((7-(((5S,8S,10aR)-3-(8-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)oct-7-ynoyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid:Intermediate A12-1 (50 mg, 0.055 mmol) was dissolved in a mixed solvent (TFA / DCM = 0.2mL / 3 mL). The mixture was stirred at room temperature for 30 minutes, then directly concentrated to obtain a crude product. The crude product was dissolved in DMF (2 mL), and A6-1 (15 mg, 0.032 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 30 minutes, then purified by C18 column chromatography (CH3CN / H2O = 2:8) to obtain final product Al 2 (22 mg, 64%).

[0268] Example 18: diethyl ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahy dropy rrol o| 1,2-a] [ 1, 5] diazocin-5 -yl)carbamoyl)naphthalen-2-

[0269] Step 1. diethyl ((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonate: Intermediate A5-13 (50 mg, 0.055 mmol) was dissolved in a mixed solvent (TFA / DCM = lmL / 3 mL). The mixture was stirred at room temperature for 3 hours, then directly concentrated to obtain a 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, then purified by silica gel column chromatography to obtain final product A13 (12 mg, 21%).

[0270] Example 19: ((((7-(((5S.8S,10aR)-3-(2-((ls.4R)-4-((l-(2,6-dioxopipendin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l- (methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahy dropy rrolo[ 1,2-a] [ 1, 5] diazocin-5 -y l)carbamoy l)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (A14)1) Na+-type cation exchange resin, THF, H2O 2) AgNO33) lodomethyl Pivalate, PhCHjstep 1

[0271] Step 1. (((difluoro(7-((perfluorophenoxy)carbonyl)naphthaIen-2-yl)methyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate): Intermediate A6-1 (300 mg, 0.64 mmol) was dissolved in THF / H2O (5 rnL / 10 mL). Na+-type cation exchange resin (1.8 g) was added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off, and silver nitrate (326 mg, 1.92 mmol) was added to the filtrate. The mixturewas stirred at room temperature for 1 hour in the dark. The solid was filtered off. washed with water, and dried. The dried solid was suspended in toluene (5 mL), then iodomethyl pivalate (620 mg, 2.6 mmol) was added. The mixture was stirred at room temperature for 2 hours, then concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5: 1) to obtain a colorless transparent oil (150 mg. 34%).1H 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).

[0272] Step 2.3-(5-(((lR,4s)-4-(2-((5S,8S,10aR)-5-amino-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-yl)-2-oxoethyl)cyclohexyl)methyl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione: Intermediate A9-5 (100 mg, 0.11 mmol) was dissolved in a mixed solvent (TFA / DCM = 1 mL / 3 mL). The mixture was stirred at room temperature for 2 hours, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20: 1) to obtain A14-2 as a white solid (70 mg, 78%).

[0273] Step 3. ((((7-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yI)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo- 1,2-dihydropy ridin-4-yl)-4-azaspiro [2.4] heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate):Intermediate A14-2 (35 mg, 0.038 mmol) was dissolved in DMF (2 mL). A14-1 (27 mg, 0.038 mmol) and DIPEA (10 mg, 0.076 mmol) were added, and 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) to obtain final product A14 (22 mg, 44%).

[0274] Example 20: ((7-(((5S,8S,10aR)-3-(2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a] [l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (A15)\

[0275] Step 1. tert-butyl ((5S,8S,10aR)-3-(2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Crude A4-4 (50 mg) was dissolved in DMF (1.5 mL). A9-4 (52 mg, 0.1 mmol), HATU (76 mg, 0.2 mmol), and DIPEA (52 mg, 0.4 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After the solvent was evaporated to dry ness, the residue was purified by silica gel column chromatography (DCM / methanol = 20: 1) to obtain A4-5 as a white solid (52 mg. 57%). LC-MS (m / z): 914.9 [M + H]+.

[0276] Step 2.3-(5-((4-(2-((5S,8S,10aR)-5-amino-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocin-3(4H)-yl)-2-oxoethyl)piperazin-l-yl)methyl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione: Intermediate A15-1 (52 mg, 0.57 mmol) was dissolved in DCM (1 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours. After TLC monitoring (DCM / methanol = 20: 1) confirmed no residual Al 5-1, the mixture was concentrated to obtain crude Al 5-2 (60 mg), which was directly used in the next reaction.

[0277] Step 3. ((7-(((5S,8S,10aR)-3-(2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)piperazin-l-yl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid: Crude intermediate A15-2 (60 mg), A6-1 (25 mg, 0.054 mmol), DIPEA (15 mg, 0.14 mmol), and DMF (1 mL) were added to a reaction flask. The mixture was stirred at room temperature for 1 hour, then the solvent was evaporated to dry ness. The residue was purified by reverse-phase silica gel column chromatography (water / acetonitrile = 4:1) to obtain final product A15 (14 mg. 24% yield over two steps).

[0278] Example 21: ((7-(((5S,8S,10aR)-3-(3-(l-(l-(2.6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-4-yl)propanoyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (A16)

[0279] Step 1. tert-butyl 3-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-4-yl)propanoate: tert-Butyl 3-(piperidin-4-yl)propanoate (447 mg, 2.1 mmol), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-l-benzoimidazolyl)piperidine-2, 6-dione (500 mg, 1.4 mmol), Ruphos (65 mg, 0.14 mmol), Pd2(dba)s (128 mg, 0.14 mmol), and potassium tert-butoxide (403 mg, 4.2 mmol) were dissolved in dry 1,4-dioxane (20 mL). The reaction was conducted at 80 °C for 2 hours under nitrogen protection. The pH of the reaction solution was adjusted to 3-4 with formic acid, then concentrated. The residue was purified by silica gel column chromatography (DCM / methanol = 30: 1) to obtain A16-1 as a yellow oil (270 mg, 41%). ' H NMR (400 MHz, CDC13) 58.13 (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]+.

[0280] Step 2. 3-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-4-yl)propanoic acid: A16-1 (270 mg, 0.57 mmol) was dissolved in DCM (5 mL), and trifluoroacetic acid (650 mg, 5.7 mmol) was added. The reactionwas conducted at room temperature for 5 hours. The reaction solution was evaporated to dryness, and the residue was purified by silica gel column chromatography (DCM / methanol = 20:1) to obtain A16-2 as a white solid (170 mg, 72%). LC-MS (m / z): 415.2 [M + H]+.

[0281] Step 3. tert-butyl ((5S,8S,10aR)-3-(3-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-4-yl)propanoyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yI)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Al 6-2 (44 mg, 0.10 mmol), 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). The reaction was conducted at room temperature for 2 hours. The reaction solution was diluted with water and extracted with EA. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM / methanol = 10:1) to obtain A16-3 as a red solid (40 mg, 48%). LC-MS (m / z): 913.7 [M + H]+.

[0282] Steps 4 and 5. ((7-(((5S,8S,10aR)-3-(3-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)piperidin-4-yl)propanoyl)-8-(6-(l-(methyl-d3)- 2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid: A16-3 (40 mg, 0.049 mmol) was dissolved in DCM (4 mL), and trifluoroacetic acid (2 mL) was added. The reaction was conducted 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 A6-1 (21 mg, 0.044 mmol) were added, and the reaction was conducted at room temperature for 1 hour. Isolation by reverse-phase column chromatography (water / acetonitrile = 4:1) gave final product Al 6 (38 mg, 72%).

[0283] Example 22: S. S'-(((((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopipendin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahy dropyrrolo[ 1,2-a] [1, 5]di azocin-5-yl)carbamoyl)benzo [b] thi ophen-5 -yl)difluoromethyl)phosphoryl)bis(oxy ))bis(ethane-2, 1 -diyl)) dibutanethioate (Al 7)o cr 0 l2, PPh3, THFHSEt3N, DCM ^Sstep 1 A17-1 step 2 A17-2

[0284] Step 1. S-(2-hydroxyethyl) butanethioate: The starting materials 2-mercaptoethanol (5.0 g, 64 mmol) and tri ethylamine (6.5 g, 64 mmol) were added to a three-necked flask, followed by the addition of DCM (50 mL). Under nitrogen protection, butyryl chloride (6.8 g, 64 mmol) dissolved in DCM (10 mL) was added dropwise to the reaction solution at -78 °C. The mixture was stirred at -78 °C for 30 minutes, then stirred at room temperature for 2 hours. The mixture was poured into water (100 mL), and the organic phase was extracted with DCM (100 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (PE / EA = 5:1) to obtain A17-1 as a colorless transparent oil (7.5 g, 79%). ‘H NMR (400 MHz, CDC13) 53.71 (t, J= 6.4 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 2.53 (t, 7.2 Hz, 2H), 2.45 (s, 1H), 1.73 - 1.59 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).

[0285] Step 2. S-(2-iodoethyl) butanethioate: Intermediate A17-1 (2.0 g, 14 mmol) was dissolved in tetrahydrofuran (40 mL). Triphenylphosphine (3.5 g. 14 mmol), iodine (3.4 g. 14 mmol), and imidazole (3.4 g, 14 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by silica gel column chromatography (PE / EA = 10:1) to obtain intermediate A17-2 as a pale-yellow liquid (2.5 g, 72%).

[0286] Step 3. perfluorophenyl 5-((bis(2- (butyrylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate:Intermediate All-1 (200 mg, 0.42 mmol) was dissolved in a mixed solvent of water / tetrahydrofuran (4 mL / 2 mL). Cation exchange resin (Amberlite IR-120 Na+, 1.5 g) was added, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off,and silver nitrate (286 mg, 1.7 mmol) was added to the filtrate. After stirring at room temperature for 1 hour, a white solid precipitated. The solid was filtered off, washed with water, dried, and then suspended in toluene (6 mL). A17-2 (433 mg, 1.7 mmol) was added, and the mixture was stirred at room temperature overnight. After concentration, the residue was purified by silica gel column chromatography (PE / EA = 4:1) to obtain intermediate A17-3 as a colorless transparent oil (45 mg, 15%).

[0287] Step 4. S, S'-(((((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)benzo [b] thiophen-5-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,l-diyl)) dibutanethioate: Intermediate A14-2 (45 mg, 0.055 mmol) was dissolved in DMF (2 mL). DIPEA (0.5 mL) and intermediate A17-3 (40 mg, 0.055 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was poured into IN aqueous hydrochloric acid solution (30 mL). and the organic phase was extracted with EA (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (DCM / methanol = 20:1) to obtain final product A17 (8 mg, 11%).

[0288] Example 24: (2-(((5S,8S.10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-I,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahy dropyrrolof 1,2-a] [ 1, 5] diazocin-5 -yl)carbamoyl)- lH-indole-5 -carbonyl)phosphonic acid (Al 8)

[0289] Step 1. (2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)- 2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)-lH-indole-5-carbonyl)phosphonic acid: Intermediate A15-2 (40 mg, 50 pmol). Intermediate P5 (16 mg. 39 pmol), DIPEA (13 mg, 0.10 mmol), and DMF (1 mL) were added to a reaction flask. The mixture was stirred at room temperature for 1 hour, then the solvent was evaporated to dry ness. The residue was purified by reverse-phase silica gel column chromatography (water / acetonitrile = 4: 1) to obtain the final product Al 8.

[0290] Example 25: S-(2-((((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopipendin-3-yl)- 3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[ 1,2-a] [1, 5]di azocin-5-yl)carbamoyl)benzo [b] thi ophen-5 -yl)difluoromethyl)(hydroxy)phosphoryl)oxy)ethyl) butanethioate (A19)

[0291] Step 1. S-(2-((((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)benzo [b] thiophen-5-yl)difluoromethyl)(hydroxy)phosphoryl)oxy)ethyl) butanethioate: Al 7 (40 mg, 0.029 mmol) was dissolved in a mixed solvent of acetonitrile / water (2 mL / 2 mL), and the mixture was stirred at 80 °C for 6 hours. The mixture was purified by reverse-phase C18 column chromatography (acetonitrile / water = 3 / 7) to obtain the final product A19 (13 mg, 36%).

[0292] Example 26: ((7-(((lS,3S,6S,10aS)-l-((7-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3 -dihydro- 1 H-benzo[d] imidazol-5 -yl)hept-6-yn- 1 -yl)oxy)-3 -(6-( 1 -(methyl-d3)-2-oxo- 1,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid (A20)OH OTBS OTBS OTBS TBSCI NalO4, RuO2 LiBHEts TEA. AcOH DMF H2O THF DMAP. DC Mstep t A20-1 step 2 A20-2 step 3 A20-3 step 4A20-4 step 5 A20-5 step 6 A20-6 step 7 A20-7step 8 A20-8 step 9 A20-9 step 10 step 11step 14 A20-14 step 15 A20-15step 16 A20

[0293] Step 1. l-(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate: Methyl N-Boc-cis-4-hydroxy-L-prolinate (50 g, 204 mmol) was dissolved in DMF (350 mL), and imidazole (28 g, 408 mmol) was added. After nitrogen replacement, the temperature was cooled to 0 °C, and tert-butyldimethylsilyl chloride (37 g, 245 mmol) was added dropwise. The mixture was stirred at room temperature overnight, then quenched with 1000 mL of ice water. EA was added for extraction until no product remained in the aqueous phase. The combined organic phases were washed with water and brine successively, dried, and concentrated to obtain A20-1 as a colorless liquid (70 g, 95%).

[0294] Step 2. 1 -(tert- butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-5-oxopyrrolidine-l,2-dicarboxylate: Sodium periodate (36 g, 167 mmol) was dissolved in water (100 mL), and ruthenium dioxide hydrate (2.0 g) was added. A20-1 (20 g, 56 mmol) dissolved in 100 mL of EA was added dropwise to the reaction system. The mixture was stirred at room temperature overnight, and the solid was filtered off. The filtrate was separated, and the EA phase was quenched with saturated aqueous sodium thiosulfate solution, then washed with water and brine successively. After dry ing and concentration, A20-2 was obtained as a yellow oil (15 g, 72%).

[0295] Step 3. l-(tert-butyl) 2-methyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-5-hydroxypyrrolidine-l,2-dicarboxylate: A20-2 (20 g, 53.6 mmol) was dissolved in anhydrous THF (80 mL). After nitrogen replacement, the temperature was cooled to -78 °C, and 1.0 N lithium triethylborohydride (59 mL) was added dropwise. The mixture was stirred at -78 °C for3 hours, then quenched with saturated aqueous sodium bicarbonate solution. EA was added for extraction until no product remained in the aqueous phase. The combined organic phases were washed with water and brine successively, dried, and concentrated to obtain A20-3 as a colorless liquid (12 g, 60%).

[0296] Step 4. l-(tert-butyl) 2-methyl (2S,4S)-5-acetoxy-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylate: A20-3 (50 g, 133 mmol) was dissolved in DCM (500 mL), and tri ethylamine (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, then quenched with saturated aqueous sodium bicarbonate solution. DCM was added for extraction until no product remained in the aqueous phase. After drying and concentration, the residue was purified by silica gel column chromatography (PE / EA = 10:1) to obtain A20-4 as a colorless liquid (40 g, 72%).

[0297] Step 5. l-(tert-butyl) 2-methyl (2S,4S)-5-allyl-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylate: A20-4 (50 g, 133 mmol) was dissolved in DCM (500 mL). After nitrogen replacement, the temperature was cooled to -78 °C, and boron trifluoride diethyl etherate (34 g, 240 mmol) and allyltrimethylsilane (49 g, 432 mmol) were added. The mixture was stirred at -78 °C for 3 hours, then quenched with saturated aqueous sodium bicarbonate solution. DCM was added for extraction until no product remained in the aqueous phase. After drying and concentration, the residue was purified by silica gel column chromatography (PE / EA = 10:1) to obtain A20-5 as a colorless liquid (35 g, 91%).NMR (400 MHz, CDC13) 56.06-5.83 (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).

[0298] Step 6. methyl (2S,4S)-5-aIlyl-4-((tert-butyIdimethylsilyl)oxy)pyrrolidine-2-carboxylate: Intermediate A20-5 (45 g, 113 mmol) was dissolved in a mixed solvent (TFA / DCM = lOOmL / 200 mL). The mixture was stirred at room temperature for 2 hours, then concentrated and quenched with saturated aqueous sodium bicarbonate solution. DCM was added for extraction until no product remained in the aqueous phase. After drying and concentration, A20-6 was obtained as a yellow liquid (27 g, 80%).

[0299] Step 7. methyl (2S,4S)-5-allyl-l-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enoyl)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate: 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). The mixture was stirred at room temperature overnight, then quenched with 150 mL of ice water. EA was added for extraction until no product remained in the aqueous phase. The combined organic phases were dried and concentrated, and theresidue was purified by silica gel column chromatography (PE / EA = 5: 1) to obtain intermediate A20-7 as an off-white solid (7.5 g, 90%).

[0300] Step 8. methyl (lS,3S,6S, Z)-6-((tert-butoxycarbonyl)amino)-l-((tert-butyldimethylsilyl)oxy)-5-oxo-l,2,3,5,6,7,10,10a-octahydropyrrolo[l,2-a]azocine-3-carboxylate: Intermediate A20-7 (7.5 g, 15 mmol) was dissolved in DCM (200 mL), and Grubbs catalyst (2.4 g, 2.9 mmol) was added. The mixture was stirred at 55 °C overnight, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 5:1) to obtain A20-8 as a brown liquid (6.1 g, 89%). LC-MS (m / z): 469.3 [M + H]+.

[0301] Step 9. methyl (lS,3S,6S)-6-((tert-butoxycarbonyl)amino)-l-((tert-butyldimethylsilyl)oxy)-5-oxodecahydropyrrolo[l,2-a]azocine-3-carboxylate: Intermediate A20-8 (6.0 g, 13 mmol) was dissolved in EA (80 mL), and 10% Pd / C (1.8 g) was added. The air was replaced with hydrogen three times, and the reaction was conducted at room temperature for 40 hours. After filtration and concentration, crude A20-9 was obtained (5 g, crude), which was directly used in the next step.

[0302] Step 10. methyl (lS,3S,6S)-6-((tert-butoxycarbonyl)amino)-l-hydroxy-5-oxodecahydropyrrolo[l,2-a]azocine-3-carboxylate: 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 reaction was conducted at room temperature for 1 hour. The reaction solution was added to saturated ammonium chloride (10 mL) and extracted with EA (10 mL x 3). The organic phase was dried and concentrated, and the residue was separated by silica gel column chromatography (PE / EA = 2: 1) to obtain A20-10 as a white solid (150 mg, 100%).

[0303] Step 11. methyl (lS,3S,6S)-6-((tert-butoxycarbonyl)amino)-l-(hept-6-yn-l-yloxy)-5-oxodecahydropyrrolo[l,2-a]azocine-3-carboxylate: A20-10 (120 mg, 0.34 mmol) was dissolved in DMF (5 mL). NaH (40 mg, 1.0 mmol) was added at 0°C, and after stirring for 30 minutes, 7 -bromohept- l-yne (70 mg, 0.40 mmol) was added. The reaction was conducted at room temperature overnight. The reaction solution was quenched with formic acid, added to saturated aqueous sodium chloride solution (10 mL), and extracted with EA (10 mL x 3). After drying and concentration, crude A20-11 was obtained (100 mg, crude). LC-MS (m / z): 451.2 [M + H]+.

[0304] Step 12. (lS,3S,6S)-6-((tert-butoxycarbonyl)amino)-l-(hept-6-yn-l-yloxy)-5-oxodecahydropyrrolo[l,2-a]azocine-3-carboxylic acid: 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 at room temperature overnight. The reaction solution was extracted with EA (10 mL x 3), and the aqueous phase was adjusted to pH 3-4 with IN aqueous HC1 solution, then extracted with EA (10 mL x 3). After dry ing and concentration, A20-12 wasobtained as a white solid (70 mg, 80%). 'H NMR (400 MHz, CDCl355.41 (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, 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]+.

[0305] Step 13. tert-butyl ((lS,3S,6S)-l-(hept-6-yn-l-yloxy)-3-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yl)carbamate: Intermediate A20-12 (80 mg, 0.18 mmol), 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). The mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with water (10 mL) and extracted with EA (10 mL x 3). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50:1) to obtain intermediate A20-13 as a pale-yellow solid (70 mg, 62%). LC-MS (m / z): 626.4 [M + H].

[0306] Step 14. tert-butyl ((lS,3S,6S,10aS)-l-((7-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)hept-6-yn-l-yI)oxy)-3-(6-(l-(methyl-d3 )-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yl)carbamate: A20-13 (50 mg, 0.080 mmol), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (40 mg, 0.12 mmol), copper(I) iodide (2.0 mg, 0.0080 mmol), TEA (40 mg, 0.40 mmol), and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0080 mmol) were dissolved in dry DMF (2 mL). Under nitrogen protection, the reaction was conducted at 80 °C for 3 hours. The reaction solution was diluted with water (10 mL) and extracted with EA (10 mL x 3). The organic phase was dried and concentrated, and the residue w as punfied by silica gel column chromatography (DCM / MeOH = 20: 1) to obtain intermediate A20-14 as a white solid (40 mg, 57%). LC-MS (m / z): 883.7 [M + H]+.

[0307] Step 15 and 16. ((7-(((lS,3S,6S,10aS)-l-((7-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)hept-6-yn-l-yl)oxy)-3-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo [ 1,2-a] azocin-6-yI)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphonic acid: Intermediate A20-14 (40 mg, 0.045 mmol) was dissolved in a mixed solvent (TFA / DCM = 3mL / 0.5 mL). The mixture was stirred at room temperature for 1 hour, then directly concentrated to obtain crude product A20-15. The crude product was dissolved in DMF (2 mL), and A6-1 (17 mg, 0.036 mmol) and DIPEA (0.5 mL) were added. The mixture was stirred at room temperature for 1 hour, then purified by reverse-phase Cl 8 column chromatography (CH3CN / H2O = 2:8) to obtain final product A20 (6 mg, 12%).

[0308] Example 27: diethyl 2.2'-((((2-(((5S.8S,10aR)-3-(2-((ls.4R)-4-((l-(2.6-dioxopipendin- 3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoryl)bis(azanediyl))(2S.2'S)-dipropionate (A21)

[0309] Step 1. ((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate: Intermediate P4-9 (1.0 g, 2.7 mmol) was dissolved in DMF (20 rnL). 3-Bromopropene (484 mg, 4.0 mmol) and potassium carbonate (745 mg, 5.4 mmol) were added, and 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 / PE = 1:1) to obtain intermediate A21-1 as a colorless transparent oil (1.0 g, 92%).

[0310] Step 2. ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid: Intermediate A21-1 (1.0 g. 2.5 mmol) was dissolved in DCM (10 mL). Trimethylsilyl bromide (2 mL) was added, and 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) to obtain A21-2 (410 mg, 47%). LC-MS (m / z): 347.0 [M - H].

[0311] Step 3. diethyl 2,2'-((((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoryl)bis(azanediyl))(2S,2'S)-dipropionate: Intermediate A21 -2 (150 mg, 0.43 mmol) was dissolved in DCM (4 mL). One drop of DMF was added, followed by the dropwise addition of oxalyl chloride (218 mg, 1.7 mmol). The compound was stirred at 40 °C for 2 hours. The mixture was concentrated, and the residue was dissolved in DCM (4 mL). L-Alanine ethyl ester hydrochloride (200 mg, 1.3 mmol) was added under an ice bath, and triethylamine (347 mg, 3.4 mmol) was added dropwise. 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 obtain intermediate A21-3 as an oil (30 mg. 13%). LC-MS (m / z): 547.1 [M + H]+.

[0312] Step 4.5-((bis(((S)-l-ethoxy-l-oxopropan-2-yl)amino)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid: Intermediate A21-3 (30 mg, 0.060 mmol) was dissolved in DCM (2 mL). Pyrrolidine (4.5 mg, 0.060 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 0.0030 mmol) were added. The compound was stirred under nitrogen protection for 1 hour, then concentrated. The residue was purified by silica gel column chromatography (DCM / methanol = 10:1) to obtain intermediate A21-4 as an oil (25 mg, 82%). LC-MS (m / z): 507.1 [M + H]+.

[0313] Step 5. diethyl 2,2'-(((difhioro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)inethyl)phosphoryl)bis(azanediyl))(2S,2'S)-dipropionate: Intermediate A21-4 (25 mg, 0.050 mmol) was dissolved in DMF (2 mL). Triethylamine (10 mg, 0.10 mmol) was added, followed by the slow addition of pentafluorophenyl 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 x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 2:1) to obtain A21-5 as a colorless transparent oil (20 mg, 59%). LC-MS (m / z): 673.2 [M + H]+.

[0314] Step 6. diethyl 2,2'-((((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yI)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)benzo [b] thiophen-5-yl)difluoromethyl)phosphoi,yl)bis(azanediyl))(2S,2'S)-dipropionate: Intermediate A14-2 (18 mg, 0.022 mmol) and A21-5 (20 mg, 0.030 mmol) were dissolved in DIPEA (0.5 mL) and DMF (2 mL). The mixture was stirred at room temperature for 1 hour. The mixture was poured into water (15 mL), and the organic phase was extracted with EA (10 mL x 3). The combinedorganic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to obtain final product A21 (23 mg, 80%).

[0315] Example 28: ethyl (((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)(phenoxy)phosphoryl)-L-alaninate (A22)

[0316] Step 1. allyl 5-(((((S)-l-ethoxy-l-oxopropan-2-yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate:Intermediate A21-2 (150 mg, 0.43 mmol) was dissolved in DCM (4 mL). One drop of DMF was added, followed by the addition of oxalyl chloride (218 mg, 1.7 mmol). The mixture was stirred at 40 °C for 2 hours, then concentrated. The residue was dissolved in DCM (4 mL), and ethyl L-alaninate hydrochloride (200 mg, 1.3 mmol) was added under an ice bath, followed by the addition of triethylamine (347 mg, 3.4 mmol). The mixture was stirred at room temperature forIll30 minutes, then concentrated. The residue was purified by silica gel column chromatography to obtain 100 mg of an intermediate.

[0317] This intermediate (100 mg, 0.22 mmol) was dissolved in DCM (5 mL), and oxalyl chloride (85 mg, 0.66 mmol) was added. The mixture was stirred at 40 °C for 2 hours, then concentrated. The residue was dissolved in DCM (5 mL). and phenol (62 mg, 0.66 mmol) was added under an ice bath, followed by the addition of tri ethylamine (133 mg, 1.3 mmol). The mixture was stirred at room temperature for 30 minutes, then concentrated. The residue was purified by silica gel column chromatography (DCM / PE = 1: 1) to obtain A22-1 as a colorless transparent oil (80 mg. 36%). LC-MS (m / z): 524.1 [M + H]+.

[0318] Step 2.5-(((((S)-l-ethoxy-l-oxopropan-2-yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid: Intermediate A22-1 (80 mg, 0.15 mmol) was dissolved in DCM (5 mL). Pyrrolidine (12 mg, 0.17 mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0090 mmol) were added. The mixture was stirred under nitrogen protection for 1 hour, then concentrated. The residue w as purified by silica gel column chromatography (DCM / methanol = 10:1) to obtain intermediate A22-2 as a pale-yellow substance (65 mg, 90%). LC-MS (m / z): 484.0 [M + H]+.

[0319] Step 3. perfluorophenyl 5-(((((S)-l-ethoxy-l-oxopropan-2-yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate:Intermediate A22-2 (65 mg, 0.13 mmol) was dissolved in DCM (2 mL). Tri ethylamine (39 mg, 0.39 mmol) was added, follow ed by the slow addition of pentafluorophenyl 2,2,2-trifluoroacetate (109 mg, 0.39 mmol). The mixture was stirred at room temperature for 10 minutes, then concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to obtain A22-3 as a colorless transparent oil (70 mg, 83%).

[0320] Step 4. ethyl (((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a] [ 1,5] diazocin-5-yl)carbamoyl)benzo [b]thiophen-5-yl)difluoromethyl)(phenoxy)phosphoryl)-L-alaninate: Intermediate A 14-2 (97 mg, 0.12 mmol) and A22-3 (70 mg, 0.11 mmol) were dissolved in DIPEA (0.5 mL) and DMF (2 mL). The mixture was stirred at room temperature for 1 hour, then poured into IN aqueous HC1 solution (20 mL). The organic phase was extracted with EA (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (DCM / methanol = 20: 1) to obtain final product A22 (80 mg, 57%).

[0321] Example 29: isopropyl (((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)(phenoxy)phosphoryl)-L-alaninate (A23)

[0322] Step 1. allyl 5-(difluoro((((S)-l-isopropoxy-l-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate: Intermediate A21-2 (250 mg, 0.70 mmol) was dissolved in DCM (25 mL). One drop of DMF was added, followed by the addition of oxalyl chloride (265 mg, 2.1 mmol). The mixture was stirred at 40°C for 2 hours, then concentrated. The residue was dissolved in DCM (25 mL), and isopropyl L-alaninate hydrochloride (125 mg, 0.75 mmol) was added under an ice bath, followed by the addition of tri ethylamine (350 mg. 3.5 mmol). The mixture was stirred at room temperature for 30 minutes, then phenol (195 mg, 2.1 mmol) was added, and stirring continued for 30 minutes. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / PE = 1: 1) to obtain A23-1 as a colorless transparent oil (210 mg, 56%). LC-MS (m / z): 538.2 [M + H]+.

[0323] Step 2.5-(difluoro((((S)-l-isopropoxy-l-oxopropan-2-yl)amino)(phenoxy)phosphoryl)inethyl)benzo[b]thiophene-2-carboxylic acid: Intermediate A23-1 (210 mg, 0.39 mmol) was dissolved in DCM (4 mL). Pyrrolidine (28 mg, 0.39 mmol) and tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.020 mmol) were added. The mixture was stirred under nitrogen protection for 1 hour, then concentrated. The residue was purified by silica gel column chromatography (DCM / methanol = 20: 1) to obtain intermediate A23-2 as an oil (210 mg, crude). LC-MS (m / z): 498.1 [M + H]+.

[0324] Step 3. perfluorophenyl 5-(difluoro((((S)-l-isopropoxy-l-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate: Crude intermediate A23-2 (180 mg, 0.36 mmol) was dissolved in DMF (4 mL). Triethylamine (180 mg, 1.8 mmol) was added, followed by the slow addition of pentafluorophenyl 2,2,2-trifluoroacetate (504 mg, 1.8 mmol). The mixture was stirred at room temperature for 30 minutes, then concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5: 1) to obtain A23-3 as a colorless transparent oil (200 mg. 83%).

[0325] Step 4. isopropyl (((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)carbamoyl)benzo [b] thiophen-5-yl)difluoromethyl)(phenoxy)phosphoryl)-L-alaninate: Intermediate A14-2 (106 mg, 0.13 mmol) and A23-3 (80 mg, 0.12 mmol) were dissolved in DIPEA (0.5 mL) and DMF (3 mL). The mixture was stirred at room temperature for 1 hour, then poured into IN aqueous HC1 solution (15 mL). The organic phase was extracted with EA (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (DCM / methanol = 20: 1) to obtain final product A23 (110 mg, 71%).

[0326] Example 30: S, S'-(((((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-IH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[I,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,l-diyl)) bis(2,2-dimethylpropanethioate) (A24)step 1 A24-1

[0327] Step 1. S-(2-hydroxy ethyl) 2,2-dimethylpropanethioate: Mercaptoethanol (1.2 g, 15 mmol) was dissolved in DCM (20 mL), cooled to -78 °C. Triethylamine (1.7 g, 17 mmol) and pivaloyl 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 another 1 hour. The mixture was concentrated, and the residue was purified by silica gel column chromatography (Hexane / EA = 20: 1) to obtain A24-1 as a colorless oil (2.4 g. 99%). 'H NMR (400 MHz, CDC1?) 53.72 (t, J = 6.0 Hz, 2H), 3.03 (t, J= 6.0 Hz, 2H), 1.22 (s, 9H).

[0328] Step 2. perfluorophenyl 5-((bis(2-(pivaloylthio)ethoxy)phosphoryl)difluoro-methyl)benzo[b]thiophene-2-carboxylate: Intermediate All-1 (50 mg, 0.10 mmol) was dissolved in DCM (2 mL). and one drop of DMF was added. Oxalyl 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 evaporated. 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 at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (Hexane / EA = 3: 1) to obtain A24-2 as a colorless oil (50 mg, 62%). LC-MS (m / z): 780.0 [M + H2O]+.

[0329] Step 3. S, S'-(((((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,l-diyl)) bis(2,2-dimethylpropanethioate): Intermediate A24-2 (50 mg, 0.066 mmol) was dissolved in DMF (2 mL). 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, then 1 N hydrochloric acid (5 mL) was added, and the mixture was extracted with EA (10 mL). The layers were separated, the organic phase was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50: 1) to obtain A24 (3 mg, 3%).

[0330] Example 31: 5-(((2R,4S)-4-(3-chlorophenyl)-2-oxido-l,3,2-dioxaphosphinan-2-yl)difluoromethyl)-N-((5S,8S, I0aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-1, 2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[ 1,2-a] [l,5]diazocin-5-yl)benzo[b]thiophene-2-carboxamide (A25)

[0331] Step 1. perfluorophenyl 5-(((2R,4S)-4-(3-chlorophenyl)-2-oxido-l,3,2-dioxaphosphinan-2-yl)difluoromethyl)benzo[b]thiophene-2-carboxylate: Al l-1 (70 mg, 0.15 mmol) was dissolved in DCE (5 mL). Oxalyl chloride (75 mg. 0.59 mmol) and a catalytic amount of DMF (0.05 mL) were added, and the reaction was conducted at 50 °C for 2 hours. The reaction solution was evaporated to dryness, diluted with DCM (5 mL), then DIPEA (76 mg, 0.59 mmol) and (S)-l-(3-chlorophenyl)-l,3-propanediol (33 mg, 0.18 mmol) were added.The reaction was conducted at room temperature overnight. Water (10 mL) was added to the reaction solution, and the mixture was extracted with DCM (10 mL x 3). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 1:1) to obtain intermediate A25-1 as a pale-yellow oil (50 mg, 54%). 'f4 NMR (400 MHz, CDCE) 6 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]+.

[0332] Step 2.5-(((2R,4S)-4-(3-chlorophenyl)-2-oxido-l,3,2-dioxaphosphinan-2-yl)difluoromethyl)-N-((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo- l,2-dihydropyridin-4-yl)-4-azaspiro [2.4] heptane-4-carbonyl)-6-oxodecahydropyrrolo [ 1,2-a] [1,5] diazocin-5-yl)benzo [b] thiophene-2-carboxamide:Intermediate A9-5 (60 mg, 0.060 mmol) was dissolved in a mixed solvent (TFA / DCM = 5 / 0.5 mL). The mixture was stirred at room temperature for 1 hour, then directly concentrated to obtain a crude product. The crude product was dissolved in DMF (2 mL), and 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 IN aqueous hydrochloric acid (5 mL), extracted with EA (10 mL x 3), and washed with saturated aqueous sodium chloride solution (15 mL). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 15:1) to obtain A25 (20 mg, 27%).

[0333] Example 32: ((((7-(((lS,3S,6S)-l-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)ethoxy)-3-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate) (A26)step 6 A26-7 step 7 A26-8 TsCIstep 8 A26-9 step 9 A26-10HATU, DIPEA DMFstep 3 A20-10 step 1 A26-1 step 2 A26-2

[0334] Step 1. methyl (lS,3S,6S)-6-((tert-butoxycarbonyl)amino)-l-(2-(4-methylenecyclohexyI)ethoxy)-5-oxodecahydropyrrolo[l,2-a]azocine-3-carboxylate: A20-10 (220 mg, 0.62 mmol) was dissolved in DMF (10 mL). Potassium tert-butoxide (138 mg, 0.86 mmol) was added at 0 °C. After stirring for 30 minutes, 1 -(2-bromoethyl)-4-methylenecyclohexane (A26-10. 175 mg, 0.40 mmol) was added, and the reaction wasconducted at 0 °C for 2 hours. The pH of the reaction solution was adjusted to 4-5 with formic acid, and the mixture was extracted with EA (EA, 10 mL x 3). The organic phase was washed with saturated aqueous sodium chloride solution (10 mL), dried, and concentrated to obtain 290 mg of crude product, which was directly used in the next step. LC-MS (m / z): 479.3 [M + H]+.

[0335] Step 2. (lS,3S,6S)-6-((tert-butoxycarbonyl)amino)-l-(2-(4-methylenecyclohexyI)ethoxy)-5-oxodecahydropyrrolo[l,2-a]azocine-3-carboxylic acid: A26-1 (290 mg, 0.62 mmol) was dissolved in THF / H2O (5 mL / 5 mL), and lithium hydroxide monohydrate (78 mg, 1.8 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was extracted with EA (10 mL x 3). and the aqueous phase was adjusted to pH 3-4 with IN aqueous HC1 solution, then extracted with EA (10 mL x 3). After drying and concentration, A26-2 was obtained as a white solid (120 mg, 42%). ’H NMR (400 MHz, CDC13) 55.50 (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 (m, 1H). 2.65 - 2.53 (m, 1H), 2.40 - 2.18 (m. 2H), 2.10 - 1.51 (m, 18H), 1.48 (d, J= 1.9 Hz, 9H), 1.17 - 1.02 (m, 1H). LC-MS (m / z): 465.2 [M + H]+.

[0336] Step 3. tert-butyl ((lS,3S,6S)-3-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-l-(2-(4-methylenecyclohexyl)ethoxy)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yl)carbamates: Intermediate A26-2 (120 mg, 0.26 mmol). 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). The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water (10 mL) and extracted with EA (10 mL x 3). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 30:1) to obtain intermediate A26-3 as a pale-yellow solid (70 mg, 41%). LC-MS (m / z): 654.5 [M + H]+.

[0337] Step 4. tert-butyl ((lS,3S,6S)-l-(2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methylene)cyclohexyl)ethoxy)-3-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yl)carbamate: A26-3 (50 mg, 0.076 mmol), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-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)a (10 mg, 0.0076 mmol) were dissolved in dry DMF (3 mL). Under nitrogen protection, the reaction was conducted at 80 °C overnight. The reaction solution was diluted with water (10 mL) and extracted with EA (10 mL x 3). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20: 1) to obtain A26-4 as a colorless oil (10 mg, 14%). LC-MS (m / z): 911.8 [M + H]+.

[0338] Step 5. tert-butyl ((lS,3S,6S)-l-(2-(4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)ethoxy)-3-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yl)carbamate: A26-4 was dissolved in methanol (2 mL), and 10% Pd / C (10 mg) was added. The air was replaced with hydrogen three times, and the reaction was conducted at room temperature for 5 hours. The reaction solution was filtered and concentrated to obtain A26-5 as a colorless oil (10 mg, crude), which was directly used in the next step. LC-MS (m / z): 913.7 [M + H]+.

[0339] Step 6. ethyl 2-(4-methylenecyclohexyl)acetate: Methyltriphenylphosphonium bromide (19 g, 54 mmol) was dissolved in anhydrous THF (50 mL). After nitrogen replacement, the temperature was cooled to -20 °C, and potassium tert-butoxide (6.1 g, 54 mmol) was added. The mixture was stirred at -20 °C for 30 minutes, then warmed to room temperature and stirred for 1 hour. Ethyl 4-oxocyclohexaneacetate (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 at room temperature overnight, quenched with 200 mL of ice water, and extracted with EA until no product remained in the aqueous phase. The combined organic phases were dried and concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 50:1) to obtain A26-7 as a colorless liquid (3.5 g, 71%).

[0340] Step 7. 2-(4-methylenecyclohexyl)ethan-l-ol: A26-7 (3.5 g, 19 mmol) was dissolved in anhydrous DCM (40 mL). After nitrogen replacement, the temperature was cooled to 0°C, and 1.0N diisobutylaluminum hydride (58 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour, quenched with ammonia water, and extracted w ith DCM until no product remained in the aqueous phase. The combined organic phases were dried and concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 20: 1) to obtain A26-8 as a colorless liquid (2.4 g, 90%). 'H NMR (400 MHz, CDC13) 84.59 (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).

[0341] Step 8. 2-(4-methylenecyclohexyl)ethyl 4-methylbenzenesulfonate: A26-8 (2.4 g, 17 mmol) was dissolved in anhydrous DCM (30 mL). Triethylamine (3.5 g, 34 mmol) and DMAP (209 mg, 1.7 mmol) were added, followed by the portionwise addition of p-toluenesulfonyl chloride (4.9 g. 26 mmol). The mixture was stirred at room temperature overnight, quenched with water, and extracted with DCM until no product remained in the aqueous phase. The combined organic phases were dried and concentrated, and the residue w as purified by silica gel column chromatography (PE / EA = 30:1) to obtain A26-9 as a yellow oil (4.5 g, 90%).

[0342] Step 9. l-(2-bromoethyl)-4-methylenecyclohexane: A26-9 (4.5 g. 15 mmol) was dissolved in acetone (50 mL), and lithium bromide (2.7 g, 31 mmol) was added. The mixture was stirred at room temperature overnight, quenched with water, and extracted with PE until no product remained in the aqueous phase. The combined organic phases were dried and concentrated, and the residue was rapidly purified by silica gel column chromatography (PE) to obtain A26-10 as a colorless liquid (3.0 g, 97%). 'H NMR (400 MHz, CDCl₃) δ 4.61 (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).

[0343] Step 10 and 11. ((((7-((( lS.3S.6S)-l-(2-((ls.4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)ethoxy)-3-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo [ 1,2-a] azocin-6-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(methylene) bis(2,2-dimethylpropanoate):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, then directly concentrated to obtain crude product A26-6. The crude product was dissolved in DMF (1 mL), and Al 4-1 (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 IN aqueous HC1 solution (5 mL), extracted with EA (10 mL x 3). and washed with saturated aqueous sodium chloride solution (15 mL). The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 15:1) to obtain A26 (5.0 mg, 32%).

[0344] Example 33: propyl (((2-(((5S.8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolof 1,2-a] [1, 5]diazocin-5-yl)carbamoyl)benzo [b]thi ophen-5 -yl)difluoromethyl)(phenoxy)phosphoryl)-L-alaninate (A27)

[0345] Step 1. allyl 5-(difluoro((((S)-l-oxo-l-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate: Intermediate A21-2 (100 mg, 0.29 mmol) was dissolved in DCM (4 mL). One drop of DMF was added, followed by the addition of oxalyl chloride (110 mg, 0.87 mmol). The mixture was stirred at 40 °C for 2 hours, then concentrated. The residue was dissolved in DCM (4 mL), and isopropyl L-alaninate hydrochloride (49 mg, 0.29 mmol) was added under an ice bath, followed by the addition of triethylamine (145 mg, 1.4 mmol). The mixture was stirred at room temperature for 30 minutes, then phenol (82 mg. 0.87 mmol) was added, and stirring was continued for 30 minutes. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / PE = 1: 1) to obtain A27-1 as a colorless transparent oil (80 mg, 51%). LC-MS (m / z): 538.1 [M + H]+.

[0346] Step 2. 5-(difluoro((((S)-l-oxo-l-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid: Intermediate A27-1 (23 mg, 0.043 mmol) was dissolved in DCM (2 mL). Pyrrolidine (3.1 mg, 0.043 mmol) and tetrakis(triphenylphosphine)palladium(0) (5.0 mg, 0.0043 mmol) were added. The mixture was stirred under nitrogen protection for 1 hour, then concentrated. The residue was purified by silica gel column chromatography (DCM / methanol = 20: 1) to obtain intermediate A27-2 as a colorless oil (15 mg, 70%).

[0347] Step 3. perfluorophenyl 5-(difluoro((((S)-l-oxo-l-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate: Intermediate A27-2 (15 mg, 0.030 mmol) was dissolved in DCM (2 mL). Triethylamine (6 mg, 0.060 mmol)was added, followed by the slow addition of pentafluorophenyl 2,2.2-trifluoroacetate (17 mg, 0.060 mmol). The mixture was stirred at room temperature for 30 minutes, then concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5: 1) to obtain A27-3 as a colorless transparent oil (20 mg, 100%).

[0348] Step 4. propyl (((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cycIohexyl)acetyl)-8-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)(phenoxy)phosphoryl)-L-alaninate: Intermediate Al 4-2 (27 mg, 0.033 mmol) and A27-3 (20 mg, 0.030 mmol) were dissolved in DIPEA (0.5 mL) and DMF (2 mL). The mixture was stirred at room temperature for 1 hour, then poured into IN aqueous HC1 solution (10 mL). The organic phase was extracted with EA (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (DCM / methanol = 20: 1) to obtain final product A27 (24 mg, 62%).

[0349] Example 34: ((2-(((lS,3S,6S)-l-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)ethoxy)-3-(6-(l-(methyl-d3)-2-oxo- 1,2-dihydropyri din-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo[ 1.2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (A28)

[0350] Step 1. ((2-(((lS,3S,6S)-l-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)ethoxy)-3-(6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-5-oxodecahydropyrrolo[l,2-a]azocin-6-yI)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid: Intermediate A26-5 (30 mg, 0.033 mmol) was dissolved in DCM (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 hours, then concentrated. The residue was dissolved in DMF (2 mL). andtriethylamine (17 mg, 0.17 mmol) and intermediate All-1 (14 mg, 0.030 mmol) were added. The mixture was stirred at room temperature for 30 minutes, then purified by Cl 8 column chromatography to obtain final product A28 (20 mg, 60%).

[0351] Example 35: ((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-((R)-6-(l- (methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (Al 1-P1)

[0352] Step 1. tert-butyl (R)-6-(2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carboxylate and tert-butyl (S)-6-(2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carboxylate: Chiral resolution was performed on A5-8 (4.0 g, 13.7 mmol) using the following conditions: Column: AD-34.6x100 mm 3 pm; Mobile phase: MeOH [0.2% NH3 (7 M in MeOH)]. This yielded A5-8-P1 (1.8 g, t = 1.556 min) and A5-8-P2 (1.7 g, t = 2.289 min). The absolute stereochemistry of the enantiomers was assigned arbitrarily.

[0353] Step 2. tert-butyl (R)-6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carboxylate: Intermediate A5-8-P1 (1.8 g, 6.4 mmol) was dissolved in DMF (30 mL). Cesium carbonate (6.2 g, 19.2 mmol) and deuterated methyl iodide (1.8 g, 12.8 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50:l) to obtain All-Pl-1 as a yellow oil (1.8 g, 91%). ¹H 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).

[0354] Step 3. (R)-l-(methyl-d3)-4-(4-azaspiro[2.4]heptan-6-yl)pyridin-2(lH)-one:Intermediate Al 1-1 (1.8 g, 5.8 mmol) was dissolved in DCM (20 mL). Trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to obtain crude intermediate All -Pl -2, which was directly used in the next step.

[0355] Step 4. benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-((R)-6-(l-(methyl-d3)-2-oxo- l,2-dihydropyridin-4-yl)-4-azaspiro [2.4] heptane-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocine-3(4H)-carboxylate: The crude All-Pl-2 from the previous step, P3-3 (2.8 g, 6.1 mmol), HATU (2.2 g, 7.0 mmol), and DIPEA (2.3 g, 17.5 mmol) were dissolved in DMF (30 mL). The mixture was stirred at room temperature for 30 minutes, then concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 50:1) to obtain All-Pl-3 as a viscous oil (3.1 g, 82%). LC-MS (m / z): 651.8 [M + H]+.

[0356] Step 5. tert-butyl ((5S,8S,10aR)-8-((R)-6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate All-Pl-3 (3.1 g, 4.8 mmol) was dissolved in ethanol (30 mL). 10% Pd / C (1.0 g, 9.5 mmol) and ammonium formate (3.0 g, 47.5 mmol) were added, and 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) to obtain intermediate Al 1-P1-4 as a white solid (2.1 g, 85%). LC-MS (m / z): 517.7 [M + H]+.

[0357] Step 6. tert-butyl ((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH- benzo [d] imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-((R)-6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate All-Pl -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). 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) to obtain intermediate Al l-Pl-5 as a white solid (1.4 g, 71%). LC-MS (m / z): 913.0 [M + H]+.

[0358] Step 7 and 8. ((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH- benzo [d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-((R)-6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid: Intermediate All-Pl-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, then directly concentrated to obtain a crude product. The crude product was dissolved in DMF (15 mL), and intermediate All-1 (810 mg, 1.71 mmol) and DIPEA (3.0 mL) were added. The mixture was stirred at room temperature for 2 hours, then purified by Cl 8 column chromatography (CH3CN / H2O = 2:8) to obtain final product Al 1-P1 (900 mg, 52%). The absolute stereochemistry of the enantiomers was assigned arbitrarily.

[0359] Example 36: ((2-(((5S.8S,10aR)-3-(2-((ls.4R)-4-((l-(2.6-dioxopipendin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-((S)-6-(l- (methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thi ophen-5-yl)difluoromethyl)phosphonic acid (Al 1-P2)

[0360] Step 1. tert-butyl (S)-6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carboxylate: Intermediate A5-8-P2 (1.6 g, 5.5 mmol) was dissolved inDMF (20 mL). Cesium carbonate (5.4 g, 16.4 mmol) and deuterated methyl iodide (1.6 g, 11.0 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, it was quenched with 150 mL of ice water. EA was added for extraction until no product remained in the aqueous phase. The combined organic phases were dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50:1) to obtain A11-P2-1 as a yellow oil (1.6 g, 94%).

[0361] Step 2. (S)-l-(methyl-d3)-4-(4-azaspiro[2.4]heptan-6-yl)pyridin-2(lH)-one:Intermediate A11-P2-1 (1.6 g, 5.2 mmol) was dissolved in DCM (15 mL). Trifluoroacetic acid (8 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, methanol was added to dissolve the residue, and sodium bicarbonate was used to adjust the pH of the system to 8-9. The concentrated residue was purified by silica gel column chromatography to obtain A11-P2-2 as a pale-yellow oil (900 mg, 84%).

[0362] Step 3. benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-((S)-6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxooctahydropyrrolo[l,2-a][l,5]diazocine-3(4H)-carboxylate: Intermediate Al 1-P2-2 (900 mg, 4.3 mmol), 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, then quenched with 50 mL of ice water. EA was added for extraction until no product remained in the aqueous phase. The combined organic phases were dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 50: 1) to obtain Al 1-P2-3 as a white solid (1.7 g, 60%). LC-MS (m / z): 651.7 [M + H]+.

[0363] Step 4. tert-butyl ((5S,8S,10aR)-8-((S)-6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate A11-P2-3 (1.7 g, 2.6 mmol) was dissolved in ethanol (50 mL). 5% Pd / C (900 mg) and ammonium formate (1.7 g, 26.1 mmol) were added, and the mixture was stirred at 80 °C for 10 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) to obtain intermediate A11-P2-4 as a white solid (1.2 g, 89%). LC-MS (m / z): 517.6 [M + H]+.

[0364] Step 5. tert-butyl ((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-8-((S)-6-(l-(methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6-oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamate: Intermediate A2-7 (483 mg, 1.2 mmol), 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). The mixture was stirred at room temperature for 2 hours.then quenched with 50 mL of ice water. EA was added for extraction until no product remained in the aqueous phase. The combined organic phases were dried and concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20: 1) to obtain intermediate Al 1-P2-5 as a white solid (630 mg, 58%).

[0365] Steps 6 and 7. ((2-(((5S,8S,10aR)-3-(2-((ls,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3- methyl-2-ox o-2, 3-dihydro-lH- benzo [d]imidazol-5-yl)methyl)cycIohexyl)acetyl)-8-((S)-6-(l- (methyl-d3)-2-oxo-l,2-dihydropyridin-4-yl)-4-azaspiro[2.4]heptane-4-carbonyl)-6- oxodecahydropyrrolo[l,2-a][l,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid: 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, then directly concentrated to obtain a crude product Al 1-P2-6. The crude product Al 1-P2-6 was dissolved in DMF (15 mL), and All-1 (329 mg, 0.69 mmol) and DIPEA (3.2 mL) were added. The mixture was stirred at room temperature for 2 hours, then purified by C18 column chromatography (CH3CN / H2O = 3:7) to obtain final product Al 1-P2 (520 mg, 68%). The absolute stereochemistry of the enantiomers was assigned arbitrarily.

[0366] The analytical structures and spectral data of Compounds A1-A28, All-Pl, and All- P2 are listed in Table 1:

[0367] Table 1. Analytical Structures and Spectral Data of Compounds A1-A28, All-Pl. and A11-P2.NO. Structure 'H-NMR & LC-MS'H NMR (400 MHz, DMSO-cp) 5 11.06 (s, 1H), 9.51 - 9.35 (m, 1H), 8.64 - 8.52 (m, 1H), N^O 8.11 - 7.91 (m, 4H), 7.73 - 7.63 (m, 1H), 7.04 / ~\ - 6.86 (m. 2H), 6.81 - 6.59 (m. 1H), 5.91 (dd, / ~N J= 44.0, 8.4 Hz, 1H), 5.40 - 5.24 (m, 1H), Al x ) I b "05.22 - 5.00 (m, 1H), 4.91 - 4.73 (m, 1H), 4.49 Qi " - 4.31 (m, 1H), 3.94 - 3.63 (m, 12H), 3.34 - 3.26 (m. 5H), 3.14 - 2.56 (m. 10H), 2.33 - Q~~ / 1.66 (m, 10H).LC-MS (m / z): 961.6 [M + H]+.'H NMR (400 MHz, DMSO-c / J 5 11.07 (S, \N^O 1H), 8.86 - 8.40 (m, 2H), 8.16 - 7.89 (m, 4H),7.66 (d, J= 9.1 Hz, 1H), 7.08 - 6.90 (m, 2H), 6.90 - 6.72 (m, 1H), 5.91 - 5.67 (m, 1H), 5.37 o^_Q0rn°- 5.25 (m, 1H), 5.07 - 4.73 (m, 2H), 4.34 - A2 / ~N4.13 (m, 1H), 3.99 - 3.51 (m, 12H), 3.31 (d, J = 4.4 Hz, 3H), 2.95 - 2.81 (m, 2H). 2.65 - 2.56 (m. 2H), 2.31 - 1.85 (m. 7H), 1.83 - 1.29 (m, 13H).d~°LC-MS (m / z): 958.9 [M + H]+.'H NMR (400 MHz, DMSO-t / J 8 11.07 (s, 1H), 8.81 - 8.60 (tn, 1H), 8.60 - 8.45 (m, 1H), 8.24 - 8.12 (m, 1H), 8.10 - 7.90 (m, 3H), 7.86 P y- 7.72 (m, 1H), 7.06 - 6.92 (m. 2H), 6.87 - o Q0fA6.70 (m, 1H), 5.46 - 5.28 (m, 1H), 5.11 - 4.91 A3 / — N(m, 1H), 4.91 - 4.74 (tn, 1H), 4.30 - 4.14 (m, 1H). 4.02 - 3.49 (m, 12H), 3.29 - 3.26 (m, 3H). 3.05 - 2.80 (m, 2H). 2.65 - 2.55 (m. 2H), 2.30 - 1.92 (m, 6H), 1.86 - 1.30 (m, 14H). o-yLC-MS (m / z): 977.0 [M + H]+.'H NMR (400 MHz, DMSO-t / 6) 8 11.12 (s, 1H), 8.69 - 8.43 (m, 2H), 8.13 - 7.87 (m, 4H), \N^O 7.81 - 7.63 (m, 1H), 7.37 - 7.07 (m, 2H), 7.02 / -^9\ _ZN N V_y y^i - 6.86 (m, 1H), 5.82 - 5.57 (m. 1H), 5.16 - ^N ° NA04.94 (m, 1H), 4.94 - 4.76 (m, 2H), 4.44 - 4.20 A4 F \ 0 FH(m, 1H), 3.87 - 3.56 (m, 8H), 3.32 - 3.25 (m, Qp^CO^ 5H). 3.05 - 2.85 (m, 4H), 2.85 - 2.57 (m. 8H), Z^N 2.45 - 2.18 (m, 4H), 2.18 - 1.89 (m, 4H), 1.89 0^- 1.67 (m, 4H).LC-MS (m / z): 961.1 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.08 (s,1H), 9.07 - 8.39 (m, 2H), 8.17 - 8.04 (m, 1H), 8.04 - 7.85 (m, 3H), 7.72 - 7.65 (m, 1H), 7.65 - 7.56 (m, 1H), 7.05 - 6.90 (m, 2H), 6.88 - KIQ'NVV- / NA,06.72 (m, 1H), 6.42 - 6.28 (m, 1H), 6.28 - 6.15 \z°_ A=o^ N (m, 1H), 5.67 – 5.44 (m, 1H), 5.38 - 5.23 (m, A5 1H). 5.10 - 4.39 (m, 1H), 4.36 - 4.09 (m. 1H),4.09 - 3.80 (m, 1H), 3.79 - 3.60 (m, 3H), 3.33 5 / ^ j 0°hxx Xy HO>f OH- 3.22 (m, 8H), 2.96 - 2.55 (m, 6H), 2.41 - 2.10 (m, 4H), 2.10 - 1.83 (m, 6H), 1.83 - 1.59o5:0 / (m, 6H), 1.55 - 1.30 (m, 6H), 1.04 - 0.78 (m,2H). 0.57 - 0.35 (m, 2H).LC-MS (m / z): 1076.2 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.08 (s, 1H), 8.70 - 8.39 (m, 2H), 8.31 - 8.10 (m, 1H), 8.10 - 7.92 (m, 3H), 7.85 - 7.71 (m, 1H), 7.67 - 7.52 (m, 1H), 7.05 - 6.91 (m, 2H), 6.91 - NA006.69 (m. 1H), 6.43 - 6.28 (m. 1H), 6.28 - 6.180(m, 1H), 5.44 - 5.23 (m, 1H), 5.11 - 4.90 (m, A6<7 A < T oA H-C / VX-xXJ V<,p 1H), 4.64 - 4.44 (m, 1H), 4.37 - 4.22 (m, 1H), / ~fX'O xAx / , Px( Jj HO OH 4.22 - 4.09 (m, 1H), 4.11 - 3.69 (m, 2H), 3.32- 3.30 (m. 6H), 3.12 - 2.55 (m, 8H), 2.40 - 0^ 1.93 (m, 8H), 1.84 - 1.31 (m, 14H), 1.07 - / 0.81 (m, 2H), 0.56 - 0.34 (m, 2H).LC-MS (m / z): 1093.9 [M + H]+.''‘N A N" X^NHO \ 7 °\ (l oz I - \ —- p - A7 0 / — ' LC-MS (m / z): 943.0 [M+H]+. / ~\A OH> 0 O A-. O=P-OHH1v - O-Z W? Vx1H NMR (400 MHz, DMSO-6) δ 11.07 (s,1H), 8.99 - 8.41 (m, 2H), 8.14 - 7.75 (m, 4H),H0 7.74 - 7.63 (m, 1H), 7.63 - 7.53 (m, 1H), 6.99 °AN\ - 6.89 (m, 1H), 6.89 - 6.79 (m, 1H), 6.67 - ^~N N AQ6.54 (m. 1H), 6.38 - 6.27 (m, 1H), 6.27 - 6.15? > 0 F1o(m, 1H), 5.69 - 5.46 (m, 1H). 5.36 - 5.22 (m, A8 / ~ QNpAxAA 1H), 5.19 - 4.90 (m, 1H), 4.65 - 4.44 (m, 1H),4.44 _ 3.94 (m, 2H), 3.30 - 3.25 (m, 6H), 2.95 - 2.56 (m, 8H), 2.28 - 1.89 (m, 12H), 1.89 - f j]CT 'N 1 1.44 (m. 10H), 1.20 - 1.14 (m, 2H), 0.53 - 0.37 (m, 2H).LC-MS (m / z): 1076.0 [M−H]−.1H NMR (400 MHz, DMSO-6) δ 11.08 (s, 1H), 8.92 – 8.49 (m, 2H), 8.28 - 8.11 (m, 1H), 8.09 - 7.90 (m, 3H), 7.83 - 7.72 (m, 1H), 7.68 - 7.55 (m. 1H), 7.08 - 6.92 (m. 2H), 6.88 - 6.69 (m, 1H), 6.41 - 6.28 (m, 1H), 6.28 - 6.16 (m, 1H), 5.47 - 5.25 (m, 1H), 5.10 - 4.83 (m, A91H), 4.71 - 4.45 (m, 1H), 4.40 - 4.10 (m, 2H), 4.09 - 3.67 (m, 3H), 3.34 - 3.27 (m, 3H), 3.09 - 2.82 (m, 5H), 2.75 - 2.56 (m, 4H), 2.40 - 2.10 (m, 4H), 2.06 - 1.90 (m, 4H), 1.84 - 1.61 (m, 6H), 1.61 - 1.30 (m, 6H), 1.06 - 0.89 (m, 2H). 0.55 - 0.37 (m, 2H).LC-MS (m / z): 1097.1 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.08 (s, 1H), 8.71 – 8.28 (m, 3H), 8.28 - 8.11 (m, 1H), 8.11 - 7.92 (m, 2H), 7.83 - 7.69 (m, 1H), 7.68 - 7.47 (m, 1H), 7.46 - 7.22 (m, 4H), 7.05 - 6.67 (m. 3H), 5.42 - 5.26 (m. 1H), 5.12 - 4.94 (m, 1H), 4.91 - 4.70 (m, 1H), 4.61 - 4.43 (m, A1000 A 1H), 4.41 - 4.10 (m, 4H), 4.10 - 3.93 (m, 4H), 0 T HFVFr-N^o0UryV 3.29 - 3.24 (m, 6H), 2.97 - 2.81 (m, 2H), 2.65 f l HCf OH- 2.55 (m. 3H), 2.41 - 2.34 (m, 2H), 2.25 - 1.85 (m. 7H). 1.82 - 1.59 (m. 5H), 1.54 - 1.31 6 oT(m, 5H). / X I0 / 0. / 0^°z 9P U. A \ ° LC-MS (m / z): 1053.0 [M + H]+.V L'°11H NMR (400 MHz, DMSO-6) δ 11.08 (s, 1H), 9.15 - 8.63 (m, 1H), 8.38 - 8.20 (m, 1H), ^ \o c / z o ° 8.11 - 8.03 (m, 1H), 8.03 - 7.94 (m, 1H), 7.69 1 1 °0Ax \.. - 7.54 (m, 2H), 7.04 - 6.92 (m, 2H), 6.89 - 6.68 (m, 1H), 6.43 - 6.28 (m, 1H), 6.28 - 6.14 o (m, 1H), 5.42 – 5.23 (m, 1H), 5.07 - 4.78 (m, O c>All o a 1H). 4.64 - 4.43 (m, 1H), 4.37 - 3.83 (m. 6H),3.35 - 3.27 (m, 5H), 3.13 - 2.82 (m, 6H), 2.64 - 2.57 (m, 2H), 2.20 - 1.92 (m, 6H), 1.85 - 1.61 (m, 6H), 1.59 - 1.30 (m, 6H), 1.09 - 0.85 (m, 2H), 0.57 - 0.36 (m, 2H).LC-MS (m / z): 1102.9 [M + H]+.'H NMR (400 MHz, DMSO-c / 6) 5 11.12 (s. 1H), 8.69 - 8.52 (m, 2H), 8.11 - 7.89 (m, 4H), 7.81 - 7.75 (m, 1H), 7.63 - 7.53 (m, 1H), 7.29 - 7.18 (m, 1H), 7.12 - 6.97 (m, 2H), 6.41 - A12 6.26 (m. 1H), 6.26 - 6.16 (m, 1H), 5.43 - 5.27(m, 1H), 4.71 - 4.11 (m, 1H). 4.08 - 3.66 (m, 1H), 3.10 - 2.80 (m, 8H), 2.64 - 2.55 (m, 1H), 2.27 - 1.87 (m, 10H), 1.87 - 1.40 (m, 14H), 1.13 - 0.97 (m, 2H), 0.51 - 0.38 (m, 2H).LC-MS (m / z): 1080.9 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.07 (s,1H), 8.91 - 8.52 (m, 2H), 8.40 - 8.24 (m, 1H), 8.22 - 8.01 (m, 3H), 7.82 - 7.68 (m, 1H), 7.68 p yA - 7.54 (m, 1H), 7.05 - 6.91 (m, 2H), 6.89 - / o\=y ^z., _ 6.74 (m. 1H), 6.45 - 6.28 (m. 1H), 6.29 - 6.14 ox> °o(m, 1H), 5.41 - 5.22 (m, 1H), 5.11 - 4.84 (m, A13 1H), 4.71 - 4.41 (m, 1H), 4.38 - 3.98 (m, 7H),|A - 3.97 - 3.50 (m, 4H), 3.31 - 3.24 (m, 6H), 3.018A>< > ° S o= / H \ m - 2.75 (m. 2H), 2.76 - 2.56 (m, 3H), 2.41 - 2.23 (m. 2H). 2.20 - 1.84 (m. 8H), 1.84 - 1.61 (m, 6H), 1.61 - 1.35 (m, 6H), 1.27 - 1.17 (m, 6H), 1.09 – 0.80 (m, 2H), 0.55 - 0.36 (m, 2H). LC-MS (m / z): 1149.8 [M + H]+.1H NMR (400 MHz, CDCl3) δ 8.61 – 8.40 (m, 1H). 8.30 - 8.10 (m, 2H), 8.10 - 7.79 (m. 4H), 7.75 (d, J= 8.4 Hz, 1H), 7.26 - 7.20 (m, 1H), 6.90 - 6.77 (m, 2H), 6.73 - 6.42 (m, 2H), 6.14 (dd, J= 26.0, 6.8 Hz, 1H), 5.70 (dd, J= 30.8,,0'~%VH11.6 Hz, 4H), 5.19 (dd, J= 12.8, 5.2 Hz, 1H), _ ^0.<^N 4.89 - 4.74 (m, 1H), 4.64 - 4.49 (m, 1H), 4.44 A14 S F - 4.05 (m, 4H), 4.04 - 3.84 (m, 1H), 3.59 - 0 yX°°HUJX » Jv. 3.51 (m, 1H), 3.42 - 3.35 (m, 3H), 3.31 - 3.15(m, 2H), 2.98 - 2.63 (m, 6H), 2.63 - 2.48 (m, «4 D3C 0° 1H). 2.39 - 2.12 (m, 6H). 2.09 - 1.96 (m. 3H),1.94 - 1.67 (m, 6H), 1.60 - 1.38 (m, 4H), 1.19 (s, 18H), 1.15 - 1.00 (m, 2H), 0.65 - 0.45 (m, 2H).LC-MS (m / z): 1324.9 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.13 (s,1H), 8.94 - 8.71 (m, 1H), 8.63 (s, 1H), 8.28 - 8.18 (m. 1H), 8.09 - 7.94 (m. 3H), 7.87 - 7.77 (m, 1H), 7.68 - 7.59 (m, 1H), 7.26 - 6.86 (m, 3H), 6.40 - 6.31 (m, 1H), 6.31 - 6.18 (m, 1H), 5.50- 5.32 (m, 1H), 5.15 - 4.98 (m, 1H), 4.66 A15- 4.49 (m. 1H), 4.39 - 4.17 (m, 2H), 4.11 - 4.02 (m. 1H), 3.88 - 3.64 (m. 5H), 3.51 - 3.48 (m, 5H), 3.31 - 3.29 (m, 3H), 3.04 - 2.85 (m, 3H), 2.75 – 2.57 (m, 5H), 2.47 - 2.21 (m, 4H), 2.14- 1.92 (m, 6H), 1.85 - 1.45 (m, 5H). o LC-MS (m / z): 1099.6 [M + H]+.S / C oZI1H NMR (400 MHz, DMSO-6) δ 11.13 – 11.05 (m, 1H), 8.88 (s, 1H), 8.63 (s, 1H). 8.25 V O - 8.17 (m, 1H), 8.06 - 7.94 (m, 3H), 7.82 (d, J - 9.0 Hz, 1H), 7.65 (d.. / - 7.0 Hz. 1H), 6.98 -, S J 0-PI ' "0-oO" 6.82 (m. 2H), 6.69 - 6.62 (m, 1H), 6.41 - 6.21 \ssOJZ ( (m, 2H), 5.37 - 5.23 (m, 1H). 5.11 (s, 1H), A16 oV ■"''YVO”" ■' 4.67 - 4.51 (m, 1H), 4.36 - 4.24 (m, 1H), 3.96 o - 3.55 (m, 11H), 3.20 - 2.81 (m, 7H), 2.74 - ouPl hr Z o<0OHHD3C 2.58 (m, 4H), 2.16 - 1.94 (m, 4H), 1.94 - 1.68(m, 6H), 1.67 - 1.52 (m, 3H). 1.49 - 1.30 (m, 4H).LC-MS (m / z): 1098.7 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.07 (s,1H), 9.23 - 8.66 (m, 1H), 8.48 - 8.28 (m, 1H), 8.28 - 8.13 (m, 2H), 7.69 - 7.50 (m, 2H), 7.07 - 6.91 (m, 2H), 6.91 - 6.73 (m, 1H), 6.44 - 6.29 (m, 1H), 6.29 - 6.09 (m, 1H), 5.39 - 5.21 (m, 1H), 5.07 – 4.71 (m, 1H), 4.71 - 4.42 (m, 1H). 4.42 - 3.97 (m, 6H), 3.97 - 3.51 (m. 4H), A173.32 - 3.27 (m, 3H), 3.13 (t, J = 6.1 Hz, 4H).3.00 - 2.57 (m, 10H), 2.37 - 2.21 (m, 2H), 2.11 - 1.90 (m, 6H), 1.86 - 1.63 (m, 6H), 1.61 - 1.50 (m, 6H), 1.50 - 1.37 (m, 4H), 1.37 - 1.18 (m. 2H), 1.04 - 0.89 (m. 2H), 0.85 (t, J = y - 7.3 Hz, 6H), 0.56 - 0.31 (m, 2H). / O'°CL LC-MS (m / z): 1362.7 [M + H]+.n °7\= ° 'H NMR (400 MHz, DMSO-c / 6) 5 12.05 - yj>11.74 (m, 1H), 11.12 (s, 1H), 8.93 (d, J= 6.4 O C / °"r,5^ '-^ LZ° / I T^. A 0 Hz, 1H), 8.83 - 8.46 (m, 1H). 7.97 (d, J= 9.2 NH Hz, 1H), 7.71 - 7.60 (m, 1H). 7.48 - 7.38 (m, XT >° 2H), 7.12 - 6.96 (m, 2H), 6.92 - 6.76 (m, 1H), i \ 6.42- 6.31 (m, 1H), 6.31 - 6.21 (m, 1H), 5.42- 5.29 (m, 1H), 5.09 - 4.76 (m, 1H), 4.68 - 4.49 (m. 1H), 4.40 - 4.26 (m. 1H), 4.27 - 4.11 A18A^Tix (m, 1H), 4.11 - 4.00 (m, 1H), 3.98 - 3.80 (m, ANA00 2H), 3.79 - 3.66 (m, 4H), 3.18 - 3.02 (m, 3H), yO 2.98 - 2.86 (m, 1H), 2.72 - 2.58 (m, 2H), 2.41 ZVNx - 2.27 (m. 3H), 2.22 - 2.14 (m, 1H), 2.11 - o 2.08 (m. 3H), 2.07 - 1.93 (m. 6H), 1.82 - 1.66 0 ^-N CDs (m, 6H), 1.53 - 1.37 (m, 5H), 1.05 - 0.88 (m,2H).LC-MS (m / z): 1061.7 [M−H]−.1H NMR (400 MHz, DMSO-6) δ 11.08 (s, 1H), 8.78 (s, 1H), 8.33 (d, J= 8.4 Hz, 1H),8.27 (d, J = 8.0 Hz, 1H), 8.11 - 7.97 (m, 2H), X T >0 7.68 - 7.56 (m, 2H), 7.04 - 6.93 (m, 2H), 6.42 \- 6.28 (m, 1H), 6.28 - 6.17 (m, 1H), 5.40 - 5.24 (m, 1H), 5.08 - 4.74 (m, 1H), 4.65 - 4.42 k.0 V 0A19 (m, 1H), 4.41 - 3.98 (m, 2H), 3.75 - 3.52 (m,( <NA ) " °N^H XXXO' \K°H4H). 3.32 - 3.27 (m, 3H). 3.04 - 2.82 (m. 4H). (j ° ( 2.78 - 2.55 (m, 8H), 2.37 - 2.11 (m, 2H), 2.08 A 'r0- 1.89 (m, 6H), 1.84 - 1.62 (m, 6H), 1.61 - 1.50 (m. 4H), 1.49 - 1.37 (m, 4H), 1.28 - 1.17 X <fr- N (m, 4H), 0.87 (t, J = 7.4 Hz, 3H), 0.52 - 0.40 0 CD3(m, 2H). LC-MS (m / z): 1232.5 [M + H]+.H. O1H NMR (400 MHz, DMSO-6) δ 11.08 (s,1H), 8.72 - 8.57 (tn, 2H), 8.22 (d, J= 28.7 Hz, I I 1H). 8.04 (s, 1H), 7.81 (d, J = 8.5 Hz, 2H),7.69 - 7.55 (m, 1H), 7.20 (m. 4H), 6.37 - 6. 19 A20 (m, 2H), 5.49 - 5.35 (m, 1H), 5.06 - 4.98 (m,1H), 4.58 - 4.31 (m, 2H), 4.12 - 3.97 (m, 2H), 3.82 - 3.65 (m, 4H), 3.25 (s, 3H), 2.41 - 2.30, X ^4 (m, 2H), 2.16 - 1.34 (m, 24H), 0.49 (s,Ok 2H). LC-MS (m / z): 1067.4 [M + H]+.LXFHO— P=OOH1H NMR (400 MHz, DMSO-6) δ 11.08 (s,1H), 8.48 - 8.25 (m, 2H), 8.21 - 8.04 (m, 2H), 7.71 - 7.54 (m, 2H), 7.07 - 6.76 (m, 3H), 6.43 A A >°^2^ \ - 6.28 (m, 1H), 6.29- 6.15 (m, 1H), 5.45 - 5.18 (m, 3H), 4.98 (s, 1H), 4.61 - 4.42 (m, E F O^X 1H), 4.11 - 3.95 (m, 4H), 3.67 - 3.53 (m, 4H), A21 r o \C / PrN>. P' A,!„■ \" NH S'^s / Hl\ typ 3.33 - 3.24 (m, 3H), 3.18 - 3.08 (m, 4H), 2.64 C]0' °A - 2.56 (m. 2H), 2.20 - 1.90 (m. 6H), 1.85 - A; ^> N. ° 1.62 (m, 6H), 1.61 - 1.37 (m, 6H), 1.28 - 1.20(m, 12H), 1.22- 1.13 (m, 5H), 1.10 (t, J= 7.1 o Hz, 3H), 1.01 -0.86 (m, 2H). 0.52- 0.37 (m, o CD32H). LC-MS (m / z): 1300.7 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.09 (s,1H). 9.19 - 8.73 (m, 1H), 8.43 - 8.32 (m. 1H), NH8.25 - 8.16 (m, 2H), 7.72 - 7.64 (m, 1H), 7.64 X T >0 - 7.56(m, 1H), 7.42- 7.31 (m, 2H), 7.24- \ 7.15 (m, 2H), 7.15 - 7.09 (m, 1H), 7.04- 6.93(m, 2H), 6.88- 6.74 (m, 2H), 6.42 - 6.29 (m, L^O F F O^ X 1H). 6.28 - 6.18 (m, 1H), 5.38 - 5.27 (m. 1H), A22 T o '9 ]ANA HXX O H ■■"' 5.04 - 4.76 (m, 1H), 4.54 (s, 1H), 4.35 - 3.53 AN O (m, 9H), 3.39- 3.35 (m, 3H), 3.32 - 3.27 (m,; - r° 3H), 2.94 – 2.56 (m, 5H), 2.37 - 2.21 (m, 2H), A^N2.17- 1.89 (m, 6H), 1.86- 1.60 (m, 6H), 1.58 - 1.29 (m. 6H), 1.29- 1.13 (m. 3H), 1.12- o^-N0 CD31.03 (m, 3H), 1.01 - 0.86 (m, 2H), 0.53 - 0.37(m, 2H). LC-MS (m / z): 1277.4 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.08 (s,1H), 9.22 - 8.70 (m, 1H), 8.46 - 8.30 (m, 1H), 8.27 - 8.13 (m, 2H), 7.71 - 7.64 (m, 1H), 7.64 - 7.55 (m, 1H), 7.41 - 7.30 (m, 2H), 7.24 - 7.15 (m, 2H), 7.15 - 7.10 (m, 1H), 7.03 - 6.93 (m, 2H), 6.87 – 6.70 (m, 2H), 6.42 - 6.28 (m, 1H). 6.28 - 6.19 (m, 1H), 5.38 - 5.23 (m. 1H), A235.04- 4.71 (m, 2H), 4.63 - 4.42 (m, 1H), 4.36 - 3.64 (m, 5H), 3.37 - 3.34 (m, 5H), 3.32 - 3.27 (m, 3H), 2.95 - 2.55 (m, 5H), 2.35 - 2.20 (m, 2H), 2.12- 1.91 (m, 6H), 1.82 - 1.61 (m, 6H). 1.58 - 1.29 (m, 6H). 1.17 - 1.02 (m. 9H), 1.01 - 0.84 (m, 2H), 0.53 - 0.36 (m, 2H). LC- MS (m / z): 1291.6 [M + H]+.A24 LC-MS (m / z): 1390.6 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.12 (s,1H). 8.37 (d, J = 16.7 Hz. 1H), 8.28 - 8.21 (m.3H), 7.71 - 7.62 (m, 2H), 7.54 - 7.47 (m, 2H), 7.44 _ 7.34 (m, 3H), 7.05 - 6.96 (m, 2H), 6.84 \ r~ 8 f _ (s, 1H), 6.32 (d, J= 32.4 Hz, 1H), 5.96 (d, J = =A25 X I X Yn 11.1 Hz, 1H), 5.38 - 5.27 (m. 1H), 5.04 - 4.54° \ ( I _\ / (m, 2H), 4.32 - 4.11 (m, 2H), 4.00 - 3.73 (m, Y71f o" H OTJ- o _ 8H), 3.30 (s, 3H), 2.75 - 2.68 (m, 2H), 2.67 - 2.61 (m, 4H), 2.40 - 2.28 (m, 4H), 2.10 - 1.97 (m, 8H), 1.82 - 1.64 (m, 8H), 1.54 - 1.42 (m, Q < O- 6H). LC-MS (m / z): 1252.5 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.14 (s, 1H), 8.73 - 8.61 (m, 2H), 8.24 (s, 1H), 8.15 / X,.."\rx5^T, N / I J XX >° (d, J= 8.5 Hz, 1H), 8.10 - 8.08 (m, 2H), 7.68- 7.58 (m, 2H), 7.02 - 6.97 (m, 2H), 6.83 (d, J = 6.9 Hz, 1H), 6.35 - 6.30 (m, 1H). 6.26 - ^yXJD X D3C-N-> ™y0 6.20 (m. 1H), 5.73 - 5.66 (m. 4H), 5.34 - 5.27 A26(m, 1H), 5.03 - 4.92 (m, 1H), 4.47 - 4.23 (m, d I) F 4H), 4.05 – 3.92 (m, 4H), 3.31 (s, 3H), 2.79 - — "y-F O-P=O2.58 (m. 2H), 2.06 - 1.81 (m, 10H), 1.71 - < <x p 1 o=( / °"f-° 1.60 (m. 4H), 1.58 - 1.50 (m. 8H), 1.44 - 1.36 (m, 8H), 1.09 (s, 18H). LC-MS (m / z): 1325.9 [M + H]+.1H NMR (400 MHz, DMSO-6) δ 11.08 (s,1H), 9.23 - 8.66 (m, 1H), 8.46 - 8.29 (m, 1H), 8.26 - 8.14 (m, 2H), 7.73 - 7.55 (m, 2H), 7.42 - 7.30 (m, 2H), 7.26 - 7.17 (m, 2H), 7.16 - j X >0 7.09 (m, 1H), 7.03 - 6.92 (m, 2H), 6.89 - 6.71? \(m, 2H), 6.43 – 6.30 (m, 1H), 6.29 - 6.16 (m, 1H). 5.40 - 5.25 (m, 1H), 5.04 – 4.73 (m, 1H), V> V o°V°^A27 4.66 - 4.41 (m, 1H), 4.36 - 3.55 (m, 9H), 3.31A HXAr-'- 3.28 (m, 5H), 3.18 - 3.08 (m, 2H), 2.94 - Ao O2.69 (m, 2H), 2.65 - 2.55 (m, 4H), 2.30 - 2.13 / VN (m, 2H), 2.13 - 1.89 (m, 6H), 1.84 - 1.59 (m,6H). 1.57 - 1.36 (m, 6H). 1.13 - 1.03 (m. 3H), X 1.00 - 0.89 (m, 2H), 0.86 - 0.75 (m, 3H), 0.51 0NCDs- 0.36 (m, 2H). LC-MS (m / z): 1291.6 [M + H]+.LC-MS (m / z): 1103.9 [M + H]+.A28Z2 0§s"HO'%HCK X NJ CD3A11-P1:1H NMR (400 MHz, DMSO-6) δ11.07 (s, 1H), 9.15 - 8.63 (m, 1H), 8.36 - 8.31 (m, 1H), 8.12 - 8.09 (m, 2H), 7.63 - 7.59 (m, 2H), 7.02 - 6.94 (m, 2H), 6.87 - 6.78 (m, 1H), All- 6.36 - 6.29 (m, 1H), 6.27 - 6.19 (m, 1H), 5.37 Pl - 5.28 (m, 1H), 5.03 - 4.80 (m, 1H), 4.64 - 4.43 (m, 1H), 4.37 - 3.83 (m, 6H), 3.35 - 3.27 (m, 5H), 3.13 - 2.82 (m, 6H), 2.64 - 2.57 (m, 2H). 2.20 - 1.92 (m, 6H), 1.85 – 1.61 (m, 6H), 1.59 - 1.30 (m, 6H), 1.09 - 0.85 (m, 2H), 0.53 - 0.39 (m, 2H). LC-MS (m / z): 1102.9 [M + H]+.A11-P2:1H NMR (400 MHz, DMSO-6) δ 11.07 (s, 1H), 9.05 - 8.71 (m, 1H), 8.38 - 8.31 (m, 1H), 8.14 - 8.09 (m, 2H), 7.63 - 7.58 (m, 2H). 6.99 - 6.95 (m, 2H), 6.85 – 6.78 (m, 1H), 6.39 - 6.33 (m, 1H), 6.25 - 6.20 (m, 1H), 5.34 - 5.30 (dd,.7 = 12.6, 5.2 Hz, 1H), 4.97 - 4.80 All- (m, 1H), 4.57 - 4.48 (m, 1H), 4.17 - 4.01 (m, P22H), 3.92 - 3.82 (m, 1H), 3.75 - 3.69 (m, 2H), 3.32 - 3.27 (m, 6H), 2.92 - 2.60 (m, 6H), 2.36 - 2.27 (m, 2H), 2.12 - 1.95 (m, 6H), 1.78 - 1.64 (m, 6H), 1.56 - 1.30 (m, 6H), 0.98 - 0.90 (m, 2H), 0.51 - 0.41 (m, 2H). LC-MS (m / z): 1103.0 [M + H]+.

[0368] Example 37: STAT6 Degradation Assay in MV4-11 Cells

[0369] Experimental Procedures:

[0370] 1. Prepare 6-well plates and seed cellsCentrifuge and count MV4-11 cells cultured to an appropriate density. Seed the cells into 6-well plates at a density of 80 - 100 x 104cells per well with a volume of 1.5 mL or 2.0 mL per well. Place the plates in a 37 °C incubator for later use.

[0371] 2. Add STAT6 PROTAC Degrader with concentration gradientAdd the pre-diluted selected test compounds (PROTAC Degrader, concentration range: 1 pM - 3000 pM) to the pre-seeded 6-well plates at a dilution ratio of 1: 1000, resulting in a final concentration range of 1 nM - 3000 nM. Swirl the 6-well plates horizontally in a crisscross manner to mix the compounds evenly.

[0372] 3. Incubate the mixed 6-well plates in a 37 °C incubator for 23 - 24 hours.

[0373] 4. Prepare protein samplesTransfer the cells from the 6-well plates to 1.5 mL centrifuge tubes and centrifuge at 13,000 x g at room temperature (RT) for 1 minute.Discard the cell supernatant, add 1 mL of PBS to rinse the cells once, and centrifuge again at 13,000 x g at RT for 1 minute. Discard the PBS.Add Lysis buffer containing protease inhibitors to each centrifuge tube according to the size of the cell pellet at the bottom and lyse the cells on ice.Centrifuge the cell lysate suspension at 13,000 x g at 4 °C for 15 minutes.Add 5x Loading buffer to a new centrifuge tube at a volume ratio of 1:4 relative to the lysate.Transfer the centrifuged lysate to this new tube, vortex to mix thoroughly, and boil in a 98 °C metal bath for 5 minutes.

[0374] 5. Protein sample electrophoresis and membrane transferCentrifuge the boiled protein samples and vortex to mix evenly. Mount the pre-prepared 7.5% SDS-PAGE gel in an electrophoresis tank, and load 20 pL of protein sample into each well. Run the electrophoresis at a constant voltage of 80 V until the protein marker bands are separated, then adjust the voltage to 150 V (constant voltage) and continue electrophoresis until completion. Perform w et transfer of the separated proteins from the SDS-PAGE gel to a membrane at 400 mA for 30 minutes.

[0375] 6. Block the transferred NC membrane with 3% skimmed milk powder for 1 hour. After blocking, rinse the membrane twice with PBS, add the pre-prepared primary antibody working solution against STAT6, and incubate overnight at 4 °C.

[0376] 7. On the next day, after rinsing the membrane, incubate it with the secondary' antibody working solution for 1 hour. Rinse the membrane three times with PBST. then perform chemiluminescence development.

[0377] Table 2. STAT6 Degradation Efficacy of Compounds in MV4-11 Cells Degradation (%) Degradation (%) Degradation (%) Cmpd. NO. at 30 nM at 100 nM at 300 nMAl / <10 <10A2 / <10 <10A3 / <10 <10A4 / / 16 A5 / / 64A6 / 83 92A7 / 24 26A8 / <10 <10A9 / 83 94A10 / <10 <10All / 79 90A12 / 62 78A13 / <10 <10A14 / 91 94A15 / <10 35A16 / 60 74A17 86 90 / A18 / 61 81A19 / 82 95A20 / 94 / A21 / 17 / A22 / <10 <10A23 / <10 <10A24 83 / 28A25 / <10 <10A26 / / 99A27 / / <10A28 / 79 94All-Pl / 88 93A11-P2 / 87 89AK1690 / 79 91

[0378] Note:indicates that the test was not performed. At the tested concentrations, a degradation rate of > 50% is considered to indicate good degradation activity. AK1690 is used as a reference compound for comparison, and its structural formula is as follows:

[0379] The results are shown in Table 2. It can be seen from Table 2 that Compounds A5, A6, A9, All, A12, A14, A16-A20, A24, A26, A28, All-Pl, and A11-P2 exhibit good degradationefficacy against STAT6. The DC50 values of Compounds A6, A9, Ai k A14, A17, Al 1-P1, and Al 1-P2 for STAT6 degradation were further examined, and the results are shown in Table 3:

[0380] Table 3. STAT6 Degradation Efficacy of Compounds in MV4-11 CellsCmpd. NO. DC50(nM)A6 27A9 14All 6.0A14 0.2A17 0.012Al l-Pl 24A11-P2 15AK1690 38

[0381] It can be seen from Table 3 that Compounds A6, A9, All, A14, A17, Al 1-P1, and Al 1-P2 all exhibit high degradation activity against STAT6, with DC50 values lower than that of the positive control (AK1690). Among them, Compounds A14 and Al 7 are two prodrug forms of Compound A9, and their degradation activity has unexpectedly increased by 70 and 1167 times, respectively over the parent drug Compound A9. The results of Compound A14 are shown in FIGs. 4 A and 4B.

[0382] Example 38: Selectivity Assay of Compounds in MV4-11 Cells

[0383] Experimental Procedures:

[0384] 1. Prepare 6-well plates and seed cellsCentrifuge and count MV4-11 cells cultured to an appropriate density. Seed the cells into 6-well plates at a density of 80 - 100 x 104cells per well, with 1.5 mL or 2.0 mL of 10% FBS RPMI medium per well. Place the plates in a 37 °C incubator for later use.

[0385] 2. Add STAT6 PROTAC Degrader with concentration gradientAdd the pre-diluted Compound A6 (concentration range: 1 pM - 3000 pM) to the preseeded 6-well plates at a dilution ratio of 1: 1000, resulting in a final concentration range of 1 nM - 3000 nM. Swirl the 6-well plates horizontally in a crisscross manner to mix the compound evenly.

[0386] 3. Incubate the mixed 6-well plates in a 37 °C incubator for 23 - 24 hours.

[0387] 4. Prepare protein samplesTransfer the cells from the 6-well plates to 1.5 mL centrifuge tubes and centrifuge at 13,000 x g at room temperature (RT) for 1 minute.Discard the cell supernatant, add 1 mL of PBS to rinse the cells once, and centrifuge again at 13,000 x g at RT for 1 minute. Discard the PBS.Add Lysis buffer containing protease inhibitors to each centrifuge tube according to the size of the cell pellet at the bottom and lyse the cells on ice.Centrifuge the cell lysate suspension at 13,000 x g at 4 °C for 15 minutes.Add 5× Loading buffer to a new centrifuge tube at a volume ratio of 1:4 relative to the lysate.Transfer the centrifuged lysate to a new centrifuge tube, vortex to mix thoroughly, and boil in a 98 °C metal bath for 5 minutes.

[0388] 5. Protein sample electrophoresis and membrane transferCentrifuge the boiled protein samples and vortex to mix evenly. Mount the pre-prepared 7.5% SDS-PAGE gel in an electrophoresis tank, and load 20 pL of protein sample into each well. Run the electrophoresis at a constant voltage of 80 V until the protein marker bands are separated, then adjust the voltage to 150 V (constant voltage) and continue electrophoresis until completion. Perform wet transfer of the separated proteins from the SDS-PAGE gel to a membrane at 400 mA for 30 minutes.

[0389] 6. Block the transferred NC membrane with 3% skimmed milk powder for 1 hour. After blocking, rinse the membrane twice with PBS, add the pre-prepared primary antibody¬ working solutions against STAT6. STAT1, STAT3. and STAT5, and incubate overnight at 4 °C.

[0390] 7. On the next day, after rinsing the membrane, incubate it with the secondary antibody working solution for 1 hour. Rinse the membrane three times with PBST, then perform chemiluminescence development.

[0391] Table 4. Degradation Activity of Compounds Against the STAT Family in MV4-11 CellsSelectivity ratio STAT6 STAT1 STAT3 STAT5 Cmpd. NO. STAT3 DC50(nM) DC50(nM) DCso (nM) DC50(nM)DC50 / STAT6 DC50A6 27 >3000 >3000 >3000 >111A9 14 / >3000 / >214 Al l 6 / >3000 / >500A17 0.012 >100 >100 >100 >8333

[0392] The results are shown in FIGs. 1 A, IB, 2A, 2B, and 2C, and Table 4. At the tested concentrations. Compounds A6 (FIGs. 1A and IB), A9 (FIGs. 2A and 2B). All (FIGs. 2A and 2C), and A17 only degrade STAT6, with DC50 values of 27 nM, 14 nM, 6 nM, and 0.012 nM, respectively. Compounds A6 and Al 7 show- no significant degradation effect on STAT1, STAT3, and STAT5 of the same family; Compounds A9 and All have no degradation effect onSTAT3. These results indicate that the compounds of the present disclosure have excellent selectivity, which can avoid the safety risks caused by STAT3 degradation.

[0393] Example 39: IL -4 Induced CCL17 Release Assay (ELISA)

[0394] Experimental Procedures:

[0395] 1. Prepare 96-well plates and seed cellsThaw one tube of PBMC cells (500 x 104cells / tube), count the cells, and seed them into 96-well plates at a density of 5 x 104cells per well with 100 pL of RPMI medium per well. Place the plates in a 37 °C incubator for later use.

[0396] 2. Sequentially add STAT6 PROTAC Degrader compounds with concentration gradientAdd the pre-diluted selected STAT6 PROTAC Degrader (concentration range: 10 pM -30 mM) to the pre-seeded 96-well plates at a dilution ratio of 1:1000, resulting in a final concentration range of 10 nM - 30,000 nM. Swirl the 96-well plates horizontally in a crisscross manner to mix the compounds evenly.

[0397] 3. Incubate the mixed 96-well plates in a 37 °C incubator for 7 hours.

[0398] 4. Add Dupilumab monoclonal antibody with concentration gradientAdd the pre-diluted Dupilumab (concentration range: 0.3 pM - 1 mM) to the pre-seeded 96-well plates at a dilution ratio of 1: 1000, resulting in a final concentration range of 0.3 nM -1000 nM. Swirl the 96-well plates horizontally in a crisscross manner to mix the monoclonal antibody evenly.

[0399] 5. Incubate the mixed 96-well plates in a 37 °C incubator for 1 hour.

[0400] 6. Dilute the 100 pg / mL IL-4 cytokine at a ratio of 1: 1000 to a final concentration of 100 ng / mL, and add it to the 96-well plates pre-treated with the selected STAT6 PROTAC Degrader or Dupilumab. Swirl the 96-well plates horizontally in a crisscross manner to mix the cytokine evenly.

[0401] 7. Incubate the mixed 96-well plates in a 37 °C incubator for 24 hours.

[0402] 8. Collect 70 pL of cell culture supernatant for subsequent CCL17 ELISA detection. The results are shown in Table 5.

[0403] Table 5. Inhibitory Effects of Compounds on IL-4 Induced CCL17 Production Cmpd. NO. IC50(nM)A6 216A9 278All 210A14 2.7A17 0.48Dupilumab 11

[0404] Note: Dupilumab is used as a reference compound for comparison. It is an approved fully human monoclonal antibody targeting the interleukin-4 receptor alpha subunit (IL-4Ra), which can inhibit the IL-4-induced type 2 inflammatory' signaling pathway.

[0405] According to Table 5, Compounds A6, A9, Al 1, A14, A17, and Dupilumab all can inhibit IL-4-induced CCL17 release. Among them, the activity of Compounds A14 and A17 is approximately 4 and 23 times, respectively, better than that of Dupilumab, indicating promising therapeutic effects on type 2 inflammation.

[0406] Example 40: Selectivity' of Compounds in Mouse Splenic Single Cells and Confirmation of Species Differences

[0407] Experimental Procedures:

[0408] 1. Preparation of mouse splenic single cells and seeding into 6-well plates Prepare 3 healthy normal mice, euthanize them and harvest the spleen tissues. Immerse the tissues in 40 mL of RPMI medium for later use.Prepare 2% FPBS reagent in advance. Transfer 10 mL of 2% FPBS to a 10 cm cell culture dish, place a 0.2 pm filter membrane in the dish, and transfer the mouse spleen tissues onto the filter membrane. Grind the tissues wi th the plunger of a 2 mL sterile syringe until no large tissue clumps remain. Transfer the cell suspension in the dish to a 50 mL centrifuge tube and centrifuge at 400 x g at room temperature (RT) for 3 minutes.Discard the supernatant. Add 2 mL of RBC Lysis buffer per spleen to lyse red blood cells for 3 - 5 minutes, then add 5 volumes of 2% FPBS to terminate the lysis. Centrifuge at 400 x g at RT for 3 minutes.Discard the supernatant, add an appropriate volume of PBS to wash the cells once, and centrifuge at 400 x g at RT for 3 minutes.Discard the supernatant, resuspend the cells in 5 mL of FBS-free RPMI medium, and filter the cell suspension through a 0.2 pm filter membrane into a new 50 mL centrifuge tube. Supplement FBS-free RPMI medium to a total volume of about 25 mL for 10 wells (2.5 mL per well).Mix the cells evenly and seed them into 6-well plates at 2.5 mL per well. Place the plates in a 37 °C incubator for later use.

[0409] 2. Add STAT6 PROTAC Degrader with concentration gradientAdd the pre-diluted Compound A6 (concentration range: 1 pM - 3000 pM) to the preseeded 6-well plates at a dilution ratio of 1: 1000, resulting in a final concentration range of 1 nM - 3000 nM. Swirl the 6-well plates horizontally in a crisscross manner to mix the compound evenly.

[0410] 3. Incubate the mixed 6-well plates in a 37 °C incubator for 23 - 24 hours.

[0411] 4. Prepare protein samplesTransfer the cells from the 6-well plates to 1.5 mL centrifuge tubes and centrifuge at 13,000 x g at RT for 1 minute.Discard the cell supernatant, transfer the remaining cells in the wells to the corresponding centrifuge tubes, and centrifuge again at 13,000 x g at RT for 1 minute.Discard the cell supernatant, add 1 mL of PBS to rinse the cells once, and centrifuge at 13,000 x g at RT for 1 minute. Discard the PBS.Add Lysis buffer containing protease inhibitors to each centrifuge tube according to the size of the cell pellet at the bottom and lyse the cells on ice.Centrifuge the cell lysate suspension at 13,000 x g at 4 °C for 15 minutes.Add 5x Loading buffer to a new centrifuge tube at a volume ratio of 1:4 relative to the lysate.Transfer the centrifuged lysate to this new tube, vortex to mix thoroughly, and boil in a 98 °C metal bath for 5 minutes.

[0412] 5. Protein sample electrophoresis and membrane transferCentrifuge the boiled protein samples and vortex to mix evenly. Mount the pre-prepared 7.5% SDS-PAGE gel in an electrophoresis tank, and load 20 pL of protein sample into each well. Run the electrophoresis at a constant voltage of 80 V until the protein marker bands are separated, then adjust the voltage to 150 V (constant voltage) and continue electrophoresis until completion. Perform wet transfer of the separated proteins from the SDS-PAGE gel to a membrane at 400 mA for 30 minutes.

[0413] 6. Block the transferred NC membrane with 3% skimmed milk powder for 1 hour. After blocking, rinse the membrane twice with PBS, add the pre-prepared primary antibody working solutions against STAT6. STAT1, STAT2. STAT3, STAT4. and STAT5, and incubate overnight at 4 °C. On the next day, after rinsing the membrane, incubate it with the secondary antibody working solution for 1 hour. Rinse the membrane three times with PBST, then perform chemiluminescence development.

[0414] Table 6. Degradation Activity of Compounds against the STAT Family in Mouse SplenocytesCmpd. STAT6 STAT1 STAT2 STAT3 STAT4 STAT5 NO. DC50(nM) DC50(nM) DC50(nM) DC50(nM) DC50(nM) DC50(nM) A6 15 >3000 >3000 >3000 >3000 >3000 Al l 8.8 >1000 >1000 >1000 >1000 >1000Al 7 0.13 >30 >30 >30 >30 >30

[0415] The results are shown in FIGs. 3A and 3B, and Table 6. Compounds A6 (FIGs. 3A and 3B), Al l, and Al 7 exhibit excellent degradation selectivity in mouse splenocytes. At the testedconcentrations, they only degrade STAT6 without significant degradation effects on STAT1-5 of the same family. Their DC50 values are 15 nM, 8.8 nM, and 0.13 nM, respectively, which are close to the results in MV4-11 cells, indicating that Compounds A6, All, and A17 have no species differences.

[0416] Example 41: Degradation Assay of Compounds against Ikaros, Aiolos, GSPT1, and SALL4 Proteins

[0417] Testing the degradation of Ikaros, Aiolos, GSPT1, and SALL4 proteins by the compounds of the present disclosure can initially assess the safety of potential off-target effects.

[0418] Experimental Procedures:

[0419] 1. Degradation testing method for Ikaros, Aiolos, and GSPT 1:The human myelomonocytic leukemia cell line MV4-11 was used. The sterile incubator was set at 37-38 °C, pH 7.2-7.4, and 5% carbon dioxide. MV4-11 cells (9xl05cells / well) were seeded in 6-well plates and treated with compounds of different concentrations for 24 hours. Proteins were extracted using RIPA lysis buffer, and the samples were electrophoresed on 7.5% SDS-PAGE and transferred to NC membranes.The membranes were blocked with 5% skimmed milk (PBS + 0.05% Tween-20) at room temperature for 1 hour, then incubated with primary antibodies overnight at 4 °C(including anti-Ikaros, A3565, ABclonal; anti-Aiolos, A8614, ABclonal; anti-GSPTl, A25506, ABclonal; anti-Actin, A2066, SIGMA). After that, the membranes were incubated with secondary antibodies at room temperature for 1 hour (Anti-rabbit IgG (H+L), DyLight 800, CST), and finally detected by the Odyssey CLx Two-ColorInfrared Laser Imaging System.

[0420] 2. Degradation testing method for SALL4:The human embryonic stem cell line H9 was used. The sterile incubator was set at 37-38 °C, pH 7.2-7.4, and 5% carbon dioxide. H9 cells (2xl05cells / well) wereseeded in 6-well plates and treated with compounds of different concentrations for 24 hours. Proteins were extracted using RIPA lysis buffer, and the samples were electrophoresed on 7.5% SDS-PAGE and transferred toNC membranes. The membranes were blocked with 5% skimmed milk (PBS + 0.05% Tw een-20) at room temperature for 1 hour, then incubated with primary antibodies overnight at 4 °C (including anti-Sall4, ab29112, Abeam; anti-GAPDH, share-bio). After that, the membranes were incubated with secondary antibodies at room temperature for 1 hour (Anti-rabbit IgG (H+L), DyLight 800, CST), and finally detected by the Ody ssey CLx Two-Color Infrared Laser Imaging System.

[0421] Experimental Results:

[0422] FIG. 5 shows the degradation of Ikaros, Aiolos, and GSPT1 proteins by Compounds All, Al 7, and the positive control Pomalidomide (denoted as Poma).

[0423] FIG. 6 shows the degradation of SALL4 protein by Compounds All, Al 7, and the positive control Pomalidomide.

[0424] Conclusion: As shown in FIGs. 5 and 6, Compounds Al 1 and Al 7 have no degradation effect on Ikaros, Aiolos, GSPT1, or SALL4 proteins, while the positive control Pomalidomide exhibits dose-dependent degradation of Ikaros, Aiolos, and SALL4 proteins. The above results demonstrate that the compounds of the present disclosure have a low risk of off-target toxicity from CRBN ligands (a class of E3 ligase ligands).

[0425] Example 42: Protein Degradomics of Compounds in hPBMCs

[0426] Experimental Procedures:

[0427] 1. The human PBMC cell line was used. The sterile incubator was set at 37-38 °C, pH 7.2-7.4, and 5% carbon dioxide. hPBMC cells (7xl05cells / well) were seeded in 6-well plates and treated with compounds for 24 hours.

[0428] 2. Sample Preparation

[0429] 2.1 Protein Extractiona) Cell lysis: Take the cell pellet sample, add 600 pL of lysis buffer, and vortex to mix evenly;b) Grinding: Transfer the sample to a grinding tube for grinding;c) Centrifugation: Centrifuge at 14,000 x g for 5 minutes, collect the supernatant, and determine the protein concentration of the supernatant by BCA assay.

[0430] 2.2 Reduction and Alkylationa) Reduction: Take 200 pg of protein, add 5 pL of DTT (1 M), vortex to mix evenly, and incubate at room temperature for 60 minutes;b) Alkylation: Add 20 pL of IAM (1 M) to the sample, vortex to mix evenly, and incubate at room temperature in the dark for 60 minutes;c) Quenching: Add 10 pL of DTT (1 M) to the sample, vortex to mix evenly, and incubate at room temperature for 30 minutes.

[0431] 2.3 SP3 Digestiona) Binding: Wash the Beads with pure water in advance to prepare a stock solution of 100 pg / pL. Mix according to the ratio of Beads / protein = 10:1 (w / w), add absolute ethanol to a final concentration of 50% (v / v), and incubate at room temperature for 15 minutes with mixing;b) Rinsing: Rinse repeatedly with 500 pL of 80% ethanol three times, and dry the Beads at room temperature;c) Digestion: Add Trypsin at a ratio of protein: enzyme = 50:1 (w / w), and incubate at 37 °C for 18 hours;d) Peptide recovery: Centrifuge the digested sample at 14,000 x g for 5 minutes at room temperature, place the centrifuged sample on a magnetic stand, let stand for 2 minutes, collect the supernatant, and determine the polypeptide concentration of the supernatant by BCA assay.

[0432] 2.4 Desaltinga) Take 10 pg of each sample and desalt with self-made Tip columns;b) Vacuum-dry the desalted samples and store them for testing.

[0433] 3. Chromatographic ConditionsMobile 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 C18 1.9 pm 75 pmx200 mm, with a flow rate of 0.4 pL / min.

[0434] 4. Software AnalysisDIA-NN (vl.8) was used for retrieval. Retrieval parameters: The database was the Swissprot human protein database (sequences); the digestion method was set to Trypsin / P with a maximum of 2 missed cleavage sites; the minimum peptide length was set to 7 amino acid residues; the mass error range of primary and secondary mass spectrometry was 20 ppm. Fixed modification was set to Carbamidomethyl (C); variable modifications were Oxidation (M) and Acetyl (N-terminus).

[0435] 5. Volcano Plot of Differentially Expressed ProteinsIn this experiment, the quantitative changes of proteins in the experimental group and the control group were used to draw a volcano plot of differentially expressed proteins. The abscissa of the volcano plot was the Log2-transformed value of the fold change (Foldchange) of the relative quantitative values of proteins between the two groups. The ordinate of the volcano plot was the -LoglO-transformed value of the P-value from the differential significance test.

[0436] Experimental ResultsThe protein degradation volcano plot of Compound Al 1 in hPBMCs is shown in FIG. 7. A total of 6013 proteins were detected for Compound Al 1, and the names of significantly degraded proteins (p<0.05) are labeled in the corresponding volcano plot (including the following proteins: STAT6, SLC37A4, MDM4, SETD2, TLNRD1, MAST3, MEPCE, TELQ2, MRTFB).

[0437] Conclusion: Compound Al 1 exhibits excellent protein degradation selectivity in hPBMCs.

[0438] Example 43: CYP Enzyme Inhibition Assay

[0439] Experimental Procedures:

[0440] 1. Prepare working solutions of test compounds and positive controls;

[0441] 2. Take human liver microsomes (HLM) out of the refrigerator and thaw on ice;

[0442] 3. Transfer 20 pL of substrate working solution to the corresponding wells, and transfer 20 pL of PB buffer to the blank wells of the incubation plate;

[0443] 4. Transfer 158 pL of HLM working solution to all wells of the incubation plate;

[0444] 5. Transfer 2 pL of test compound or positive control working solution to the wells, and transfer 2 pL of vehicle to the wells without inhibitor control;

[0445] 6. Preheat the incubation plate at 37.0°C for 10 minutes;

[0446] 7. Add 20 pL of NADPH working solution to initiate the reaction, and incubate the plate at 37.0°C for 10 minutes;

[0447] 8. After the reaction, add 400 pL of stop solution containing internal standard to terminate the reaction;

[0448] 9. Stir the reaction solution for 10 minutes and centrifuge at 3220 x g for 20 minutes;

[0449] 10, Take 200 pL of supernatant and mix with 100 pL of ultrapure water;

[0450] 11. After shaking for 10 minutes, analyze the substrate metabolites by LC-MS / MS.

[0451] Experimental Results

[0452] The IC50 values of the compounds of the present disclosure for CYP inhibition are shown in Table 7.

[0453] Table 7. CYP inhibition by Compound Al 1Cmpd. 1A2 (pM) 2C9 (pM) 2C19 (pM) 2D6 (pM) CYP3A4 (pM) NO.All > 50 > 50 43.5 > 50 > 50

[0454] Conclusion: For the tested CYP isoenzymes (1A2, 2C9. 2C19, 2D6, and CYP3A4), the IC50 values of Compound Al 1 of the present disclosure are all greater than 40 pM. This indicates that Compound Al 1 has weak inhibition on CYP isoenzymes and a low risk of drugdrug interactions.

[0455] Example 44: hERG Inhibition Assay

[0456] Experimental Procedures:

[0457] 1. Test samples were first dissolved in an appropriate solvent, then diluted with ECS at a ratio of 0.3% to prepare working solutions of different concentrations: 0.3, 1, 3, 10, and 30 pM. Cisapride is a known hERG current inhibitor and is widely used as a positive control inhERG assays (in this experiment, the inhibition rate of Cisapride at 0.1 pM was greater than 50%, confirming that the sensitivity of the experimental system meets the requirements).

[0458] 2. The cell line used was a Chinese Hamster Ovary (CHO) cell line stably expressing hERG in vitro. The complete medium was F12 medium supplemented with 10% fetal bovine serum, 1% Geneticin® selective antibiotic (G418), and 89 pg / mL hygromycin B (HB). The recovery medium was Fl 2 medium supplemented with 10% fetal bovine serum. CHO-hERG cells were cultured in a high-humidity incubator at 37 °C (±2 °C) with 5% CO2 (range: 4% to 8%).

[0459] 3. CHO-hERG cells in the exponential growth phase were collected and resuspended in ECS for later use. hERG currents were recorded using the whole-cell patch clamp technique at room temperature. The output signal of the patch clamp amplifier was subjected to digital -to-analog conversion and 2.9 KHz low-pass filtering. Data was collected using Patchmaster Pro software.

[0460] 4. At the initial stage of recording with vehicle control working solution perfusion, the peak tail current was monitored until more than 3 stable scan curves were obtained. Then, the test sample / positive control working solution was perfused until the inhibitory effect of the test sample / positive control working solution on the peak hERG current reached a steady state. The inhibition rate of hERG current in cells at different concentrations was recorded.

[0461] Experimental Results

[0462] The ICso values of the Compound A17 of the present disclosure for hERG inhibition are listed in Table 8.

[0463] Table 8. hERG inhibition by Compound Al 7Cmpd. NO. IC50A17 >10 pM

[0464] Conclusion: Compound Al 7 of the present disclosure has no significant inhibitory effect on hERG, indicating a low risk of cardiotoxicity.

[0465] Example 45: Pharmacokinetics of Compounds Administered Intratracheally in C57 Mice

[0466] Experimental Procedures:

[0467] The rodent pharmacokinetic characteristics of the compounds after intratracheal administration were tested according to standard protocols. In the experiment, candidate compounds were prepared into solutions and administered to mice as a single intratracheal dose using a pulmonary liquid quantitative nebulizer, with normal saline as the vehicle. Female C57 mice were used in this study. After administration, lung and blood samples were collected fromthe mice at 2 h, 6 h, 24 h, and 48 h. The collected samples were then analyzed by LC / MS / MS and data were collected.

[0468] Experimental Results

[0469] The pharmacokinetic test results of Compound Al 1 in mice are shown in Table 9.

[0470] Table 9. Pharmacokinetic test results of Compound Al 1AllIntratracheal administrationPK parameters 1 mg / kglung plasmaCmax(ng / mL or ng / g) 6345 1507Tmax(h) 2.00 2.00T1 / 2(h) 25.2 3.01Tlast(h) 48.0 24.0AUCo-iast (ng.h / mL or ng.h / g) 158824 7484AUCO-24 (ng.h / mL or ng.h / g) 102528 7484aAUC Ratio 21.2

[0471] a: AUC Ratio — Tissue AUCo-iast / Plasma AUCo-iast

[0472] Conclusion: Compound Al 1 exhibits excellent pharmacokinetic characteristics in mice after intratracheal administration. The drug can be selectively exposed in lung tissue, with a lung / plasma ratio (AUC Ratio) as high as 21, which reduces systemic circulation exposure of the drug, lowers safety risks to other organs, and is suitable for local treatment of respiratory tract and lung diseases.

[0473] Example 46: STAT6 Protein Degradation of Compounds in C57 Mice

[0474] Experimental Procedures:

[0475] Fifteen female C57 mice were administered intratracheally, and lung and blood samples were collected at 0 h, 2 h, 6 h, 24 h, and 48 h respectively to study in vivo STAT6 protein degradation.

[0476] PBMC Isolation and Lysis:

[0477] Blood was collected from mice in each group (3 mice per group) using EDTA-K2 crystal anticoagulant centrifuge tubes (approximately 0.5 mL per mouse). According to the same group and time point, the whole blood samples were mixed and transferred to centrifuge tubes for centrifugation at 2000 x g at room temperature (RT) for 10 minutes (Accel 9, Decel 9).

[0478] After centrifugation, discard the upper plasma, add PBS buffer containing 2% FBS to the centrifuge tube to a volume of 3 mL, mix evenly, and slowly add the suspension dropwise toa centrifuge tube containing 1.5 mL of human lymphocyte separation medium for centrifugation at 400 x g at RT for 25 minutes (Accel 2, Decel 2).

[0479] After centrifugation, carefully aspirate the thin, dense white membrane layer in the middle into a centrifuge tube containing 8 mL of PBS buffer with 2% FBS. and centrifuge at 400 x g at RT for 5 minutes (Accel 9, Decel 9).

[0480] After centrifugation, discard the supernatant, add 100 pL of red blood cell lysis buffer to lyse red blood cells, let stand at room temperature for 5 minutes, add 2 mL of PBS buffer containing 2% FBS, and centrifuge at 400 x g at RT for 5 minutes (Accel 9, Decel 9).

[0481] Discard the supernatant, resuspend the pellet with 1 mL of PBS, transfer to a 1.5 mL centrifuge tube, and centrifuge at 13,000 x g at RT for 2 minutes.

[0482] After centrifugation, discard the supernatant, place on wet ice, resuspend the pellet with 40 pL of cell lysis buffer (RIPA Lysis buffer containing PMSF), pipette quickly and evenly, lyse on ice for 15 minutes (scrape and shake multiple times during lysis to break nucleic acids until there are no viscous clumps in the solution), and centrifuge at 13,000 x g at 4 °C for 10 minutes.

[0483] After centrifugation, transfer the supernatant to a 1.5 mL centrifuge tube and place on wet ice for later use.

[0484] Tissue Homogenization:

[0485] Take tissue samples of approximately the same size, place in a centrifuge tube containing 300 pL of Westem / IP lysis buffer with PMSF, and place in a wet ice box.Homogenize the tissue pieces using a PRO 200 homogenizer, lyse on wet ice for 30 minutes, and centrifuge at 13,000 x g at 4 °C for 25 minutes. Transfer the supernatant to a 1.5 mL centrifuge tube and place on wet ice for later use.

[0486] Protein Sample Preparation:

[0487] Determine the protein concentration using Biyuntian BCA Protein Assay Kit (Cat. No.: P0009), add a certain volume of SDS loading buffer and Lysis buffer, mix evenly, and prepare 50 pL of sample with a protein concentration of 3 pg / pL or 100 pL of sample with a protein concentration of 5 pg / pL. Heat in a 98 °C metal bath for 5 minutes.

[0488] Western Blot Analysis:

[0489] Centrifuge the prepared protein samples and vortex to mix evenly. Mount the preprepared 10% SDS-PAGE gel in an electrophoresis tank, add the samples to the loading lanes, run electrophoresis at a constant voltage of 80 V until the protein marker bands are separated, then adjust the voltage to 150 V (constant voltage) until electrophoresis is completed. Perform wet transfer of the SDS-PAGE gel at 400 mA for 40 minutes. Block the NC membrane with transferred protein samples with 3% skimmed milk pow der for 1 hour, rinse twice with PBS,add the pre-prepared STAT6 primary antibody working solution (STAT6 antibody CST 5397 diluted 1 OOO-fold), and incubate overnight at 4 °C. On the next day, after rinsing, incubate with secondary antibody working solution (1 hour), and rinse with PBST, then perform chemiluminescence development.

[0490] Experimental Results:

[0491] The STAT6 degradation in mice after intratracheal nebulization administration of Compound Al 1 in lung tissues and plasma (peripheral blood mononuclear cell (PBMC) cells) is shown in FIGs. 8A and 8B, respectively. According to FIG. 8A, Compound All of the present disclosure can effectively degrade STAT6 protein in lung tissue, with a pharmacodynamic duration of up to 48 hours.ADVANTAGE OF THE COMPOUNDS

[0492] The compounds provided by the present disclosure have high STAT6 protein degradation activity and can be used for preventing and / or treating diseases and / or disorders that are at least partially responsive to STAT6. including, for example, type 2 inflammation mediated by Th2 cells, group 2 innate lymphoid cells, and related cytokines.

[0493] The compounds provided by the present disclosure also have high selectivity for STAT6 protein degradation, and do not cause biologically significant degradation of other proteins in the STATs family (especially STAT3 protein). This STAT6 selectivity may avoid or reduce safety risks caused by off-target activities against other STATs (especially STAT3 protein).

[0494] The compounds provided by the present disclosure exhibit no significant species differences, low risk of off-target toxicity from CRBN ligands, weak inhibition on CYP isoenzymes, low risk of drug-drug interactions, no inhibitory effect on hERG, and low risk of cardiotoxicity.

[0495] The compounds provided by the present disclosure can effectively degrade STAT6 protein in lung tissue with a long duration of pharmacodynamic effect, exhibit excellent pharmacokinetic properties, can be selectively exposed in lung tissue, reduce systemic circulation exposure of the drug, lower safety risks to other organs, and are suitable for local treatment of respiratory tract and lung diseases.

[0496] The compounds provided by the present disclosure can also be used as prodrugs of highly selective STAT6 protein degraders, which can improve the degradation activity against STAT6 protein.

[0497] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examplesprovided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

What is claimed is:

1. A compound of Formula (I):(I)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:X is (i) NR6a, CHR6a, O, S, S(=O), or S(=O)2, or (ii) N or CR6a, when X is linked to Lm; each n is independently 0, 1, 2, or 3;m is 1, 2, 3, 4, 5, 6. 7, or 8;Ring A is selected from 4-6 membered saturated or partially unsaturated heterocyclyl comprising at least one nitrogen, 5-6 membered heteroaryl comprising at least one nitrogen, 8-10 membered fused heterobicyclyl comprising at least one nitrogen, and 6-12 membered bridged heterobicyclyl comprising at least one nitrogen;Ring B is absent, or selected from 5-6 membered heteroaryl comprising 1-4 heteroatoms each independently selected from nitrogen, oxygen, and sulfur, phenyl, saturated or partially unsaturated 5-6 membered heterocyclyl comprising 1-2 heteroatoms each independently selected from oxygen and nitrogen, and saturated or partially unsaturated C3.6 cycloalkyl; when Ring B is absent, (R4)nis H and connects with Ring A directly;Ring C is selected from phenyl, 5-6 membered heteroaryl, naphthyl, and 8-10 membered fused heterobicyclyl comprising 1-3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; each of said phenyl, 5-6 membered heteroaryl, naphthyl, or 8-10 membered fused heterobicyclyl is unsubstituted or substituted with 0, 1, 2, or 3 Rcgroups;R1is selected from -C(RlaR2a)P(=O)(ORb)(ORb), -C(RlaR2a)P(=O)[ORb][NH(CH2)qC(=O)ORT], -C(RlaR2a)P(=O)[NH(CH2)qC(=O)ORT] [NH(CH2)qC(=O)ORT], -C(RlaR2a)P(=O)[NHRT] [NHRT], -C(RlaR2a)P(=O)[NHCH( CH3)C(=O)ORT][NHCH(CH3)C(=O)ORT], -C(RlaR2a)P(=O)[ORb][NHCH(CH3)C(=O)ORT], -C (RlaR2a)P(=O)[ORb][NHC(CH3)2C(=O)ORT], -P(=O)(ORb)(ORb), -P(=O)[ORb][NH(CH2)qC(=O)ORT], -P(=O)[NH(CH2)qC(=O)ORT][NH(CH2)qC(=O)ORT], -P(=O)[NHRT][NHRT], -P( =O)[NHCH(CH3)C(=O)ORT] [NHCH(CH3)C(=O)ORT], and-P(=O)[ORb][NHCH(CH3)C(=O)ORT];preferably, R1is selected from -C(RlaR2a)P(=O)(ORb)(ORb), -C(RlaR2a)P(=O)[ORb][NH(CH2)qC(=O)ORT], -C(RlaR2a)P(=O)[NH(CH2)qC(=O)ORT][NH(CH2)qC(=O)ORT]. -C(RlaR2a)P(=O)[NHRT] [NHRT], -C(RlaR2a)P(=O)[ NHCH(CH3)C(=O)ORT] [NH CH(CH3)C(=O)ORT], -C(RlaR2a)P(=O)[ORb][NHCH(CH3)C(=O)ORT], -P(=O)(ORb)(ORb), -P( =O)[ORb][NH(CH2)qC(=O)ORT], -P(=O)[NH(CH2)qC(=O)ORT][NH(CH2)qC(=O)ORT], -P(=O)[ NHRT][NHRT], -P(=O)[NHCH(CH3)C(=O)ORT][NHCH(CH3)C(=O)ORT], and -P(=O)[ORb] [NHCH(CH3)C(=O)ORT];each q is independently 0, 1, 2, or 3;when present, Rlaand R2aare each independently selected from hydrogen, deuterium, halogen, cyano, C1.4 alkyl, hydroxyl, and -OC1.4 alkyl, or Rlaand R2atogether with the carbon to which they are attached form a carbonyl group, or Rlaand R2atogether with atoms to which they are attached form a 4-5 membered heterocycle comprising an oxygen atom;when present, each Rbis independently selected from hydrogen, C1.20 alkyl, phenyl, benzyl. 5-6 membered heteroaryl, naphthyl. C1.4 alkylene-0-Ci.2o alkyl, C1.4 alkylene-C(=O)O-Ci-io alkyl, C alkylene-OC(=0)-Ci-io alkyl, C1.4 alkylene-OC(=O)NH-Ci-4 alkylene-C(=O)O-Ci-io alkyl, C1.4 alkylene-OC(=0)0-Ci-io alky l, C1.4 alkylene-C(=O)O-5-7 membered heterocyclyl, C1.4 alkylene-C(=O)O-phenyl, C1.4 alkylene-OC(=O)-5-7 membered heterocyclyl, C1.4 alkylene-O-5-7 membered heterocyclyl, CM alkylene-OC(=O)O-5-7 membered heterocyclyl, C alkylene-C(=0)S-Ci.io alkyl. C alkylene-SC(=0)-Ci.io alkyl, CM alkylene-C(=O)S-5-7 membered heterocyclyl, and CM alkylene-SC(=O)-5-7 membered heterocyclyl; said CM alkyl, C O alkyl, CM alkylene, C1.20 alkyd, or 5-7 membered heterocyclyl is each unsubstituted or substituted with one or more deuterium, halogen, cyano, Ci-3alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methyl amino, or dimethyl amino; alternatively, two Rhgroups together with the atoms to which they are attached form a 5-7 membered saturated heterocycle comprising a phosphorus, said heterocycle is unsubstituted or substituted with one or more deuterium, halogen, cyano, Ci-3alkyl, isopropyl, cyclopropyl, phenyl, benzyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino, and said phenyl is unsubstituted or substituted with one or more halogen;preferably, when present, each Rbis independently selected from hydrogen, Ci-2o alkyl, phenyl, benzyl, 5-6 membered heteroaryl, naphthyl, CM alkylene-O-Ci.20alkyl, CM alkylene-C(=0)0-CMO alkyl, CM alkylene-OC(=0)-Ci-io alkyl, CM alkylene-OC(=O)NH-Ci-4 alkylene-C(=0)0-CMO alkyl, C alkylene-OC(=0)0-Ci-io alkyl, CM alkylene-C(=O)O-5-7 membered heterocyclyl, CM alkylene-C(=O)O-phenyl, CM alkylene-OC(=O)-5-7 membered heterocyclyl, CM alkylene-O-5-7 membered heterocyclyl, CM alkylene-OC(=O)O-5-7 memberedheterocyclyl, C1.4 alkylene-C(=0)S-Ci-io alkyl, C1.4 alkylene-SC(=0)-Ci.io alkyl, C1.4 alkylene-C(=O)S-5-7 membered heterocyclyl and C1-4 alkylene-SC(=O)-5-7 membered heterocyclyl; said C1-4 alkyl, C1-20 alkyl, C1-4 alkylene, C1-20 alkyl, or 5-7 membered heterocyclyl is each unsubstituted or substituted with one or more deuterium, halogen, cyano, C1-3 alkyl, isopropyl, cyclopropyl, phenyl, benzy l, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethyl amino; alternatively, two Rbgroups together with the atoms to which they are attached form a 5-7 membered saturated heterocycle comprising a phosphorus;when present, each RTis independently selected from C1-10 alkyl, benzyl, and phenyl; said C1-10 alkyl, benzyl, or phenyl is each unsubstituted or substituted with one or more deuterium, halogen, cyano, C1-3 alkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, or dimethylamino; alternatively, two RTtogether with the atoms to which they are attached form a 5-7 membered saturated heterocycle comprising a phosphorus;alternatively. Rhand RTtogether with the atoms to which they are attached form a 5-7 membered saturated heterocycle comprising the phosphorus in R1;when present, each Rcis independently selected from hydrogen, deuterium, halogen, cyano, C1.4 alkyl, C1.4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino;R2is selected from hydrogen, phenyl, and C1.4 alkyl;when present, each R3is independently selected from hydrogen, deuterium, halogen, cyano, C1.4 alkyl, C1.4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; alternatively, two R3groups substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl or heterocycle;when present, each R4is independently selected from hydrogen, deuterium, halogen, cyano, C1-10 alkyl, C1-10 haloalkyl, isopropyl, cyclopropyl, 4-6 membered heterocyclyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, dimethylamino, C6-11 spiroalkyl, C5-8 bridged alkyl, 5-12 membered spiroheterobicyclyl, 6-10 membered bridged heterobicyclyl, and 8-10 membered fused heterobicyclyl; said C1-10 alkyl, 4-6 membered heterocyclyl, C6-11 spiroalkyl, C5-8 bridged alkyl, 5-12 membered spiroheterobicyclyl, 6-10 membered bridged heterobicyclyl, or 8-10 membered fused heterobicyclyl is each unsubstituted or substituted with one or more deuterium, halogen, cyano, hydroxyl, methoxy, methylamino, dimethylamino, C5-8 bridged alkyl, phenyl, or 5-6 membered heteroaryl; alternatively, two R4groups substituted on the same carbon atom together with the carbon atom to which they areattached form a 3-5 membered cycloalkyl or heterocycle; alternatively, two R4groups substituted on the same carbon atom are combined to form an oxo (=0) group;when present, each R5is independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; alternatively, two R5groups substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl or heterocycle;when present, each R6is independently selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino; alternatively, two R6groups substituted on the same carbon atom together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl or heterocycle; alternatively, two R6groups located on adjacent or non- adjacent carbon atoms together with the carbon atoms to which they are attached form a C3-6 cycloalkane or 3-6 membered saturated heterocycle;when present, R61is selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, isopropyl, cyclopropyl, hydroxyl, methoxy, ethoxy, cyclopropoxy, isopropoxy, amino, methylamino, and dimethylamino;Lmis a linking moiety of m identical, partially identical, or different L groups; one end of Lmis linked to DIM via a covalent bond, and another end of Lmis linked to any ring atom other than the bridged nitrogen in the 5-8 fused ring skeleton structure via another covalent bond; each L is independently selected from:(1) C3-12 cycloalkylene substituted with 0-3 R1fgroups;(2) C6-10 arylene substituted with 0-3 R1fgroups;(3) 4-12 membered heterocyclylene substituted with 0-3 R11groups;(4) 8-10 membered fused heterobicyclylene substituted with 0-3 R11groups;(5) 5-12 membered heteroarylene substituted with 0-3 R1fgroups;(6) C1-12 alkylene substituted with 0-3 R2fgroups;(7) C2-12 alkenylene substituted with 0-3 R2fgroups;(8) C2-12 alkynylene substituted with 0-3 R2fgroups;(9) 1-6 ethylene glycol or propylene glycol units; and(10) -C(=O)-. -C(=O)O-, -O-, -N(R3f)-, -S-, -S(=O)-, -C(=S)-, -C(=S)O-, -S(=O)2-, -S(=O)N(R3f)-, -S(=O)2N(R3f)-. -C(=O)-N(R3f)-. -N(R3f)C(=O)-N(R3f)-. and -OC(=O)-N(R3f)-;when present, each R11is independently selected from hydrogen, deuterium, halogen, cyano, CM alkyl, C3.6cycloalkyl, C6-io aryl, 5-12 membered heteroaryl, -OR'1. -C(=O)R'f. -C(=O)OR3f, -C(=O)N(R3f)2, -N(R3f)2, -N(R3f)C(=O)R3f, -N(R3f)C(=O)OR3f, -N(R3f)C(=O)N(R3f)2, -OC(=O)R3f, -OC(=O)N(R3f)2, -SR3f, -S(=O)R3f, -S(=O)2R3f. and -S(=O)2N(R3f)2; said C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, or 5-12 membered heteroaryl is each unsubstituted or substituted with 0-3 R3fgroups; alternatively, any two R1fgroups together with the carbon atoms to which they are attached form a bridged ring; alternatively, two R1fgroups on the same carbon atom together with the carbon atom to which they are attached form a cycloalkyl or heterocycle;when present, each R2fis independently selected from hydrogen, C1-6 alkyl, and C3-6 cycloalkyl;when present, each R3fis 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 ligase;preferably, DIM is selected from small-molecule affinity ligands for CRBN, VHL, cIAP, MDM2, RNF4, AhR, DCAF16, RNF114, FEM1B, KEAP1, and DCAF15.

2. The compound of claim 1, wherein the compound is of Formula (I’):Y^8R8(I’)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring A is a 4-6 membered saturated or partially unsaturated heterocyclyl comprising at least one nitrogen atom;Ring C is selected from naphthyl and 8-10 membered fused heterobicyclyl comprising 1-3 heteroatoms each independently selected from nitrogen, oxygen, and sulfur; said naphthyl or 8-10 membered fused heterobicyclyl is each unsubstituted or substituted with 0, 1, 2, or 3 Rcgroups;preferably, Ring C is selected from the following moieties:R7is selected from hydrogen, C1-10 alkyl, 4-6 membered heterocyclyl, C6-11 spiroalkyl, C5-8 bridged alkyl, 5-12 membered spiroheterobicyclyl, 6-10 membered bridged heterobicyclyl, and 8-10 membered fused heterobicyclyl; said C1-10 alkyl, C4-6 heterocyclyl, C6-11 spiroalkyl, C5-8 bridged alkyl, 5-12 membered spiroheterobicyclyl, 6-10 membered bridged heterobicyclyl, or 8-10 membered fused heterobicyclyl is each unsubstituted or substituted with one or more deuterium, halogen, cyano, hydroxyl, methoxy, methylamino, dimethylamino, C5.8 bridged alky l, or 5-6 membered heteroaryl;Rlaand R2aare each independently selected from hydrogen, fluorine, and cyano, or Rlaand R2aare combined to form an oxo (=0) group;each Y is independently selected from -O- or -NH-; wherein (i) when Y is -O-, R8attached to Y is Rb; (ii) when Y is -NH-, R8attached to Y is RT, -(CH2)qC(=O)ORT, or -CH(CH3)C(=O)ORT:DIM is selected from small-molecule affinity ligands for CRBN, VHL, and cIAP; preferably, DIM is selected from the following moieties:R9is selected from hydrogen, deuterium, halogen, cyano, Ci-6 alkyl, and C3.6 cycloalkyk X is (i) NR6aand CHR6a; or (ii) N or CR6a, when X is linked to Lm; andn, q, R3, R4, R5, R6, R6a, Rc, Rb, RT, and Lmare as defined in claim 1.

3. The compound of claim 2, wherein the compound is of Formula (I’-l):(I’-l)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring C, Y, R8, R7, Lm, DIM, and X are as defined in claim 2.

4. The compound of claim 2, wherein the compound is of Formula (II):or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring A, Ring C, Rla, R2a, Y, R8, R7, n, R3, R4, R5, R6, Lm, and DIM are as defined in claim 2.

5. The compound according to of 4, wherein the compound is of Formula (II- 1):(II-l)or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring C. Y, R8, R7, Lm, and DIM are as defined in claim 4.

6. The compound of claim 2, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring A, Ring C, Rla, R2a. Y, R8, R7, n, R3, R4, R5, R6, Lm, DIM, and X are as defined in claim 2.

7. The compound of claim 6, wherein the compound is of Formula (III- 1 ):or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring C, Y, R8, R7, Lm, DIM, and X are as defined in claim 6;preferably, X is CHR6a, and R6ais H.

8. The compound of any one of claims 2-7. or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:R7is selected from hydrogen and C1-10 alkyl; the C1-10 alkyl is unsubstituted or substituted with one or more deuteriums;preferably, R7is selected from hydrogen and C1.4 alkyl; the C1.4 alkyl is unsubstituted or substituted with one or more deuteriums;more preferably, R7is C1-4 alkyl; the C1-4 alkyl is unsubstituted or substituted with one or more deuteriums.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:, wherein * indicates a covalent bond with R1, -C(Rla)(Rlb)-, or CF2; and Rcis as defined in claim 1, preferably hydrogen.

10. The compound of any one of claims 2-9, or a pharmaceutically acceptable salt solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Y is an oxygen atom, and each R8is independently selected from hydrogen, C1-4 alkylene-OC(=O)-C1-10 alkyl, and C1-4 alkylene-SC(=O)-C1-10 alkyl; preferably, R8is hydrogen;DIM is selected from the following groups: / ,0 oO; more preferably, DIM is0R9is selected from hydrogen, deuterium, halogen, cyano, C1-4 alkyl, and C3-6 cycloalkyl, preferably, R9is hydrogen.

11. The compound of any one of claims 1, 2, 4, 6 and 8-10, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Ring A is selected from the following groups:

12. The compound of any one of claims 1-11. or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Lmis selected from the following groups:,oDIM;preferably, Lmis selected from the following groups:more preferably, (i) when X is linked to Lm, or in the compound represented by Formula (II) or Formula (II- 1 ), Lmis selected from the following groups:(ii) when X is not linked to Lm, or in the compound represented by Formula (III) or Formula (III-l ), Lmis selected from the following groups:further preferably, Lmis selected from the following groups:

13. The compound of any one of claims 2-12. or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Y^R8r8is selected from the following groups:O'^'Y^R8most preferably, R® is selected from the following groups:

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt. solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein:Rlaand R2aare each independently selected from hydrogen and fluorine, or Rlaand R2aare combined to form an oxo (=0) group; preferably, both R1aand R2aare fluorine;R3, R5, and R6are each independently selected from hydrogen and C1.4 alkyl; preferably, R3, R5, and R6are hydrogen.

15. A compound selected from the group consisting of:, and, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, wherein the pharmaceutically acceptable salt of the compound is an acid addition salt or a base addition salt;preferably, the acid addition salt comprises a salt formed by the compound and any one acid 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 base addition salt comprises alkali metal salts, alkaline earth metal salts, and organic base salts, preferably lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, and N+(C1-6alkyl)4salts;preferably, in the base addition salt, the compound is in a phosphate anion state.

17. A pharmaceutical composition comprising the compound of any one of claims 1-16, or apharmaceutically acceptable salt solvate, prodrug, isotopically labeled derivative, or isomer thereof, and a pharmaceutically acceptable carrier.

18. A pharmaceutical combination comprising (i) the compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, or the pharmaceutical composition according to claim 17, and (ii) an additional therapeutic agent.

19. Use of the compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, or the pharmaceutical composition of claim 17, or the pharmaceutical combination of claim 18, in the preparation of a medicament for preventing and / or treating diseases and / or disorders that are at least partially responsive to STAT6;preferably, the disease and / or disorder is type 2 inflammation; more preferably, the disease and / or disorder is type 2 inflammation mediated by Th2 cells and / or group 2 innate lymphoid cells;preferably, the diseases and / or disorders is atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, bullous pemphigoid, chronic rhinosinusitis with or without nasal polyps, allergic rhinitis, asthma, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, food allergy, or eosinophilic esophagitis.

20. A method for preventing and / or treating diseases and / or disorders that are at least partially responsive to STAT6, comprising administering a therapeutically effective amount of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, prodrug, isotopically labeled derivative, or isomer thereof, or the pharmaceutical composition of claim 17, or the pharmaceutical combination of claim 18 in a subject in need thereof;preferably, the disease and / or disorder is type 2 inflammation; more preferably, the disease and / or disorder is type 2 inflammation mediated by Th2 cells and / or group 2 innate lymphoid cells; orpreferably, the diseases and / or disorders is atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, bullous pemphigoid, chronic rhinosinusitis with or without nasal polyps, allergic rhinitis, asthma, allergic bronchopulmonary aspergillosis, chronic obstructive pulmonary disease, eosinophilic granulomatosis with polyangiitis, food allergy, or eosinophilic esophagitis.

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