Peptidomimetic stat degradation drugs, compositions, and uses

Abstract

This invention discloses a compound having the structure shown in general formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. This invention also discloses a composition, formulation, and application containing the above compound. The compound of this invention degrades the transcription factor STAT3, exhibits antiproliferative inhibitory activity against the Karpas299 cell line, and has a favorable tumor / plasma AUC ratio.

Description

Technical Field

[0001] This invention relates to a class of small molecule protein-degrading drugs, optical isomers, or pharmaceutically acceptable salts that can degrade the transcription factor STAT3, and as pharmaceutical treatments for hyperproliferative diseases such as cancer. Background Technology

[0002] The JAK-STAT signaling pathway is an important tumor-associated signaling pathway. After cytokine receptors, hormone receptors, or growth factor receptors on the cell surface bind to their corresponding ligands, intracellular JAK kinases are activated, thereby inducing phosphorylation of the downstream transcription factor STAT and the formation of homodimers. These homodimers then enter the cell nucleus and initiate or inhibit the transcription of a series of tumor-associated genes.

[0003] Transcription factor STAT regulates various tumor-associated genes, such as cMyc, Survivin, BCL-XL, VEGF, HIF, and NF-κB. Mutations in STAT gain-of-function are common in tumor cells, leading to overactivation of the pathway. This overactivation results in increased tumor cell proliferation and survival, abnormal angiogenesis, tumor cell invasion and migration, tumor immune escape, and maintenance of tumor stem cell-like structures.

[0004] In addition, recent studies have found a close relationship between STAT3 and the suppressive immune microenvironment of tumor tissues. Overactivation of STAT in dendritic cells (DCs) leads to a decrease in the expression of MHC type II molecules and co-stimulatory factors, thereby reducing their antigen presentation and T cell activation capabilities. Expression in neutrophils, NK cells, and effector T cells reduces their ability to recognize, activate, and kill tumor cells. Simultaneously, it can promote M2 polarization of tumor-associated macrophages, the maturation and expansion of myeloid-derived suppressor cells, induce T cell differentiation into regulatory T cells, and increase PD-L1 expression in tumor cells and the aforementioned immunosuppressive cells, thereby forming a suppressive immune microenvironment and promoting tumor immune escape.

[0005] In summary, the JAK-STAT signaling pathway can promote tumor proliferation through multiple pathways, and therefore is a potential target for anti-tumor drug development.

[0006] Although several small-molecule STAT3 inhibitors have been reported in recent years, none have yet received market approval due to their poor efficacy. Therefore, there is an urgent need to develop a new generation of potent STAT3 inhibitors.

[0007] Significant progress has been made in targeted protein degradation technology (PROTAC) in recent years. This technology achieves target protein degradation by inducing ubiquitination. Drugs using this technology do not need to continuously occupy the target protein; the catalytic concentration is sufficient to achieve target degradation. Therefore, developing targeted degradation molecules against STAT3 holds promise for overcoming the insufficient efficacy of current small-molecule STAT3 inhibitors. Summary of the Invention:

[0008] The purpose of this invention is to provide a novel, unreported STAT3-degrading molecule with highly efficient STAT3-degrading activity, its optical isomer, or a pharmaceutically acceptable salt thereof.

[0009] The present invention also provides a pharmaceutical composition comprising the above-described compound or its stereoisomers or mixtures thereof or pharmaceutically acceptable salts thereof.

[0010] The present invention also provides the use of the above-mentioned compound or its stereoisomer or mixture of stereoisomers or its pharmaceutically acceptable salt in the preparation of a medicament for treating diseases, disorders or conditions that benefit from STAT3-degrading molecules having STAT3-degrading activity.

[0011] The compounds of this invention are effective in treating and preventing diseases and conditions that benefit the treatment of STAT3 degradation and can be used to treat a variety of diseases and disorders.

[0012] To achieve the above objectives, the present invention provides a structure as shown in general formula (I):

[0013]

[0014] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0015] in:

[0016] E3 represents a chemical ligand that can bind to E3 ubiquitin ligase;

[0017] Linker has the following structure:

[0018] -T1-L1-T2-Cyc1-T3-L2-T4-Cyc2-T5-L3-T6-Cyc3-T7-L4-T8-; T1, T2, T3, T4, T5, T6, T7, T8 are selected from: not found, -O-, -S-, -NR a -;

[0019] R aThe substituent is selected independently from: H, C1-C4 haloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and the substituent is selected from methyl, ethyl, isopropyl, -CF3, -CHF2, halogen, -CN, -OMe, -OEt, -OiPr, amino, -OH;

[0020] L1, L2, L3, and L4 are independently selected from: non-existent, chemical bonds, C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl. Alkyl, alkenyl, and alkynyl groups can be substituted by oxo, alkyl, halogen, cyano, or haloalkyl groups.

[0021] Cyc1, Cyc2, and Cyc3 are independently selected from: non-existent, 3-12 membered heterocycles, benzene rings, 5-12 membered aromatic heterocycles, 3-12 membered cycloalkanes, 3-12 membered cycloalkynes, and 3-12 membered cycloalkenes. Their heterocycles, benzene rings, aromatic heterocycles, cycloalkanes, cycloalkynes, and cycloalkenes may be substituted by alkyl groups, halogens, cyano groups, or haloalkyl groups.

[0022] STAT stands for a chemical ligand that can bind to the transcription factor STAT.

[0023] Preferably, in the compounds disclosed in this invention, the E3 Ligand is selected from:

[0024]

[0025]

[0026] Furthermore, in the compounds disclosed in this invention, E3 Ligand is selected from:

[0027]

[0028]

[0029] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0030] Furthermore, the compounds disclosed in this invention have the structure of general formula I:

[0031]

[0032] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0033] in:

[0034] E3 represents a chemical ligand that can bind to E3 ubiquitin ligases, selected from the following structures:

[0035]

[0036] Linker has the following structure:

[0037] -T1-L1-T2-Cyc1-T3-L2-T4-Cyc2-T5-L3-T6-Cyc3-T7-L4-T8-;

[0038] T1, T2, T3, T4, T5, T6, T7, and T8 are selected from: non-existent, -O-, -S-, and -NRa-.

[0039] L1, L2, L3, and L4 are independently selected from: non-existent, chemical bonds, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, alkyl, alkenyl, alkynyl can be substituted by oxo, alkyl, halogen, cyano, and haloalkyl.

[0040] Cyc1, Cyc2, and Cyc3 are independently selected from: non-existent, 3-12 membered heterocycles, benzene rings, 5-12 membered aromatic heterocycles, 3-12 membered cycloalkanes, 3-12 membered cycloalkynes, and 3-12 membered cycloalkenes. Their heterocycles, benzene rings, aromatic heterocycles, cycloalkanes, cycloalkynes, and cycloalkenes may be substituted by alkyl groups, halogens, cyano groups, or haloalkyl groups.

[0041] STAT represents a chemical ligand that can bind to the transcription factor STAT, and has the following structure:

[0042]

[0043] in:

[0044] X1 is selected from: NH, S, O, NR 11 ;

[0045] X2 is selected from: CH, N, CR 12 ;

[0046] X3 is selected from: CH, N, CR 13 ;

[0047] X4 is selected from: CH, N, CR 14 ;

[0048] X5 is selected from: CH, N, CR 15 ;

[0049] Y is selected from: -CH2-, -O-, -NH-, -CH2O-, -OCH2-, -CH2CH2-, -CH2NH-, -NHCH2-;

[0050] Z is selected from: -CO-, -CH2-, -CF2-,

[0051] R1,R1' are selected from: H, Me, Et,

[0052] R4 is selected from: H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 acyl, C1-C4 alkyl-O-CO-, C1-C4 alkyl-NH-CO-;

[0053] R5 is selected from: R a C1-C4 alkyl-R a ;

[0054] R6 is selected from: R b C1-C4 alkyl-R b ;

[0055] R7 is selected from: H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, halogen, cyano;

[0056] R 11 Selected from: -Me, -Et, -CF3, -CHF2, -iPr;

[0057] R 12 R 13 R 14 R 15 Independently selected from: C1-C4 alkyl, C1-C4 haloalkyl, halogen, -CN;

[0058] R a R b The substituent is selected independently from: H, C1-C4 haloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, and the substituent is selected from methyl, ethyl, isopropyl, -CF3, -CHF2, halogen, -CN, -OMe, -OEt, -OiPr, amino, -OH;

[0059] Indicates connection to other atoms;

[0060] When E3 is selected from structures (B) and (C): at least one of X2, X3, X4, and X5 is C-CN or Z is selected from:

[0061] When E3 is selected from the structure (A)(D)(E)(F)(G)(H)(I), STAT is not one of the following structures:

[0062]

[0063] Furthermore, the compounds of the present invention have structures of general formulas IIa and IIb:

[0064]

[0065] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0066] in:

[0067] Z is preferably derived from: -CO-, -CH2-, -CF2-;

[0068] Y is preferably derived from: CH2, O, NH;

[0069] X1 is preferably derived from: NH, S, NCH3;

[0070] R4 is selected from: H, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 acyl, C1-C4 alkyl-O-CO-, C1-C4 alkyl-NH-CO-;

[0071] R5 is selected from p-fluorobenzyl and p-tert-butylbenzyl;

[0072] W and W' are independently selected from: N and CH;

[0073] Rc and Rc' are independently selected from: H, F, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -CF3, tert-butyl, difluoromethyl, -CH2CF3, -CH2CHF2, -CHCH3CF3, -SO2-Me, -SO2-CF3, -SO2-iPr, -NH-SO2-Me, -NH-SO2-CF3, -NH-SO2-iPr, -SO2-NH2, -CN, -OH, -COOH, -CONH2, -NH2. Furthermore, the compounds of the present invention have the structures of general formulas IIIa and IIIb:

[0074]

[0075] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0076] in:

[0077] R4 is preferably derived from: H, methyl, ethyl, isopropyl, -CF3, -CHF2.

[0078] Rc and Rc' are independently preferred from: H, F, and -CF3.

[0079] Furthermore, the compounds of the present invention have structures of general formulas IVa, IVb, and IVc:

[0080]

[0081] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0082] Furthermore, the compounds of the present invention are characterized by having the general formulas Va, Vb, Vc, and Vd:

[0083]

[0084] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0085] Furthermore, the compounds of the present invention have the structures of general formulas VIa, VIb, VIc, and VId:

[0086]

[0087] R1 and R1' are independently selected from: H, -Me,

[0088] Z is selected from: -CO-, -CH2-, -CF2-;

[0089] X1 is selected from: NH, S;

[0090] W and W' are independently selected from: N and CH;

[0091] Rc is selected from: H, F, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, -CF3;

[0092] R4 is selected from: H, methyl, ethyl, isopropyl, -CF3, -CHF2.

[0093] E3 is selected from:

[0094] R7 is selected from: -Me, -Et, -CF3, -OMe, -OH, -F, -Cl, -CN;

[0095] W1, W2, and W3 are independently selected from: CH and N.

[0096] Furthermore, the compounds of the present invention have the structure of general formula VII:

[0097]

[0098] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0099] in:

[0100] Z is selected from: -CO-, -CF2-;

[0101] X1 is selected from: NH, S;

[0102] R4 is selected from: H, C1-C6 alkyl, C1-C6 alkyl-O-CO-, C1-C6 alkyl-NH-CO-, C1-C6 haloalkyl, C1-C6 haloalkyl-O-CO-, C1-C6 haloalkyl-NH-CO-, C1-C6 alkyl-SO2-, C1-C6 haloalkyl-SO2-;

[0103] R5 is selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C3-C8 cycloalkyl, heterocycloalkyl, C1-C6 alkyl-aryl, C1-C6 alkyl-heteroaryl, C1-C6 alkyl-cycloalkyl, C1-C6 alkyl-heterocycloalkyl. The alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups mentioned above can be substituted by one or more substituents, selected from: halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyanogen. C1-C6 alkoxy, C1-C6 haloalkoxy, carboxyl, amino, hydroxyl, amide, C1-C6 alkyl-sulfonamide, C1-C6 haloalkyl-sulfonamide, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, alkylamino, haloalkylamino, C3-C8 cycloalkylamino, acyl, C1-C6 alkyl-SO2-, C1-C6 haloalkyl-SO2-, C3-C8 cycloalkylamino, aminosulfonyl, acyl, carbamoyl;

[0104] E3 is selected from:

[0105] R7 can be selected independently from: H, F, Cl, -CH3, -OMe, -CN, -CF3.

[0106] Furthermore, the compounds of the present invention are characterized by having the structure of general formulas VIIIa to VIIIc:

[0107] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0108] in:

[0109] R4 is selected from: C1-C6 alkyl, C1-C6 alkyl-O-CO-, C1-C6 haloalkyl, C1-C6 alkyl-SO2-.

[0110] Furthermore, the compound of the present invention is characterized by having the structure of general formula IX:

[0111]

[0112] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0113] in:

[0114] X1 is selected from: NH, S;

[0115] W1 is selected from: N, CH;

[0116] Rc is selected from: H, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, difluoromethyl, F, -CH2CF3, -CH2CHF2, -CHCH3CF3, -SO2-Me, -SO2-CF3, -SO2-iPr, -NH-SO2-Me, -NH-SO2-CF3, -NH-SO2-iPr, -SO2-NH2, -CN, -OMe, -OH, -COOH, -CONH2, -NH2.

[0117] E3 ligase is selected from:

[0118] R7 can be selected independently from: H, F, Cl, -CH3, -OMe, -CN, -CF3.

[0119] Furthermore, the compound of the present invention is characterized by having a structure of general formula X:

[0120]

[0121] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0122] Z is selected from: -CO-, -CH2-, -CF2-;

[0123] X1 is selected from: NH, S, O;

[0124] R 16 Selected from: H, C1-C6 alkyl, halogen, C1-C6 haloalkyl, amino, hydroxyl, amide, sulfonyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy; preferably, R 16 Selected from fluorine and tert-butyl;

[0125] r is selected from: 0, 1, 2, 3;

[0126] E3 is selected from:

[0127]

[0128]

[0129] R7 can be selected independently from: H, F, Cl, -CH3, -OMe, -CN, -CF3.

[0130] Furthermore, the compound of the present invention is characterized by having a structure of general formula (Xa):

[0131]

[0132] Or its stereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

[0133] in:

[0134] Z is selected from: -CO-, -CH2-, -CF2-;

[0135] X1 is selected from: NH, S, O;

[0136] V is selected from: -CH2-, -CO-, -NH-, -O-, -CF2-, C3-C 10 Cycloalkylene, 3-10 membered heterocyclic alkylene, phenylene, 5-6 membered heteroaryl alkylene;

[0137] R 16 Selected from: H, C1-C6 alkyl, halogen, C1-C6 haloalkyl, amino, hydroxyl, amide, sulfonyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy; preferably, R 16 Selected from fluorine and tert-butyl;

[0138] r is selected from: 0, 1, 2, 3;

[0139] E3 is selected from:

[0140]

[0141]

[0142] R7 can be selected independently from: H, F, Cl, -CH3, -OMe, -CN, -CF3.

[0143] When V is selected from O, E3 is not a structure of the following:

[0144]

[0145] Linker is selected from the following structure: (If it does not exist,)

[0146]

[0147]

[0148] Z1, Z2, Z5, and Z6 are independently selected from: CH and N;

[0149] Z3 and Z4 are independently selected from: non-existent, -NRd-, -O-; Z3 and Z4 cannot both be non-existent at the same time.

[0150] Rd is selected from: H, C1-C4 alkyl, and halo-C1-C4 alkyl;

[0151] m1, m2, m3, m4, m5, and m6 are independently selected from: 0, 1, 2, 3, 4, 5, and 6;

[0152] v and v' are selected from: CH and N;

[0153] n and n' are independent integers selected from 1 to 4;

[0154] m is selected from integers between 0 and 10;

[0155] o is selected from: integers between 0 and 4;

[0156] It indicates that it is connected to other atoms.

[0157] As a preferred choice, Linker is selected from:

[0158]

[0159]

[0160] o is selected from 1, 2, 3, and 4;

[0161] o' is selected from 1, 2, 3, and 4;

[0162] “o” is selected from 1, 2, 3, and 4;

[0163] p is selected from 1, 2, 3, and 4;

[0164] p' is selected from 1, 2, 3, and 4;

[0165] q is selected from 1, 2, 3, and 4;

[0166] q' is selected from 1, 2, 3, and 4;

[0167] # indicates that the E3 part is connected.

[0168] Preferably, the compound or its stereoisomer or mixture of stereoisomers or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0169] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid001

[0170] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)butyl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid002

[0171] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)methyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid003

[0172] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(((4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propyl)cyclohexyl)methyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid004

[0173] ((2-(((5S,10aR)-8-(((S)-5-amino-1-(diphenylmethylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid005

[0174] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((di(3-trifluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid006

[0175] ((2-(((5S,10aR)-8-(((S)-5-amino-1-(diphenylmethylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1-methyl-1H-indole-5-yl)difluoromethyl)phosphoric acid007

[0176] (2-(((5S,10aR)-8-(((S)-5-amino-1-((di(3-fluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-carbamoyl)phosphoric acid 008

[0177] (2-(((5S,10aR)-8-(((S)-5-amino-1-((di(3-fluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbamoyl)phosphate009

[0178] (2-(((5S,10aR)-8-(((S)-5-amino-1-((di(pyridin-3-yl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-carbamoyl)phosphate010

[0179] (3-(2-(((5S,10aR)-8-(((S)-5-amino-1-(diphenylmethylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-yl)oxetane-3-yl)phosphoric acid 011

[0180] ((2-(((5S,10aR)-8-(((S)-5-amino-1-(diphenylmethylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)-1H-3-cyanoindoline-5-yl)difluoromethyl)phosphoric acid 012

[0181] ((2-((5S,10aR)-8-((2S)-5-amino-1-((2S)-1-((7-(1-(2,6-dioxopiridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hep-6-yn-1-yl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 013

[0182] ((2-((5S,10aR)-8-((2S)-5-amino-1-((2S)-1-((7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 014

[0183] ((2-((5S,10aR)-8-((2S)-5-amino-1-((2S)-1-((8-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)octyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 015

[0184] ((2-((5S,10aR)-8-((2S)-5-amino-1-((2S)-1-((8-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oct-7-yn-1-yl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 016

[0185] ((2-((5S,10aR)-8-((2S)-5-amino-1-((2S)-1-((4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)butyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 017

[0186] ((2-((5S,10aR)-8-((2S)-5-amino-1-((2S)-1-((5-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)pentyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 018

[0187] ((2-((5S,10aR)-8-((2S)-5-amino-1-((2S)-1-((8-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)octyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 019

[0188] ((2-((5S,10aR)-8-((S)-5-amino-1-((di(3-fluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hept-6-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 020

[0189] ((2-((5S,10aR)-8-((S)-5-amino-1-((di(3-fluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)nonanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 021

[0190] ((2-((5S,10aR)-8-((S)-5-amino-1-((di(3-fluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)butyryl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 022

[0191] ((2-((5S,10aR)-8-((S)-5-amino-1-((di(3-fluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-4-yl)butyryl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 023

[0192] ((2-((5S,10aR)-8-((S)-5-amino-1-((di(3-fluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)propionyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 024

[0193] ((2-((5S,10aR)-8-((S)-5-amino-1-((di(3-fluorophenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(4-(1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)azacyclobutane-3-yl)butyryl)-6-oxodecahydropyrrole[1,2-a][1,5]azacyclooctyl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 025

[0194] ((2-((5S,10aR)-8-((S)-5-amino-1-(diphenylmethylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(1-(5-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)pentan-4-yn-1-yl)azacyclobutane-3-carbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctan-5-yl)carbamoyl)-3-cyano-1H-indol-5-yl)difluoromethyl)phosphoric acid 026

[0195] ((2-(((5S,10aR)-8-((S)-5-amino-1-(diphenylmethylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(1-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl)pentan-4-yn-1-yl)piperidin-4-carbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctan-5-yl)carbamoyl)-3-cyano-1H-indol-5-yl)difluoromethyl)phosphoric acid 027

[0196] (2-(((5S,10aR)-8-(((S)-5-amino-1-(diphenylmethylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindole-4-yl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)-3-cyano-1H-indole-5-carbamoyl)phosphate 028

[0197] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 029

[0198] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)azacyclobutane-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]azacyclooctyl-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 030

[0199] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(((4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethynyl)cyclohexyl)methyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 031

[0200] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(((4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)ethyl)cyclohexyl)methyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 032

[0201] ((2-(((5S,10aR)-8-(((S)-5-amino-1-(diphenylmethylamino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2-(4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)cyclohexyl)acetyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 033

[0202] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(tert-butyl)phenyl)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 034

[0203] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 035

[0204] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(4-(2,6-dioxopiperidin-3-yl)phenyl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 036

[0205] ((2-(((5S,10aR)-8-(((S)-5-amino-1-(((S)-1-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 037

[0206] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperazin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 038

[0207] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 039

[0208] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-((2-(2-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)ethoxy)ethyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 040

[0209] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)azacyclobutane-3-yl)methyl)piperazin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]azacyclooctyl-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 041

[0210] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 042

[0211] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(4-(2,6-dioxopiperidin-3-yl)phenyl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 043

[0212] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-((6-(1-(2,6-dioxopiridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hexyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 044

[0213] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-((6-(1-(2,6-dioxopiridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hex-5-yn-1-yl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 045

[0214] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propyl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 046

[0215] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((3-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)phenyl)(phenyl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 047

[0216] ((2-(((5S,10aR)-8-(((S)-5-amino-1-(((S)-1-(4-(4-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 048

[0217] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2--2,3-dihydro-1H-benzi[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 049

[0218] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzi[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphoric acid 050

[0219] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-((2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethyl)amino)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 051

[0220] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(6-(2,6-dioxopiperidin-3-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 052

[0221] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-((2-(2-(((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)ethoxy)ethyl)amino)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 053

[0222] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-ffluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methanesulfonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 054

[0223] ((2-(((5S,10aR)-8-(((2S)-5amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-5-yl)prop-2-yn-1-yl)oxy)piperidine-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 055

[0224] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(3,4-difluorophenyl)-1-(4-((3-(1-(2,6-dioxoperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 056

[0225] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((1S)-1-cyclohexyl-2-(4-((3-(1-(2,6-dioxoperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-2-oxoethyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 057

[0226] ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-((1r,4R)-4-(2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-5-yl)ethyl)cyclohexane-1-carbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 058

[0227] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((di(pyridin-3-yl)methyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)hep-6-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 059

[0228] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxo-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 060

[0229] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(tert-butyl)phenyl)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 061

[0230] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methylsulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)hep-6-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 062

[0231] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methylsulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxyphenyl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 063

[0232] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(3-(((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)methyl)azacyclobutane-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methylsulfonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 064

[0233] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(3-(((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)methyl)azacyclobutane-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 065

[0234] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(3,4-difluorophenyl)-1-(3-(((3-(1-(2,6-dioxopiperidin-3-)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)methyl)azacyclobutane-1-yl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 066

[0235] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 067

[0236] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(3,4-difluorophenyl)-1-(4-(4-(6-((2,6-dioxoperidin-3-yl)carbamoyl)pyridin-2-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxobut-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 068

[0237] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(tert-butyl)phenyl)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 069

[0238] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(tert-butyl)phenyl)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 070

[0239] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 071

[0240] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(3,4-difluorophenyl)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 072

[0241] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(3,4-difluorophenyl)-1-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)propoxy)piperidin-1-yl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 073

[0242] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)propoxy)piperidin-1-yl)-3-(4-fluorobenzene)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 074

[0243] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(3,4-difluorophenyl)-1-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)but-3-yn-1-yl)oxy)piperidin-1-yl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 075

[0244] 2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)but-3-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 076

[0245] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)but-3-yn-1-yl)oxy)piperidin-1-yl)-3-(4-methoxyphenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 077

[0246] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(3,4-difluorophenyl)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)butoxy)piperidin-1-yl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 078

[0247] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)butoxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 079

[0248] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)propoxy)methyl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid080

[0249] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(((3-(1-(2,6-dioxopiridine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)methyl)piperidine-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyll)-3-(methoxycarbonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 081

[0250] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)methyl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxycarbonyl)-66-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)indol-5-yl)difluoromethyl)phosphoric acid 082

[0251] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)heptanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 083

[0252] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(isopropylsulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)heptanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 084

[0253] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methylsulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)octanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoctanoyl)carbamoyl)indole-5-yl)difluoromethyl)phosphoric acid 085

[0254] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)indole-5-yl)difluoromethyl)phosphoric acid 086

[0255] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-isopropylbenzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)indole-5-yl)difluoromethyl)phosphoric acid 087

[0256] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methylsulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)octanoyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoctanoyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 088

[0257] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 089

[0258] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methylsulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(3-((2,6-dioxopiperidin-3-yl)carbamoyl)phenyl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 090

[0259] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(3-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)but-3-yn-1-yl)oxy)azacyclobutane-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxyyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 091

[0260] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)butoxy)azacyclobutane-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methoxyyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 092

[0261] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-5-yl)propoxy)piperidin-1-yl)-3-(4-fluorobenzene)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methanesulfonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 093

[0262] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-5-yl)butoxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methylsulfonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 094

[0263] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)butoxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methylsulfonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 095

[0264] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)but-3-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methylsulfonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 096

[0265] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazolin-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methanesulfonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 097

[0266] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazoline-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxoprop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(methanesulfonyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)indole-5-yl)difluoromethyl)phosphoric acid 098

[0267] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 099

[0268] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-yl)difluoromethyl)phosphoric acid 100

[0269] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 101

[0270] (2-(((5S, 10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate102

[0271] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(tert-butyl)phenyl)-3-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)but-3-yn-1-yl)piperidin-1-yl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)-1H-indole-5-carbonyl)phosphate103

[0272] (2-(((5S, 10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)but-3-yn-1-yl)piperazin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 104

[0273] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 105

[0274] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)but-3-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 106

[0275] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 107

[0276] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 108

[0277] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 109

[0278] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 110

[0279] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 111

[0280] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 112

[0281] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-fluorophenyl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 113

[0282] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methylphenyl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 114

[0283] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-3-methoxyphenyl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 115

[0284] ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methylsulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(8-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxyphenyl)oct-7-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 116

[0285] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(tert-butyl)phenyl)-3-(4-(4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)but-3-yn-1-yl)piperidin-1-yl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 117

[0286] (2-(((5S,10aR)-8-(((2S)-5-amino-1-(((1S)-1-(1-(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oct-7-ynyl)-1H-imidazol-2-yl)-2-(4-fluorophenyl)ethyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 118

[0287] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((1S)-2-(4-(tert-butyl)phenyl)-1-(1-(8-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oct-7-ynyl)-1H-imidazol-2-yl)ethyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 119

[0288] (2-(((5S, 10aR)-8-(((2S)-5-amino-1-(((1S)-1-(1-(8-(4-(2,6-dioxopiperidin-3-yl)phenyl)oct-7-ynyl)-1H-imidazol-2-yl)-2-(4-fluorophenyl)ethyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclicoct-5-yl)carbamoyl)benzo[b]thiophene-5-carbonyl)phosphoric acid 120

[0289] ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((1S)-1-(1-(8-(4-(2,6-dioxopiperidin-3-yl)phenyl)oct-7-ynyl)-1H-imidazol-2-yl)-2-(4-fluorophenyl)ethyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 121

[0290] Terminology Explanation

[0291] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. Unless otherwise stated, all patent documents, publicly disclosed materials, etc., referenced in this invention are included in the full text of the references. If the same term has multiple definitions in this invention, the definition in this section shall prevail.

[0292] It should be understood that the general description above and the detailed description below are merely exemplary and explanatory, and are not restrictive on any of the claims. In this invention, unless otherwise stated, the singular includes the plural. It should be noted that in the specification and appended claims, unless otherwise stated, the singular form refers to "a," "an," or "this," and includes the plural. It should also be noted that unless otherwise stated, "or" means "and / or." Furthermore, terms such as "comprising," "including," and similar terms are not restrictive.

[0293] "Substitution" refers to the replacement of a hydrogen atom by a substituent. It's important to note that the substituent on a specific atom is restricted by its valence state. In the definition section, "C..." i -C j "" refers to a range including both the starting and ending points, where i and j are integers representing the number of carbon atoms. For example, C 1- C4, C 1- C 10 C 3- C 10 wait.

[0294] In this invention, the terms “E3 ligase” and “E3” both refer to a chemical ligand that can bind to E3 ubiquitin ligase.

[0295] As used in this invention, the term "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group containing 1 to 8 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, p-pentyl, 1-hexyl, 2-hexyl, etc. An alkyl group may be substituted with one or more substituents; in cases of multiple substitutions, the substituents may be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylic acid ester, acyl, amide, sulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 alkoxy, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkylamino, C3-C 12 cycloalkyl, halogenated C3-C 12 Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C6-C 12 Aryl, C5-C14 heteroaryl, C3-C 12 Heterocyclic group.

[0296] As used in this invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group containing at least one C=C double bond, including but not limited to C2-C10 alkenyl, C2-C8 alkenyl, etc., preferably vinyl, allyl, but-1-alkenyl, but-2-alkenyl, pent-1-alkenyl, pent-1,4-di-alkenyl, etc. The alkenyl group can be substituted by one or more substituents; in cases of multiple substitutions, the substituents can be the same or different. The substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocyclic, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, and amino.

[0297] As used in this invention, the term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group containing at least one C≡C triple bond, including but not limited to C2-C8 alkynyl, C2-C6 alkynyl, etc., preferably ethynyl, propynyl, but-1-alkynyl, but-2-alkynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted by one or more substituents; in cases of multiple substitutions, the substituents can be the same or different. The substituents are independently D, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halohydroxyalkyl, cycloalkyl, halocycloalkyl, heterocyclic, aryl, heteroaryl, hydroxyl, halogen, cyano, nitro, and amino.

[0298] The term "halogen" as used in this invention refers to fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine or bromine.

[0299] The term "halogenation" as used in this invention refers to the substitution of the same atom or different atoms by a halogen. This substitution can be done once or multiple times, such as di-substitution or tri-substitution.

[0300] As used in this invention, the term "cycloalkyl" refers to a non-aromatic monovalent hydrocarbon group having 3 to 12 carbon atoms, either monocyclic or polycyclic (two monocyclic rings connected by chemical bonds, or bridged rings, spirocyclic rings, or fused rings), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, etc. Cycloalkyl groups can be substituted by one or more substituents; in cases of multiple substitutions, the substituents can be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylic acid ester, acyl, amide, sulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halogenated C1-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkylamino, C3-C8 alkyl, halogenated C1-C8 alkoxy, halogenated C1-C8 hydroxyalkyl, halogenated C1-C8 alkylamino, C3-C8 alkyl, oxoalkyl, oxoalkyl, cyclo ... 12 cycloalkyl, halogenated C3-C 12Cycloalkyl, cycloalkenyl, cycloalkynyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C6-C 12 Aryl, C5-C 14 heteroaryl, C3-C 12 Heterocyclic group.

[0301] As used in this invention, the terms "cycloalkene" and "cycloalkenyl" refer to non-aromatic monovalent hydrocarbon groups having three to twelve carbon atoms and containing at least one C=C double bond, including but not limited to cyclobutenyl, cyclopentenyl, and cyclohexenyl. Cycloalkenes and cycloalkenyl groups can be substituted by one or more substituents; in cases of multiple substitutions, the substituents can be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, alkylamino, alkenyl, alkynyl, carboxyl, carboxylic acid ester, acyl, amide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C3-C12 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, C6-C12 aryl, C5-C12 heteroaryl, and C3-C12 heterocyclic groups.

[0302] As used in this invention, the terms "cycloalkyne" and "cycloalkyne group" refer to non-aromatic monovalent hydrocarbon groups having three to twelve carbon atoms and containing at least one C≡C triple bond, including but not limited to cyclobutynyl, cyclopentynyl, and cyclohexynyl. Cycloalkynes and cycloalkyne groups can be substituted by one or more substituents; in cases of multiple substitutions, the substituents can be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, alkylamino, alkenyl, alkynyl, carboxyl, carboxylic acid ester, acyl, amide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C3-C12 cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, alkylamide, hydroxyalkylamide, sulfonamide, C6-C12 aryl, C5-C12 heteroaryl, and C3-C12 heterocyclic groups.

[0303] As used in this invention, the terms "heterocyclic group" and "heterocyclic alkyl group" refer to non-aromatic cyclic groups having 3 to 12 ring atoms, either monocyclic or polycyclic (two monocyclic rings connected by chemical bonds, or bridged rings, spirocyclic rings, or fused rings), having one or more heteroatoms selected from N, O, and S, and may have one or more double or triple chemical bonds. Heterocyclic groups include, but are not limited to, piperidinyl, piperazineyl, morpholinyl, dihydrofuranyl, tetrahydrofuranyl, oxetylpropyl, azironeylpropyl, oxetylbutyl, and azironeylbutyl. The heterocyclic group can be substituted by one or more substituents; in the case of multiple substitutions, the substituents can be the same or different. The substituents are independently D (deuterium), oxo, halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, carboxylic acid ester, acyl, amide, sulfone, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 alkoxy, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkylamino, C3-C 12 cycloalkyl, halogenated C3-C 12 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C6-C 12 Aryl, C5-C 14 heteroaryl, C3-C 12 Heterocyclic group.

[0304] As used in this invention, the term "aryl" refers to a monocyclic or fused polycyclic group having 6 to 12 carbon atoms (one of which may be partially saturated), including but not limited to benzene rings, naphthalene rings, anthracene rings, indene rings, dihydroindene (indene-monyl), etc. The aryl group may be unsubstituted or substituted, and may be monosubstituted (e.g., ortho, meta, para substitution), disubstituted, or trisubstituted, etc. In cases of multiple substitutions, the substituents may be the same or different. The substituents are independently D (deuterium), halogen, cyano, nitro, hydroxyl, amino, aminoalkyl, alkenyl, alkynyl, carboxyl, acyl, amide, alkylamide, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 hydroxyalkyl, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 alkoxy, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkylamino, C3-C 12 cycloalkyl, halogenated C3-C 12 Cycloalkyl, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C6-C 12 Aryl, C5-C 14 heteroaryl, C3-C 12 Heterocyclic group.

[0305] As used in this invention, the terms "aromatic heterocycle" and "heteroaryl" refer to a monocyclic or fused polycyclic group having 5 to 14 ring atoms (one of the fused rings may be partially saturated), equivalent to one or more carbon atoms in the aforementioned "aryl" group being replaced by heteroatoms such as N, O, S, etc. A heteroaromatic ring can be monocyclic or bicyclic, i.e., formed by the fusion of two rings. Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, pyrazolyl, thiazolyl, oxazolyl, imidazole, indole, dihydroindole, benzimidazole, etc. The heteroaryl group can be unsubstituted, monosubstituted, or polysubstituted; in polysubstituted cases, the substituents can be the same or different. The substituents are independently D (deuterium), halogen, cyano, nitro, amino, aminoalkyl, hydroxyl, carboxyl, carboxylic acid ester, acyl, amide, alkylamide, alkoxycarbonyl, alkylthio, alkylsulfonyl, hydroxyalkylamide, sulfonamide, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkoxy, halo-C1-C8 alkylamino, C3-C 12 cycloalkyl, halogenated C3-C 12 cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Mixed aromatic compounds.

[0306] As used in this invention, the term "alkylamino" refers to alkyl-NH-, wherein the alkyl group is as defined above. Examples of "alkylamino" as used in this invention include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, etc. "Alkamino" also includes substituted alkylamino groups, wherein the substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkoxy, halo-C1-C8 alkylamino, C3-C 12 cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl groups can have substituents on either alkyl groups or nitrogen-containing groups.

[0307] As used in this invention, the term "alkoxy" refers to an alkyl-O- group, wherein the alkyl group is as defined above. Examples of "alkoxy" as used in this invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and tert-butoxy. "Alkoxy" also includes substituted alkoxy groups, the substituents of which may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkoxy, halo-C1-C8 alkylamino, C3-C 12 cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Mixed aromatic compounds.

[0308] As used in this invention, the term "cycloalkylamino" refers to cycloalkyl-NH-, wherein the cycloalkyl group is as defined above. "Cycloalkylamino" also includes substituted cycloalkylamino groups, wherein the substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkoxy, halo-C1-C8 alkylamino, C3-C 12 cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Heteroaryl groups can have substituents on either alkyl groups or nitrogen-containing groups.

[0309] As used in this invention, the term "cycloalkoxy" refers to cycloalkyl-O-, wherein the cycloalkyl group is as defined above. "Cycloalkoxy" also includes substituted cycloalkoxy groups, wherein the substituents may be D, halogen, oxo, amino, hydroxyl, cyano, nitro, C1-C8 alkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxy, C1-C8 alkylamino, halo-C1-C8 alkyl, halo-C1-C8 hydroxyalkyl, halo-C1-C8 alkoxy, halo-C1-C8 alkylamino, C3-C 12 cycloalkyl, C3-C 12 Heterocyclic group, C6-C 12 Aryl, C5-C 14 Mixed aromatic compounds.

[0310] As used in this invention, the term "haloalkyl" refers to a straight-chain or branched alkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), wherein "alkyl" is as defined above. Examples of "haloalkyl" as used in this invention include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, tetrafluoroethyl, pentafluoroethyl, and 1,1,1-trifluoropropyl-2-yl. A "haloalkyl" group may be substituted with a halogen once or multiple times.

[0311] As used in this invention, the term "haloalkoxy" refers to a hydroxyalkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), wherein the alkoxy group is as defined above. A "haloalkoxy" may be substituted with a halogen once or multiple times.

[0312] As used in this invention, the term "haloalkoxy" refers to a hydroxyalkyl group substituted with a halogen (preferably fluorine, chlorine, bromine, or iodine), wherein the alkoxy group is as defined above. A "haloalkoxy" may be substituted with a halogen once or multiple times.

[0313] This invention provides methods well-known to those skilled in the art for preparing salts of the compounds described herein. The salts can be organic acid salts, inorganic acid salts, etc. Organic acid salts include citrates, fumarates, oxalates, malates, lactates, camphor sulfonates, p-toluene sulfonates, methanesulfonates, etc.; inorganic acid salts include hydrohalides, sulfates, phosphates, nitrates, etc. For example, they can form methanesulfonates and trifluoromethanesulfonates with lower alkyl sulfonic acids, such as methanesulfonic acid and trifluoromethanesulfonic acid; they can form p-toluene sulfonates and benzene sulfonates with aryl sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid; they can form corresponding salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, or citric acid; and they can form glutamate or aspartate with amino acids, such as glutamic acid or aspartic acid. They can also form corresponding salts with inorganic acids, such as hydrohalic acids (e.g., hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid, or phosphoric acid.

[0314] The compounds described in this invention include compounds in which one of their atoms is substituted with an isotope. An isotope refers to an atom having the same atomic number but different atomic masses. For example, isotopes of hydrogen include deuterium and tritium. In the compounds of this invention, one or more atoms may be substituted with natural or non-natural isotopes. For example, in some embodiments, a hydrogen atom may be substituted with one or more deuterium atoms. The methods for synthesizing compounds containing isotopic atoms are existing known techniques.

[0315] This invention provides a pharmaceutical formulation comprising at least one active ingredient, said active ingredient being one or more compounds as described in any of the foregoing technical solutions. The pharmaceutical formulation comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, wherein the active ingredient may be any one or more of the following: a BTK inhibitor compound of this invention, an optical isomer of said compound, a pharmaceutically acceptable salt of said compound or its optical isomer, or a solvate of said compound or its optical isomer.

[0316] The carrier includes conventional pharmaceutical diluents, excipients, fillers, binders, humectants, disintegrants, absorption promoters, surfactants, adsorbents, lubricants, etc., and flavorings, sweeteners, etc. may be added if necessary.

[0317] The drug of this invention can be made into various forms such as tablets, powders, granules, capsules, oral liquids and injections. All of the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0318] A second object of the present invention is to provide a pharmaceutical composition comprising one or more of the compounds described in any of the foregoing technical solutions. The pharmaceutical composition of the present invention may be composed of one or more of the compounds described in any of the foregoing technical solutions combined with other compounds, or may be composed of one or more of the compounds described in any of the foregoing technical solutions.

[0319] On the other hand, the present invention provides the use of the compounds of general formulas I to XI disclosed herein, or their stereoisomers, mixtures thereof, or pharmaceutically acceptable salts thereof, in the treatment of diseases, disorders, or conditions that benefit from the degradation of STAT3.

[0320] In a further preferred embodiment, the present invention provides a method for degrading STAT3 in a patient by administering a composition containing a therapeutically effective amount of at least one compound, wherein the compound has a structural formula of general formula I to general formula XI. In some embodiments, the patient has cancer.

[0321] In a further embodiment, the patient in need of treatment suffers from cancer, including but not limited to:

[0322] Hematologic malignancies, including lymphoma, leukemia, multiple myeloma, and myelodysplastic syndromes such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma / Waldenström macroglobulinemia. Macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma, AML, CML, multiple myeloma, or lymphomatoid granulomatosis.

[0323] Autoimmune diseases or conditions, including single-organ or single-cell type autoimmune diseases, such as Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis with pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasseur's disease, autoimmune thrombocytopenic purpura, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic invasive hepatitis, ulcerative colitis and membranous glomerulonephritis, those involving systemic autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, Reiter's syndrome, polymyositis dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid), and other O-cell (humoral) or T-cell autoimmune diseases (including Kurgan's syndrome), ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I diabetes or juvenile-onset diabetes or thyroiditis;

[0324] Solid tumors include, but are not limited to, cancers of the digestive tract / gastrointestinal tract, colorectal cancer, liver cancer, skin cancer (including mast cell carcinoma and squamous cell carcinoma), breast and breast cancer, ovarian cancer, prostate cancer, kidney cancer, lung cancer, myoma, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, thyroid cancer, retinoblastoma, and rhabdomyosarcoma.

[0325] The inventors have demonstrated through experiments that the compound of this invention can degrade transcription factor STAT3.

[0326] The inventors of this invention have demonstrated through experiments that the compound of this invention has an anti-proliferation inhibitory effect on the Karpas299 cell line.

[0327] The inventors of this invention have demonstrated through experiments that the compound of this invention has a good AUC ratio in tumors / plasma. Detailed implementation method:

[0328] Synthesis of intermediate 1:

[0329]

[0330] Intermediate 1 was synthesized using a method similar to that described in patent document WO2020198435A1. ESI-MS: m / z = 869 [M+H] + .

[0331] Synthesis of intermediate 2

[0332]

[0333] first step:

[0334] Boc-L-pyroglutamic acid methyl ester (10 g, 41.11 mmol, 1 equiv) was dissolved in methanol (100 mL) and cooled to -10 °C. Sodium borohydride (2.19 g, 57.55 mmol, 1.4 equiv) was added in portions. The reaction mixture was stirred at -10 °C for 1 hour, and the reaction was monitored by TLC until completion. Water (80 mL) was slowly added to the reaction mixture at 0 °C, and after stirring for about half an hour, the mixture was extracted with EA (100 mL × 3). The extract was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried to give 1-(tert-butyl)-2-methyl(2S)-5-hydroxypyrrolidine-1,2-dicarboxylate (8.9 g, 36.28 mmol, yield 88.2%). The crude product was directly used for the next reaction. LC-MS: (ESI) [M+H] + =246.1.

[0335] Step Two:

[0336] 1-(tert-butyl)-2-methyl(2S)-5-hydroxypyrrolidine-1,2-dicarboxylate (25.6 g, 104.38 mmol, 1 equiv) was dissolved in anhydrous methanol (250 mL), and p-toluenesulfonic acid (3.60 g, 20.88 mmol, 0.2 equiv) was added at room temperature. The reaction mixture was stirred at room temperature for 18 hours, and the reaction was completed by TLC. The reaction mixture was concentrated, and the crude product was subjected to column chromatography (PE:EA = 85:15, v / v) to give 1-(tert-butyl)-2-methyl(2S)-5-methoxypyrrolidine-1,2-dicarboxylate (24.74 g, 95.40 mmol, yield 91.4%). The crude product was used directly in the next step of the reaction. LC-MS: (ESI) [M+H] + =260.1. 1 H NMR: (400MHz, CDCl3): δ5.36–5.16(m,1H),4.42–4.25(m,1H),3.81–3.73(m,3H) ),3.53–3.37(m,3H),2.53–2.29(m,1H),2.23–1.80(m,3H),1.54–1.43(m,9H).

[0337] Step 3:

[0338] 1-(tert-butyl)-2-methyl(2S)-5-methoxypyrrolidine-1,2-dicarboxylate (10.0 g, 38.56 mmol, 1 equiv) and allyltrimethylsilane (13.22 g, 115.70 mmol, 3 equiv) were mixed in DCM (200 mL), and the mixture was then cooled to -72 °C. Under nitrogen protection, boron trifluoride diethyl ether (5.47 g, 38.56 mmol, 1 equiv) was added dropwise at -72 °C. After the addition was complete, the mixture was stirred at -72 °C for 1 hour, and the reaction was monitored by TLC until completion. Water (100 mL) was added dropwise to the reaction mixture at -72 °C. The mixture was then brought to room temperature, and the layers were separated. The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was subjected to column chromatography (PE:EA = 10:1, v / v) to give 1-(tert-butyl)-2-methyl(2S)-5-allylpyrrolidine-1,2-dicarboxylate (5.3 g, 19.68 mmol, yield: 51%). LC-MS: (ESI) [M+H] + =270.2. 1 H NMR: (400MHz, CDCl3): δ5.86–5.72(m,1H),5.11–5.02(m,2H),4.37–4.19(m,1H),4.00–3.81(m,1H),3.74–3 .71(m,3H),2.76–2.53(m,1H),2.26–2.14(m,2H),2.01–1.89(m,2H),1.81–1.71(m,1H),1.47–1.40(m,9H).

[0339] Step 4:

[0340] 1-(tert-butyl)-2-methyl(2S)-5-allylpyrrolidine-1,2-dicarboxylate (4.6 g, 17.08 mmol, 1 equiv) was dissolved in DCM (40 mL), and a solution of 1,4-dioxane hydrochloric acid (21 mL, 168 mmol, 9.8 equiv) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and the reaction was confirmed by TLC. The reaction mixture was concentrated and evaporated, and the residue was dried under vacuum to obtain methyl(2S)-5-allylpyrrolidine-2-carboxylate hydrochloride (3.52 g, 17.11 mmol, crude).

[0341] Step 5:

[0342] Methyl(2S)-5-allylpyrrolidine-2-carboxylic acid ester hydrochloride (3.52 g, 17.11 mmol, 1 equiv) and (S)-3-((benzyloxycarbonyl)amino)-2-((tert-butoxycarbonyl)amino)propionic acid (5.79 g, 17.11 mmol, 1 equiv) were dissolved in N,N-dimethylformamide (40 mL). Then, N,N-diisopropylethylamine (6.63 g, 51.34 mmol, 3 equiv) was added at 10 °C and stirred for 5 minutes. Then, HATU (6.83 g, 17.97 mmol, 1.05 equiv) was added in portions at 10 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (100 mL), extracted with EA (50 mL × 3), and the extract was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and crudely purified by column chromatography (PE:EA = 2:3, v / v) to give methyl (2S)-5-allyl-1-((S)-3-((benzyloxy)carbonylamino)-2-((tert-butoxycarbonyl)amino)propionyl)pyrrolidine-2-carboxylic acid ester (6.50 g, 13.28 mmol, yield: 77.6%). LC-MS: (ESI) [M+H] + =490.3, tR=15.547min.

[0343] Step 6:

[0344] Methyl(2S)-5-allyl-1-((S)-3-((benzyloxycarbonyl)amino)-2-((tert-butoxycarbonyl)amino)propionyl)pyrrolidine-2-carboxylic acid ester (1.72 g, 3.51 mmol, 1 equiv) was dissolved in DCM (60 mL). The reaction solution was cooled to -78 °C, and ozone was bubbled through the reaction solution until it turned light blue. The ozone bubbling was then stopped. TLC analysis showed the disappearance of the starting material and the formation of new spots. Air was bubbled into the reaction solution to remove excess ozone, and triethylamine (7.46 g, 73.78 mmol, 21 equiv) was added at -78 °C. After the addition was complete, the reaction solution was brought to room temperature and stirred for 1 hour. TLC analysis showed the reaction was complete. The concentrated and evaporated reaction solution was subjected to crude column chromatography (PE:EA = 2:3, v / v) to yield methyl (2S)-1-((S)-3-((benzyloxycarbonyl)amino)-2-((tert-butoxycarbonyl)amino)propionyl)-5-(2-oxoethyl)pyrrolidine-2-carboxylic acid ester (1.30 g, 2.64 mmol, yield: 75.2%).

[0345] Step 7:

[0346] Methyl(2S)-1-((S)-3-((benzyloxycarbonyl)amino)-2-((tert-butoxycarbonyl)amino)propionyl)-5-(2-oxyethyl)pyrrolidine-2-carboxylate (1.3 g, 2.64 mmol, 1 equiv) was dissolved in isopropanol (20 mL), followed by the addition of palladium on carbon (130 mg, 10% wt). The reaction mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere (1 atm). LC-MS analysis showed the disappearance of the starting material, with the de-Cbz product being the main product. The reaction mixture was filtered, and the filter cake was washed with methanol (10 mL × 3). The filtrate was concentrated and dried. The crude product was dissolved in THF (100 mL), and sodium triacetoxyborohydride (1.68 g, 7.94 mmol, 3 equiv) was added at room temperature. The reaction mixture was stirred at room temperature for 18 hours after the addition, and LC-MS analysis confirmed the reaction was complete. Saturated saline solution (20 mL) was added to the reaction solution and stirred for half an hour. THF was removed by evaporation under reduced pressure. The aqueous phase was extracted with a chloroform / isopropanol mixture (chloroform:isopropanol = 3:1, 20 mL × 3). The organic phase was dried under evaporation. Crude product was subjected to column chromatography (EA:MeOH = 20:1, v / v) to give intermediate 2: (5S,8S,10AR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooctyl-8-carboxylic acid methyl ester (270 mg, 0.79 mmol, yield 30%). LC-MS: (ESI) [M+H] + =342.2, tR=0.895min. 1 H NMR: (400MHz, CDCl3): δ5.43(d,J=8.0Hz,1H),4.76-4.68(m,1H),4.54(t, J=8.8Hz,1H),4.36-4.29(m,1H),3.77(s,3H),3.25-3.18(m,2H),2.95-2.8 5(m,1H),2.74(dd,J=13.6,10.8Hz,1H),2.40-2.33(m,1H),2.20-2.12(m, 1H),2.01-1.95(m,1H),1.90-1.79(m,2H),1.67-1.61(m,1H),1.42(s,9H).

[0347] Synthesis of intermediate 3

[0348]

[0349] first step:

[0350] (5S,8S,10AR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooctyl-8-carboxylic acid methyl ester (220 mg, 0.64 mmol, 1 equiv) and triethylamine (130 mg, 1.29 mmol, 2 equiv) were mixed in DCM (5 mL) and cooled to 0 °C. 2,2-difluoroethyltrifluoromethanesulfonate (152 mg, 0.71 mmol, 1.1 equiv) was then added dropwise under nitrogen protection. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 18 hours. The reaction solution was evaporated to dryness, and the crude product was subjected to column chromatography (PE:EA = 7:3, v / v) to give (5S, 8S, 10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl-8-carboxylic acid methyl ester (150 mg, 0.37 mmol, yield: 50%). LC-MS: (ESI) [M+H] + =406.2. 1 H NMR: LYQ9906-007-P1 (400MHz, CDCl3): δ5.88 (d, J=56.0Hz, 1H), 5.64 (d, J=7.2Hz, 1H), 4.50–4.43 (m, 2H), 4.34–4.28 (m, 1H), 3.75 (s, 3H), 3.1 8–3.01(m,5H),2.87–2.80(m,1H),2.38–2.29(m,1H),2.17–2.07(m,1H) ,2.03–1.94(m,1H),1.83–1.78(m,1H),1.73–1.69(m,1H),1.42(s,9H).

[0351] Step Two:

[0352] (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl-8-carboxylic acid methyl ester (880 mg, 2.17 mmol, 1 equiv) was dissolved in THF (12 mL), and an aqueous solution of lithium hydroxide (312 mg, 13.02 mmol, 6 equiv) (4 mL) was added at room temperature. After the addition was complete, the reaction solution was stirred at room temperature for 4 hours. The reaction solution was then diluted with water (10 mL) and concentrated under reduced pressure at low temperature. After removing THF, the aqueous phase was adjusted to pH 7 at 0°C with dilute hydrochloric acid (1N) and extracted with a chloroform / isopropanol mixed solvent (chloroform:isopropanol = 3:1, 15 mL × 6). The extract was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl-8-carboxylic acid (800 mg, 2.04 mmol, yield 98.7%). LC-MS: (ESI) [M+H] + =392.2.

[0353] Synthesis of intermediate 4

[0354]

[0355] first step:

[0356] Take a single-necked flask and add 1-fluoro-4-iodo-2-nitrobenzene (10 g, 37.5 mmol, 1 equiv.), (S)-4,5-diamino-5-oxovalerate tert-butyl hydrochloride (10.7 g, 44.9 mmol, 1.2 equiv.), triethylamine (11.4 g, 112.5 mmol, 3 equiv.), THF (200 mL), and MeOH (100 mL). The mixture is aerated three times and then stirred at room temperature for 48 hours. The reaction mixture was added to water (200 mL), and extracted three times with dichloromethane (200 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by Flash column chromatography (DCM:MeOH = 20:1, v / v) to obtain intermediate 4-1: (S)-tert-butyl-5-amino-4-((4-iodo-2-nitro-phenyl)amino)-5-oxovalerate (9 g, 20 mmol, yield 53%). LC-MS: (ESI) [M-56+H] + =393.6tR=1.74min. 1H NMR: HSY10178–011–P1 (400MHz, DMSO): δ8.36(d,J=7.2Hz,1H),8.34(d,J=2.0Hz,1H),7.82(dd,J=9.2,2.0Hz,1H),7.74(s,1 H),7.42(s,1H),6.79(d,J=9.2Hz,1H),4.26(dd,J=12.4,6.0Hz,1H),2.28(t,J=7.6Hz,2H),2.16–1.95(m,2H),1.36(s,9H).

[0357] Step Two:

[0358] Take a single-necked flask, add intermediate 4-1 (6 g, 13.4 mmol, 1 equiv.), iron powder (3.74 g, 66.8 mmol, 5 equiv.), ammonium chloride (2.93 g, 66.8 mmol, 5 equiv.), ethanol (100 mL), and water (100 mL). The mixture is purged three times and heated to 80 °C with stirring for 1 hour. TLC shows the reaction is complete. The reaction solution is cooled to room temperature, and iron powder is removed by filtration with diatomaceous earth through a Buchner funnel. Water (100 mL) is then added, and the filtrate is extracted three times (100 mL * 3). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue is purified by Flash column chromatography (DCM:MeOH = 10:1, v / v) to obtain (S)-tert-butyl-5-amino-4-((2-amino-4-iodophenyl)amino)-5-oxovalerate (3.8 g, 9.07 mmol, yield 67.6%). 1 HNMR: (400MHz, DMSO) δ7.42(s,1H),7.09(s,1H),6.87(d,J=1.9Hz,1H),6.74(dd,J=8.2,1.8Hz,1H),6.14(d,J=8.3 Hz,1H),4.89(s,2H),4.69(d,J=8.0Hz,1H),3.70-3.57(m,1H),2.44-2.28(m,2H),2.06-1.83(m,2H),1.41(s,9H).

[0359] Step 3:

[0360] Take a single-necked flask and add (S)-tert-butyl5-amino-4-((2-amino-4-iodophenyl)amino)-5-oxovalerate (3.8 g, 9.07 mmol, 1 equiv.), dichloromethane (60 mL), N,N-diisopropylethylamine (3.51 g, 27.21 mmol, 3 equiv.), and slowly add triphosgene (672 mg, 2.27 mmol, 0.25 equiv.) under ice bath conditions. The mixture is purged three times and then stirred at room temperature for 4 hours. The reaction mixture was added to water and extracted three times with ethyl acetate (60 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by Flash column chromatography (DCM:MeOH = 10:1, v / v) to give (S)-tert-butyl-5-amino-4-(5-iodo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxoglutarate (3.2 g, 7.2 mmol, yield 79.4%). LC-MS: (ESI) [M-56+H] + =389.8. 1 H NMR (400MHz, DMSO) δ11.07(s,1H),7.53(s,1H),7.31(d,J=8.4Hz,1H),7.27(s,2H),6.86(d,J=8.4Hz,1 H),4.83(dd,J=9.6,4.8Hz,1H),2.39–2.28(m,1H),2.20–2.06(m,2H),2.04–1.94(m,1H),1.34(s,9H).

[0361] Step 4:

[0362] Take a single-necked flask and add (S)-tert-butyl-5-amino-4-(5-iodo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxoglutarate (3.2 g, 7.2 mmol, 1 equiv.), cesium carbonate (2.8 g, 8.64 mmol, 1.2 equiv.), acetonitrile (40 mL), and then iodomethane (5.1 g, 36 mmol, 5 equiv.). The mixture is aerated three times, then heated to 85 °C and stirred for 2 hours. The reaction solution was cooled to room temperature, then water was added, and the mixture was extracted three times with ethyl acetate (60 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by Flash column chromatography (DCM:MeOH = 10:1, v / v) to give (S)-tert-butyl-5-amino-4-(5-iodo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxoglutarate (2 g, 4.36 mmol, yield 60.6%). LC-MS: (ESI)[M+H] +=459.8.1H NMR: (400MHz, DMSO): δ7.55(s,1H),7.51(s,1H),7.37(d,J=8.4Hz,1H),7.28(s,1H),6.89(d,J=8.4Hz,1H),4. 87(dd,J=10.2,4.8Hz,1H),3.33(s,3H),2.43-2.30(m,1H),2.21-2.06(m,2H),2.05-1.95(m,1H),1.33(s,9H).

[0363] Step 5:

[0364] Take a single-necked flask and add (S)-tert-butyl5-amino-4-(5-iodo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-5-oxoglutarate (2 g, 4.36 mmol, 1 equiv.), add tetrahydrofuran (200 mL), and slowly add potassium tert-butoxide (978 mg, 8.72 mmol, 2 equiv.) under ice bath conditions. The mixture is purged three times, and then stirred under ice bath conditions for 1 hour. The reaction mixture was added to water and extracted three times with ethyl acetate (100 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by Flash column chromatography (DCM:MeOH = 10:1, v / v) to give 3-(5-iodo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (1 g, 2.6 mmol, yield 59.6%). LC-MS: (ESI) [M-56+H] + =330.0. 1 H NMR: (400MHz, DMSO): δ11.13(s,1H),7.59(d,J=1.6Hz,1H),7.40(dd,J=8.4,1.6Hz,1H),7.00(d,J=8.4Hz ,1H),5.39(dd,J=12.8,5.2Hz,1H),3.34(s,3H),2.97-2.82(m,1H),2.76-2.59(m,2H),2.09-1.99(m,1H).

[0365] Synthesis of intermediate 5

[0366]

[0367] Referring to the synthesis of intermediate 4, the 1-fluoro-4-iodo-2-nitrobenzene in the first step was replaced with 1-bromo-3-fluoro-2-nitrobenzene. LC-MS: (ESI) [M+H] + =338.

[0368] Synthesis of intermediate 6

[0369]

[0370] Following the synthesis of intermediate 3, intermediate 6 was obtained in the first step by reacting intermediate 2 with Cbz-Cl, followed by demethylation. LC-MS: (ESI)[M+H] + =462.2.

[0371] Synthesis of intermediate 7

[0372]

[0373] first step:

[0374] Take a single-necked flask, add 2.0 g (8.1 mmol, 1 equiv.) of 4-(3-hydroxypropyl)piperidin-1-carboxylic acid tert-butyl ester, add 30 mL of DCM, and slowly add dimethyl phthalate (10.45 g, 24.3 mmol, 3 equiv.) at 0 °C. The mixture is purged three times, and then stirred at room temperature for 4 hours. TLC shows the reaction is complete. Slowly add 30 mL each of saturated solutions of sodium thiosulfate and sodium bicarbonate to the reaction mixture, extract three times with ethyl acetate (50 mL * 3), combine the organic phases, dry to anhydrous sodium sulfate, concentrate the organic phase by vacuum distillation, and purify the residue using a Flash column (PE:EtOAc = 4:1, v / v) to obtain 1.6 g (6.6 mmol, yield: 80%) of 4-(3-oxopropyl)piperidin-1-carboxylic acid tert-butyl ester. 1 H NMR(400MHz,DMSO)δ9.69(s,1H),3.99–3.88(m,2H),2.75–2.57(m,2H),2.50–2.44(m,2H) ,1.64–1.58(m,2H),1.50–1.45(m,2H),1.40(s,9H),1.37–1.26(m,1H),1.00–0.91(m,2H).

[0375] Step Two:

[0376] Take a single-necked flask, add 1.6 g (6.6 mmol, 1 equiv.) of 4-(3-oxopropyl)piperidin-1-carboxylic acid tert-butyl ester, 30 mL of MeOH, and 6.3 g (33 mmol, 5 equiv.) of (1-diazo-2-oxopropyl)phosphonate dimethyl ester. The mixture is purged three times and then stirred at room temperature for 3 hours. The reaction mixture is cooled to room temperature, then water is added, and the mixture is extracted three times with ethyl acetate (50 mL * 3). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue is purified by Flash column chromatography (PE:EtOAc = 5:1, v / v) to obtain 1.20 g (5.1 mmol, yield: 77%) of 4-(butyl-3-yn-1-yl)piperidin-1-carboxylic acid tert-butyl ester. 1 H NMR (400MHz, DMSO) δ3.93-3.91(m,2H),2.77(t,J=2.8Hz,1H),2.71-2.65(m,2H),2.22–2 .18(m,2H),1.66-1.62(m,2H),1.56–1.48(m,1H),1.49-1.40(m,11H),1.02-0.91(m,1H).

[0377] Step 3:

[0378] Take a single-necked flask and add intermediate 4 (1194 mg, 3.1 mmol, 1.0 equiv.), tetrakis(triphenylphosphine)palladium (358 mg, 0.31 mmol, 0.1 equiv.), cuprous iodide (118 mg, 0.62 mmol, 0.2 equiv.), triethylamine (1.56 g, 15.5 mmol, 5 equiv.), and tert-butyl 4-(butyl-3-yn-1-yl)piperidine-1-carboxylate (1.2 g, 5.1 mmol, 1.6 equiv.), then add dimethyl sulfoxide (8 mL). The mixture is aerated three times and then stirred at 80 °C for 4 hours. The reaction solution was cooled to room temperature, then water was added, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by Flash column chromatography (DCM:MeOH = 5:1, v / v) to give tert-butyl 4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-carboxylic acid (742 mg, 1.5 mmol, yield: 49%). LCMS: (ESI) [M+1] + =495.3.

[0379] Step 4:

[0380] Take a single-necked flask, add 4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-carboxylic acid tert-butyl ester (742 mg, 1.5 mmol, 1 equiv.), add DCM (10 mL), and slowly add trifluoroacetic acid (513 mg, 4.5 mmol, 3 equiv.) under ice bath conditions. Then stir at room temperature for 1 hour. The reaction solution was cooled to room temperature, then water was added, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by column chromatography to give 3-(3-methyl-2-oxo-5-(4-(piperidin-4-yl)but-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (414 mg, 1.05 mmol, yield 70%). LCMS: (ESI) [M+1] + =395.2.

[0381] Synthesis of intermediate 8

[0382]

[0383] first step:

[0384] 6-Bromopyridinecarboxylic acid (2 g, 10.00 mmol) was dissolved in 20 mL of ethylene glycol dimethyl ether. Methyl hepta-6-ynyleneate (1.7 g, 12.00 mmol), tetrakis(triphenylphosphine)palladium (570 mg, 0.50 mmol), cuprous iodide (380 mg, 2.00 mmol), and DIPEA (4 mL, 30.00 mmol) were added sequentially to the system, and the reaction was carried out at 120 °C for 20 min. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, dissolved in DCM, and subjected to column chromatography to obtain 1 g of 6-(7-methoxy-7-oxohept-1-yn-1-yl)pyridinecarboxylic acid, in 40% yield. ESI-MS (M+H) + =262.0.

[0385] Step Two:

[0386] 6-(7-methoxy-7-oxohepta-1-yn-1-yl)pyridinecarboxylic acid (522 mg, 2 mmol) was dissolved in 15 mL of DMF. 3-aminopiperidin-2,6-dione (307 mg, 2.4 mmol), HATU (912 mg, 2.4 mmol), and DIPEA (645 mg, 5 mmol) were added sequentially to the system, and the reaction was carried out at room temperature for 2 h. After the reaction was complete, water was added, and a solid precipitated. The solid was extracted with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 534 mg of a white solid, 72% yield, of methyl 7-(6-((2,6-dioxopetaridin-3-yl)carbamoyl)pyridin-2-yl)hepta-6-yn-oyl acid. ESI-MS (M+H) + =372.1.

[0387] Step 3:

[0388] In a single-necked flask, add methyl 7-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)hepta-6-ynyl ester (1 equiv), add DCM (10 mL), and slowly add trifluoroacetic acid (513 mg, 4.5 mmol, 3 equiv.) under ice bath conditions. Stir at room temperature for 1 hour. Cool the reaction mixture to room temperature, add water, and extract three times with ethyl acetate (50 mL * 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate by vacuum distillation to obtain 7-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)hepta-6-ynyl ester. ESI-MS (M+H) + =358.1.

[0389] Synthesis of intermediate 9

[0390]

[0391] Step 1: 5-Bromobenzothiophene-2-carbonyl chloride

[0392] In a single-necked flask, add 10 g (39 mmol, 1 equiv.) of 5-bromobenzothiophene-2-carboxylic acid, 200 mL of DCM, and slowly add 15 g (117 mmol, 3 equiv.) of oxaloyl chloride under ice bath conditions, followed by 1 mL of DMF. The mixture was purged three times and then stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated by vacuum distillation to obtain 5-bromobenzothiophene-2-carbonyl chloride, which was directly used in the next step (11 g, 39 mmol, 100% yield).

[0393] Step 2: 5-Bromobenzothiophene-2-carboxylic acid benzyl ester

[0394] In a single-necked flask, add 11 g (39 mmol, 1 equiv.) of 5-bromobenzothiophene-2-carbonyl chloride, 200 mL of DCM, and slowly add benzyl alcohol (51 g, 46.8 mmol, 1.2 equiv.) and triethylamine (118 g, 117 mmol) under ice bath conditions. The mixture is purged three times and then stirred at room temperature for 1 hour. The reaction mixture is cooled to room temperature, then water is added, and the mixture is extracted three times with ethyl acetate (100 mL x 3). The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue is purified by Flash column chromatography (DCM:MeOH = 10:1, v / v) to obtain benzyl 5-bromobenzothiophene-2-carboxylic acid ester (9 g, 26 mmol, yield: 67%). 1 HNMR: (400MHz, DMSO): δ8.30(d,J=2.0Hz,1H),8.24(s,1H),8.08(d,J=8.0Hz,1H), 7.70(dd,J=8.0,2.0Hz,1H),7.51(d,J=6.8Hz,2H),7.47–7.40(m,3H),5.42(s,2H).

[0395] Step 3: 5-Iodobenzo[b]thiophene-2-carboxylic acid benzyl ester

[0396] Take a sealed tube and add 4.8 g (13.8 mmol, 1 equiv) of 5-bromobenzothiophene-2-carboxylic acid benzyl ester, N1,N2-dimethylethane-1,2-diamine (244 mg, 2.8 mmol, 0.2 equiv), and 263 mg (1.38 mmol, 0.1 equiv) of cuprous iodide to 1,4-dioxane (48 mL). Seal and heat to 110 °C for 16 h. Cool the reaction solution to room temperature, filter, evaporate the filtrate to dryness, and purify the concentrate by column chromatography (PE:EA = 10:1) to give 4.8 g (12.2 mmol, yield: 88.8%) of 5-iodobenzo[b]thiophene-2-carboxylic acid benzyl ester. LC-MS: (ESI)[M+Na] + =417. 1 H NMR: (400MHz, DMSO): δ8.47(d,J=1.6Hz,1H),8.22-8.19(m,1H),7.92(d,J=8.4Hz,1 H),7.82(dd,J=8.4,1.6Hz,1H),7.53-7.48(m,2H),7.46-7.38(m,3H),5.41(s,2H).

[0397] Step 4: 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid benzyl ester

[0398] In a 250 mL three-necked flask, zinc powder (3.4 g, 48.7 mmol, 3 equiv) was uniformly dispersed in anhydrous tetrahydrofuran. Dibromoethane (457 mg, 2.4 mmol, 0.05 equiv) was added at room temperature. The mixture was heated to 50 °C under nitrogen protection and maintained for 15 minutes. After cooling to room temperature, trimethylchlorosilane (317 mg, 2.9 mmol, 0.06 equiv) was added and stirred at room temperature for 15 minutes. Diethyl phosphonate (13.0 g, 48.7 mmol, 3 equiv) was slowly added dropwise to the reaction mixture. After the addition was complete, the mixture was heated to 50 °C and stirred for 1 hour. After cooling to room temperature, cuprous bromide (3.5 g, 24.4 mmol, 1.5 equiv) was rapidly added to the reaction mixture and stirred at room temperature for 30 minutes. 5-Iodobenzo[b]thiophene-2-carboxylic acid benzyl ester (6.4 g, 16.2 mmol, 1 equiv) was dissolved in tetrahydrofuran (60 mL) and added dropwise to the above reaction solution at room temperature. After the addition was complete, the mixture was heated to 45 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filtrate was evaporated to dryness. The residue was subjected to column chromatography (PE:EA = 5:1) to give 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid benzyl ester (2.3 g, 5.0 mmol, yield: 31%). 1 H NMR: (400MHz, CDCl3): δ8.19(s,2H),7.99(d,J=8.8Hz,1H),7.74(d,J=8.8Hz,1H),7.5 3-7.51(m,2H),7.48–7.39(m,3H),5.45(s,2H),4.34-4.20(m,2H),1.46-1.30(m,6H).

[0399] Step 5: 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0400] Take a 250 mL single-necked flask and dissolve 5.8 g (12.8 mmol, 1 equiv) of benzyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid in methanol (58 mL). Add palladium on carbon (5.8 g) and degas three times with hydrogen. Stir overnight at room temperature. Filter, evaporate the filtrate to dryness, and perform column chromatography (PE:EA = 1:1) to give compound 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (1.6 g, yield 35%). LC-MS: (ESI) [M+H] + =365.0. 1 H NMR: (400MHz, DMSO): δ8.30-8.24(m,3H),7.66(d,J=8.0Hz,1H),4.21–4.10(m,4H),1.26-1.23(m,6H).

[0401] Synthesis of Intermediate 10

[0402]

[0403] Step 1: 5-Bromobenzo[b]thiophene-2-carboxylic acid tert-butyl ester

[0404] 5-Bromobenzo[b]thiophene-2-carboxylic acid (25.00 g, 97.24 mmol) was dissolved in DMF (200 mL), and CDI (20.34 g, 125.44 mmol) was added. The mixture was stirred at 35 °C for 0.5 h, followed by the sequential addition of t-BuOH (32.34 mL, 436.33 mmol) and DBU (17.43 mL, 114.51 mmol), and stirring was continued for another 5 h. After the reaction was complete, it was quenched with H₂O and extracted with ethyl acetate (500 mL * 3). The organic layers were combined, washed three times with brine, dried over anhydrous sodium sulfate, filtered, and the filter cake was concentrated under vacuum to give 19 g of a yellow solid compound, 5-bromobenzo[b]thiophene-2-carboxylic acid tert-butyl ester, yield: 62%. LC / MS (ESI, m / z): [(M+H)] + =313.0.

[0405] Step 2: 2-(tert-Butoxycarbonyl)benzo[b]thiophene-5-carboxylic acid

[0406] Add tert-butyl 5-bromobenzo[b]thiophene-2-carboxylic acid (8.00 g, 25.54 mmol), Pd(AcO)₂ (1.15 g, 5.11 mmol), PPh₃ (4.02 g, 15.33 mmol), oxalic acid (10.06 g, 111.8 mmol), DIEA (17.80 mL, 137.7 mmol), Ac₂O (9.71 mL, 95.07 mmol), and DMF (100 mL) to a 400 mL sealed tube. Seal the reaction tube and stir at 100 °C for 8 hours. After the reaction is complete, cool the system to room temperature, quench with 0.5 M HCl aqueous solution and adjust the pH to 3-5, then extract with ethyl acetate (500 mL * 3). The organic layers were combined, washed three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Flash column chromatography (DCM:MeOH = 20:1) to give 7.5 g of a yellow solid compound 2-(tert-butoxycarbonyl)benzo[b]thiophene-5-carboxylic acid, yield: 90%. LC / MS (ESI, m / z): [(M+H)] + =279.1.

[0407] Step 3: 5-((diethoxyphosphoryl)carbonyl)benzo[b]thiophene-2-carboxylic acid tert-butyl ester

[0408] 2-(tert-Butoxycarbonyl)benzo[b]thiophene-5-carboxylic acid (9.00 g, 32.34 mmol) was dissolved in 100 mL CHCl3, stirred, and PC15 (7.41 g, 35.58 mmol) (tetramethyldipropylenetriamine) was added in portions. The mixture was stirred at room temperature for 5 minutes until the solution became clear. P(OEt)3 (10.75 g, 64.70 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, it was quenched with ice / water and extracted with DCM (500 mL * 3). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow oily crude product of 5-((diethoxyphosphoryl)carbonyl)benzo[b]thiophene-2-carboxylic acid tert-butyl ester, which was used directly in the next reaction. LC / MS (ESI, m / z): [(M+H)] + =399.2.

[0409] Step 4: 5-((diethoxyphosphoryl)carbonyl)benzo[b]thiophene-2-carboxylic acid

[0410] 15.00 g (37.65 mmol) of 5-((diethoxyphosphoryl)carbonyl)benzo[b]thiophene-2-carboxylic acid tert-butyl ester was dissolved in 150 mL of DCM. TFA (75 mL) was added dropwise under nitrogen protection at 25 °C and stirred for 2 h. After the reaction was complete, the mixture was concentrated under vacuum. The residue was purified using a reverse-phase Flash column (column: WelFlash™ C18-I, 20-40 mm, 330 g; eluent A: water (with 10 mmol / L FA); eluent B: CAN; gradient: 20%-55% B for 30 min; flow rate: 85 mL / min; detector: 220 / 254 nm; the desired fraction was collected under 48% B). The purified product was concentrated under reduced pressure to give 1.5 g of intermediate 10 as a white solid, in 12% yield. LC / MS (ESI, m / z): [(M+H)] + =343.0.

[0411] Synthesis of intermediate 11

[0412]

[0413] (S)-2-(tert-butoxycarbonylamino)-3-(4-fluoro-phenyl)propionic acid (1132 mg, 4.0 mmol) was dissolved in 5 mL of methanol, and glyoxal trimer dehydrated product (348 mg, 2.0 mmol) and 10 mL of 2N NH3 MeOH solution were added. The mixture was stirred at room temperature for 15 hours. After the reaction was complete, the solvent was evaporated under reduced pressure, and the mixture was extracted three times with EtOAc / saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give (S)-(1-(1H-imidazol-2-yl)-2-(4-fluoro-phenyl)ethyl)carbamate tert-butyl ester (165 mg, 0.54 mmol). LC-MS: (ESI) [M+H] + =306.2.

[0414] Synthesis of intermediate 12

[0415]

[0416] Intermediate 7 (1.0 equiv) was dissolved in methanol (5 mL), and 10% Pd / C (50 mg) was added. The mixture was stirred at room temperature for 1 h under hydrogen conditions. Pd / C was removed by filtration, and the filtrate was concentrated and evaporated. The filtrate was extracted three times with EtOAc / saturated brine. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 12: 3-(3-methyl-2-oxo-5-(4-(piperidin-4-yl)butyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione.

[0417] Example 001: ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctane-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid(001)

[0418]

[0419] first step:

[0420] Ethyl (S)-2-amino-3-(4-fluorophenyl)propionate (1.0 mmol) and (tert-butyloxycarbonyl)-L-glutamine (1.0 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (2.0 mmol). The mixture was stirred at room temperature for 3 minutes, and then HATU (1.0 mmol) was added in portions at 10 °C. After the addition was complete, the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL * 3). The extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was subjected to column chromatography to obtain 001-1: ethyl (S)-2-(5-amino-2-((tert-butyloxycarbonyl)amino)-5-oxopentamido)-3-(4-fluorophenyl)propionate.

[0421] Step Two:

[0422] 0.6 mol of 001-1 was dissolved in 5 mL of DCM, and a 1,4-dioxane solution (1 mL, 4 mmol) of hydrochloric acid was added at 0 °C. The reaction mixture was stirred at 0 °C for 10 minutes, concentrated, and evaporated. The residue was dried under vacuum to give product 001-2: (S)-2-(2,5-diamino-5-oxopentanamido)-3-(4-fluorophenyl)propionate ethyl ester. LC-MS: (ESI) [M+H] + =340.2.

[0423] Step 3:

[0424] Dissolve 001-2 (0.54 mmol) and N,N-diisopropylethylamine (211 mg, 1.64 mmol) in N,N-dimethylformamide (5 mL), add HATU (228 mg, 0.60 mmol) while stirring at 10 °C, stir for 10 minutes after addition, add intermediate 3 (0.6 mmol) to the above reaction solution, and after the reaction solution is added, raise the temperature to room temperature and stir for 18 hours. The reaction solution was poured into water (20 mL), extracted with EA (10 mL * 3), and the extract was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to crude column chromatography (EA:MeOH = 10:1, v / v) to give ethyl 2-(5-amino-2-((5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyll)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctane-8-amido)-5-oxopentamido)-3-(4-fluorophenyl)propionate. LC-MS: (ESI) [M+H] + =713.3.

[0425] Step 4:

[0426] 0.4 mmol of 001-3 was dissolved in 4 mL of THF, and 1 mL of an aqueous solution of 2.52 mmol of lithium hydroxide was added at room temperature. After the addition was complete, the reaction solution was stirred at room temperature for 4 hours. The reaction solution was diluted with 3 mL of water and concentrated under reduced pressure at low temperature to remove THF. The aqueous phase was adjusted to pH 5 by adding dilute hydrochloric acid (1 N) at 0 °C and extracted with a mixed solvent of chloroform and isopropanol (chloroform:isopropanol = 3:1, 5 mL * 4). The extract was washed with saturated brine (5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and dried to give product 001-4: 2-(5-amino-2-((5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-3-(2,2-difluoroethyll)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctane-8-amido)-5-oxopentamido)-3-(4-fluorophenyl)propionic acid. LC-MS: (ESI) [M+H] + =685.3.

[0427] Step 5:

[0428] 001-4 (0.36 mmol) and intermediate 7 (0.36 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (0.73 mmol) and T3P (0.36 mmol). The reaction mixture was stirred at room temperature for 18 hours after the addition was complete. The reaction mixture was poured into water (15 mL), extracted with EA (5 mL * 3), and the extract was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to crude column chromatography (EA:MeOH = 10:1, v / v) to give the corresponding product 001-5: ((5S,8S,10aR)-8-((5-amino-1-((1-(4-(4-(1-(2,6-dioxopyridin-3-yl)) 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyll)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctane-5-yl)tert-butyl carbamate. LC-MS: (ESI) [M+H]+=1061.5.

[0429] Step 6:

[0430] 001-5 (0.22 mmol) was dissolved in DCM (2 mL) and a 1,4-dioxane solution (4 mmol) of hydrochloric acid was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour, concentrated and evaporated, and the residue was dried under vacuum to give the corresponding deBoc product 001-6. LC-MS: (ESI) [M+H] + =961.4.

[0431] Step 7:

[0432] 001-6 (0.35 mmol) and intermediate 9 (0.39 mmol) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (1.04 mmol) and T3P (0.35 mmol). The reaction mixture was stirred at room temperature for 18 hours after the addition was complete. The reaction mixture was poured into water (15 mL), extracted with EA (5 mL * 3), and the extract was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (EA:MeOH = 10:1, v / v) to obtain the corresponding product 001-7: ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3- Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-3-(4-fluorophenyl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctane-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)diethyl phosphate. LC-MS: (ESI) [M+H] + =1307.5.

[0433] Step 8:

[0434] 001-7 (0.085 mmol) was dissolved in DCM (4 mL) and cooled to 0 °C. Under nitrogen protection, BSTFA (0.85 mmol) and TMS-I (1.27 mmol) (trimethyliodosilane) were added dropwise. After the addition was complete, the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was evaporated to dryness at low temperature. The residue was dissolved in a mixed solvent of acetonitrile / water / trifluoroacetic acid (CH3CN:H2O:TFA = 10:10:3, 7 mL), filtered, and the filtrate was sent to prepare HPLC to obtain compound 001. LC-MS: (ESI) [M+1] + =1251.1t R =0.98min; 1H NMR: N210759-016-P2 (400MHz, DMSO): δ11.09(s,1H),8.74-8.64(m,1H),8.33-8.27(m,1H),8.10-8.08(m,2H),8.07(s,1H) ),7.99-7.75(m,1H),7.59(d,J=8.4Hz,1H),7.26-7.16(m,3H),7.11-7.00(m,4H),6.95(d,J=8.4Hz,1H),6.79-6.72(m,1H) ,6.30–6.00(m,1H),5.39-5.32(m,1H),4.97-4.83(m,2H),4.39-4.21(m,6H),4.12-4.10(m,1H),3.34(s,3H),3.20-3.01( m,8H),2.95-2.60(m,6H),2.47-2.37(m,1H),2.17-1.93(m,5H),1.90-1.77(m,2H),1.69-1.07(m,10H),0.97-0.24(m,2H).

[0435] Example 002. ((2-(((5S,10aR)-8-(((2S)-5-amino-1-(((2S)-3-(4-(tert-butyl)phenyl)-1-(4-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-yl)piperidin-1-yl)-1-oxopropyl-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid (034)

[0436]

[0437] Referring to the synthetic route and method of Example 001, in the first step, ethyl (S)-2-amino-3-(4-fluorophenyl)propionate was replaced with ethyl (S)-2-amino-3-(4-(tert-butyl)phenyl)propionate to obtain the target compound 034. (ESI)[M+H] + =1289.

[0438] Referring to the synthetic method of compound 001 in Example 001, the following molecules were synthesized:

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452] The implementation of 41((2-(((5S, 10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid 107

[0453]

[0454] first step:

[0455] Take a single-necked flask and add intermediate 4 (1194 mg, 3.1 mmol, 1.0 equiv.), tetrakis(triphenylphosphine)palladium (358 mg, 0.31 mmol, 0.1 equiv.), cuprous iodide (118 mg, 0.62 mmol, 0.2 equiv.), triethylamine (1.56 g, 15.5 mmol, 5 equiv.), and tert-butyl 4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (1.22 g, 5.1 mmol, 1.6 equiv.), then add dimethyl sulfoxide (8 mL). The mixture is aerated three times and then stirred at 80 °C for 4 hours. The reaction solution was cooled to room temperature, then water was added, and the mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by Flash column chromatography (DCM:MeOH = 5:1, v / v) to give 107-1: tert-butyl-4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-carboxylic acid ester (745 mg, 1.5 mmol), yield: 49%. LCMS: (ESI) [M+1] + =497.

[0456] Step Two:

[0457] tert-butyl 4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-carboxylic acid ester was added to DCM (10 mL), and trifluoroacetic acid (513 mg, 4.5 mmol, 3 equiv.) was slowly added under ice bath conditions. The mixture was then stirred at room temperature for 1 hour. The reaction solution was cooled to room temperature, and water was added. The mixture was extracted three times with ethyl acetate (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by vacuum distillation. The residue was purified by column chromatography to give 107-2: 3-(3-methyl-2-oxo-5-(3-(piperidin-4-oxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione. LCMS:(ESI)[M+1] + =397.

[0458] Step 3:

[0459] 538 mg, 2 mmol of tert-butyl (1-(4-fluorophenyl)-3-hydroxypropane-2-yl)carbamate was dissolved in 5 mL of anhydrous THF solution, 761 mg, 4 mmol of 4-toluenesulfonyl chloride was added, and 1 mL of triethylamine solution was added dropwise. The mixture was stirred at room temperature for 6 h, and the solvent was recovered under reduced pressure. The residue was purified by silica gel column chromatography to give 2-(tert-butyloxycarbonyl)amino)-3-(4-fluorophenyl)propyl4-toluenesulfonate. 2-(tert-Butoxycarbonyl)amino)-3-(4-fluorophenyl)propyl 4-toluenesulfonate (1 mmol) and intermediate 107-2 (1.2 mmol) were dissolved in anhydrous DMF solution. Potassium carbonate (276 mg, 2.0 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was quenched by adding an aqueous solution of ammonium chloride under ice bath conditions. The solvent was recovered under reduced pressure, and the residue was purified by silica gel column chromatography to give tert-butyl((2S)-1-(4-(3-(1-(2,6-dioxopyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)propane-2-yl)carbamate. LCMS:(ESI)[M+1] + =648.

[0460] Step 4:

[0461] Referring to the synthetic steps of Example 001, compound 107 was obtained: ((2-(((5S, 10aR)-8-(((2S)-5-amino-1-(((2S)-1-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)-3-(4-fluorophenyl)prop-2-yl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(2,2-difluoroethyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooctyl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid, (ESI)[M+H) + =1239.

[0462] Referring to the synthesis of compound 107 in Example 41, the following compounds were synthesized.

[0463]

[0464]

[0465]

[0466]

[0467] Example 057. ((2-(((5S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-3-(7-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)hept-6-ynyl)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)phosphoric acid (062)

[0468]

[0469] first step:

[0470] (4-(methanesulfonyl)phenyl)methylamine (25 mmol) and (tert-butyloxycarbonyl)-L-glutamine (25 mmol) were dissolved in N,N-dimethylformamide (120 mL), followed by the addition of N,N-diisopropylethylamine (50 mmol). The mixture was stirred at room temperature for 3 minutes, and then HATU (26 mmol) was added in portions at 10 °C. After the addition was complete, the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water (500 mL) and extracted with EA (150 mL × 3). The extract was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was obtained by column chromatography to yield product 062-1: (S)-(5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-oxopentan-2-yl)carbamate tert-butyl ester. LC-MS: (ESI) [M+H] + =414.

[0471] Step Two:

[0472] 4.5 mmol of 062-1 was dissolved in 50 mL of DCM, and a 10 mL (40 mmol) solution of 1,4-dioxane in hydrochloric acid was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours, concentrated, evaporated, and the residue was dried under vacuum to give the deBoc product 062-2: (S)-2-amino-N1-(4-(methanesulfonyl)benzyl)glutaramide. LC-MS: (ESI) [M+H] + =314.

[0473] Step 3:

[0474] Dissolve 062-2 (2 mmol) and intermediate 6 (2.4 mmol) in N,N-dimethylformamide (20 mL), then add N,N-diisopropylethylamine (6 mmol), stir at room temperature for 3 minutes, and then add HATU (2.2 mmol) in portions at 10 °C. After the reaction solution is completely added, bring the temperature to room temperature and stir for 18 hours. The reaction solution was poured into water (50 mL), extracted with EA (20 mL × 3), and the extract was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to crude column chromatography (EA:MeOH = 20:1, v / v) to give product 062-3: (5S,8S,10aR)-8-((5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentan-2-yl)carbamoyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrole[1,2-a][1,5]diazacyclooct-3(4H)-carboxylic acid benzyl ester. LC-MS: (ESI) [M+H] + =757.

[0475] Step 4:

[0476] 062-3 (3 mmol) was dissolved in DCM (30 mL), and a solution of 1,4-dioxane in hydrochloric acid (6.7 mL, 26.7 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours, concentrated and evaporated, and the residue was dried under vacuum to give the deBoc product 062-4: (5S,8S,10aR)-5-amino-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentane-2-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-3(4H)-carboxylic acid benzyl ester. LC-MS: (ESI) [M+H] + =657.

[0477] Step 5:

[0478] Dissolve 062-4 (5 mmol) and intermediate 9 (5 mmol) in N,N-dimethylformamide (25 mL), then add N,N-diisopropylethylamine (10 mmol) and T3P (5.2 mmol) (1-propyl phosphate cyclic anhydride T3P). After the reaction solution is added, stir at room temperature for 18 hours. The reaction solution was poured into water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was subjected to column chromatography to obtain the corresponding product 062-5: (5S, 8S, 10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentane-2-yl)carbamoyl)-5-(5-(((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-formylamino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-3(4H)-carboxylic acid benzyl ester. LC-MS: (ESI) [M+H] + =1003.

[0479] Step 6:

[0480] 062-5 (2 mmol) was dissolved in THF, and 200 mg of Pd / C was added. After three purgings with hydrogen, the mixture was refluxed under a hydrogen atmosphere for 6 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth to remove Pd / C. The reaction solution was concentrated to obtain the de-Cbz crude product 062-6: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentane-2-yl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)diethyl phosphate, which was directly added to the next step of the reaction. LC-MS: (ESI) [M+H] + =869.

[0481] Step 7:

[0482] Dissolve 062-6 (1 mmol) and intermediate 8 (1 mmol) in N,N-dimethylformamide (15 mL), then add N,N-diisopropylethylamine (2 mmol) and T3P (1.05 mmol), and stir at room temperature for 15 hours after the reaction solution is added. The reaction solution was poured into water and extracted with EA. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was then subjected to column chromatography to obtain the corresponding product 062-7: ((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-((4-(methanesulfonyl)benzyl)amino)-1,5-dioxopentane-2-yl)carbamoyl)-3-(7-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-2-yl)hept-6-ynyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazacyclooct-5-yl)carbamoyl)benzo[b]thiophene-5-yl)difluoromethyl)diethyl phosphate. LC-MS: (ESI) [M+H] + =1208.

[0483] Step 8:

[0484] 062-7 (0.15 mmol) was dissolved in DCM (6 mL) and cooled to 0 °C. BSTFA (0.15 mmol) and TMS-I (1.5 mmol) were then added dropwise under nitrogen protection. After the addition was complete, the reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was evaporated to dryness at low temperature, filtered, and the HPLC yielded compound 062. LC-MS: (ESI)[M+H] + =1152.

[0485] Following the synthetic method of compound 062 in Example 057, the following molecules were synthesized.

[0486]

[0487]

[0488]

[0489]

[0490]

[0491] Example 092 STAT3 Degradation Activity Test

[0492] MOLM16 cells were seeded at 500,000–1,000,000 per well in 6-well plates. Compounds were diluted to different concentrations and added to the plates. After incubation for 16 hours, cells were harvested. After cell lysis, the total protein concentration in each well was determined using a BCA assay kit. STAT3 levels were determined using Western blot or ELISA. Degradation curves were plotted based on protein content at different drug concentrations, and dendritic ratio (DC) was calculated. 50 .

[0493] Table 1. Degradation activity of the compounds of the present invention against STAT3.

[0494] serial number <![CDATA[DC 50 ]]> serial number <![CDATA[DC 50 ]]> serial number <![CDATA[DC 50 <!-- 69 -->]]> 001 A 002 A 003 A 004 A 005 A 006 A 008 A 010 A 011 A 012 A 013 A 014 A 015 A 016 A 017 A 018 A 021 A 026 A 028 A 029 A 030 A 031 A 032 A 034 A 035 A 038 A 039 A 040 A 041 A 044 A 045 A 046 A 047 A 048 A 049 A 050 A 051 A 052 A 053 A 058 A 060 A 061 A 063 A 083 A 087 A 099 A 100 A 101 A 103 A 104 A 105 A 107 A 110 A 112 A 113 A 114 A 115 A 116 A 117 A 119 A 120 A

[0495] A:IC 50 <30nM; B:IC 50 >30nM

[0496] As shown in Table 1, the compounds of the present invention exhibit significant STAT3 degradation activity against STAT3 compounds.

[0497] Example 093 Tumor cell proliferation inhibition activity

[0498] The antitumor efficacy of the compound was assessed by determining its inhibitory effect on the proliferation of Karpas299 cells. Karpas299 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Cells were seeded at a concentration of 4000 Karpas299 cells / well in 96-well plates and incubated overnight at 37°C with 5% CO2. Different concentrations (1000 nM, 4-fold dilution, 8 spots) of the compound were added to the 96-well plates and incubated at 37°C with 5% CO2 for 96 hours. After incubation, 10 μL of CCK8 was added to each well. After 2 hours of incubation, the absorbance at 450 nm was measured using a microplate reader. The IC50 was calculated using GraphPad Prism 5.0. 50 .

[0499] Table 2. Inhibitory activity of the compounds of the present invention against the proliferation of Karpas299 cells.

[0500]

[0501]

[0502] As shown in Table 2, the compounds of this invention have a significant inhibitory effect on the proliferation of Karpas299 cells.

[0503] Example 094: Drug exposure ratio in plasma and tumor tissue

[0504] MOLM16 cells in logarithmic growth phase were collected, and a 1:1 mixture of cells and Matrigel was applied to the right axilla of SCID mice at a seeding density of 5 × 10⁶ cells / mL. 6 One mouse per mouse was used to establish a tumor-bearing mouse model. The tumors were allowed to grow to 300-400 mm. 3 Subsequently, mice were divided into groups and administered the drug at a dose of 10 mg / kg via tail vein injection. Blood and tumor samples were collected at corresponding time points: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours, with three mice at each time point. Plasma and tumor drug concentrations were detected by LC-MS / MS. Drug-time curves were plotted, and the AUC of the drug in plasma and tumor was calculated.

[0505] Table 3. Exposure levels of the compounds of the present invention in tumor tissues and plasma.

[0506] Compound numbering AUC of tumor tissue / AUC of plasma (fold) 001 >0.5 034 >0.5 048 >0.5 107 >0.5

[0507] As shown in Table 3, the compounds of the present invention have a high exposure level in tumor tissues, which can reduce the drug dosage and have better safety.

Claims

1. A compound, characterized in that, one or more selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition, characterized by, including one or more of the compounds of claim 1.

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