Covalent targeting of E3 ligases

Abstract

In particular, compositions and methods for targeting E3 ligases are disclosed herein. In one aspect, a target protein degrader comprises 1) a target protein binder and 2) an E3 ubiquitin ligase binder, wherein the E3 ubiquitin ligase is human RNF4 or human RNF114. In one aspect, a pharmaceutical composition is provided comprising a compound as described herein, comprising an embodiment, and a pharmaceutically acceptable excipient.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 743,337, filed on October 9, 2018, which is incorporated herein by reference in its entirety for all purposes.

[0003] Reference to a "Sequence Listing", table or computer program listing appendix submitted as an ASCII file

[0004] The sequence listing written in the file 052103-517001WO_Sequence_Listing_ST25.txt, created on October 4, 2019, with 18,670 bytes, machine format IBM-PC, and using MSWindows operating system, is incorporated herein by reference. Background Art

[0005] Target protein degradation has become a powerful strategy for treating diseases. This method uses a bifunctional degradation agent, which is composed of a protein targeting ligand connected to an E3 ligase recruiting agent, which brings the E3 ligase to specific protein substrates, thereby ubiquitinating and degrading these substrates in a proteasome-dependent manner. However, a challenge faced by this method is that there are relatively few E3 ligase recruiting agents currently available for target protein degradation applications. This article particularly describes solutions to these and other problems in the art. Summary of the invention

[0006] In one aspect is a target protein degrader comprising 1) a target protein binder and 2) an E3 ubiquitin ligase binder, wherein the E3 ubiquitin ligase is human RNF4 or human RNF114.

[0007] In one aspect, a pharmaceutical composition is provided, comprising a compound as described herein, including the Examples, and a pharmaceutically acceptable excipient.

[0008] In one aspect, a method of reducing (eg, reducing relative to a control) the level of a cellular protein is provided, the method comprising contacting the cellular protein with a target protein degrading agent. In embodiments, the target protein degrading agent is a compound described herein.

[0009] In one aspect, a method of treating cancer is provided, the method comprising contacting a cellular protein associated with the cancer with a target protein degrading agent (eg, a compound described herein).

[0010] In one aspect, a method of treating cancer is provided, the method comprising administering to a subject in need thereof a therapeutically effective amount of a target protein degrader as described herein, including the embodiments.

[0011] In one aspect, a method for reducing cellular protein levels is provided, the method comprising contacting the cellular protein with a target protein degrader, and thereby forming a target protein degrader-cellular protein complex; wherein the target protein degrader comprises: (i) a monovalent E3 ubiquitin ligase binder; (ii) a monovalent target protein binder; and (iii) a binder linker directly bonded to the monovalent E3 ubiquitin ligase binder and the target protein binder.

[0012] In one aspect, a method for identifying a cellular protein contacted by a target protein binding agent is provided, the method comprising: (A) contacting a first sample of a cellular proteome or cell with the target protein binding agent, thereby forming a cellular protein-target protein binding agent complex; (B) contacting the resulting first sample of the cellular proteome or cell of step A and a second sample of the cellular proteome or cell that has not been contacted with the target protein binding agent with a compound having the formula: (C) contacting the first sample obtained in step B with a first detectable agent, and contacting the second sample obtained in step B with a second detectable agent; (D) measuring the levels of the first detectable agent and the second detectable agent bound to a selected protein; and (E) identifying the cellular protein in the cellular protein-target protein binding agent complex by measuring the difference between the levels of the first detectable agent and the second detectable agent, wherein the first detectable agent and the second detectable agent each bind to the cellular protein capable of forming the cellular protein-target protein binding agent complex.

[0013] In one aspect is a method of preparing an E3 ubiquitin ligase-E3 ubiquitin ligase binder-cellular protein complex, the method comprising: (A) contacting the E3 ubiquitin ligase with an E3 ubiquitin ligase binder, thereby forming an E3 ubiquitin ligase-E3 ubiquitin ligase binder complex; and (B) contacting the E3 ubiquitin ligase-E3 ubiquitin ligase binder complex with the cellular protein, thereby forming the E3 ubiquitin ligase-E3 ubiquitin ligase binder-cellular protein complex.

[0014] In one aspect, a method for preparing a cellular protein-E3 ubiquitin ligase binder-E3 ubiquitin ligase complex is provided, the method comprising: (A) contacting the cellular protein with an E3 ubiquitin ligase binder, thereby forming a cellular protein-E3 ubiquitin ligase binder complex; and (B) contacting the cellular protein-E3 ubiquitin ligase binder complex with the E3 ubiquitin ligase, thereby forming a cellular protein-E3 ubiquitin ligase binder-E3 ubiquitin ligase complex.

[0015] In one aspect, a method of inhibiting the formation of a cellular protein-E3 ubiquitin ligase complex is provided, the method comprising contacting the E3 ubiquitin ligase with an E3 ubiquitin ligase binding agent, and thereby inhibiting the formation of the cellular protein-E3 ubiquitin ligase complex. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figures 1A-1E . Screening of covalent ligands for RNF4 using gel-based ABPP. Figure 1A ) Gel-based ABPP labeling of E3 ligases MDM2, RNF4, and UBE3A. Pure proteins were labeled with IA-rhodamine for 30 minutes at room temperature, followed by SDS / PAGE and visualization by in-gel fluorescence. Figure 1B ) Schematic diagram of gel-based ABPP screening of IA-rhodamine-labeled covalent ligands (50 μM) against pure RNF4, looking for compounds that inhibit probe labeling, resulting in loss of fluorescence. Figure 1C-1D ) Gel-based ABPP screening of IA-rhodamine-labeled cysteine-reactive covalent ligands against RNF4. Covalent ligands were pre-incubated with pure RNF4 protein for 30 minutes, followed by IA-rhodamine labeling (250 nM) for 1 hour. Proteins were subjected to SDS / PAGE and visualized by in-gel fluorescence. Potential hits from this screen are highlighted. ( Figure 1E )like( Figure 1C-1D ) Structural and gel-based ABPP confirmation of reproducible RNF4 screening hits performed as described in . The gel was also silver stained.

[0017] Figures 2A-2C TRH 1-23 interacts nonfunctionally with the zinc-coordinating cysteine ​​in RNF4. Figure 2A)LC-MS / MS analysis of TRH 1-23 covalent adducts on RNF4. RNF4 was incubated with TRH 1-23 (50 μM) for 30 minutes at room temperature. RNF4 was digested with trypsin, and the tryptic digest was analyzed by LC-MS / MS and searched for adducts modified with TRH 1-23. MS / MS spectra of C132 and C135 RNF4 tryptic peptides modified with TRH1-23 are shown. The modified cysteine ​​is highlighted in the peptide sequence. The peptide sequence corresponds to residues 118-147 of SEQ ID NO: 1. ( Figure 2B ) Schematic diagram of the reactivity of TRH 1-23 with C132 or C135 of RNF4. ( Figure 2C )TRH 1-23 does not inhibit RNF4 autoubiquitination assay. RNF4 was pre-incubated with TRH 1-23 (100 μM) and then UBA1, E2 enzyme and ATP were added at 37°C for 40 minutes. The reaction was quenched and subjected to SDS / PAGE and Western blotting analysis for RNF4. ( Figure 2C ) The gel shown is a representative gel of n=3.

[0018] Figures 3A-3C Optimization of RNF4 covalent ligands using gel-based ABPP. Figure 3A-3B ) Analogs of TRH 1-23 were tested against IA-rhodamine labeling of RNF4 using gel-based ABPP. Figure 3C ) CCW16 was tested for IA-rhodamine labeling of RNF4 using gel-based ABPP. Figures 3A-3C ), the covalent ligand was preincubated with the pure RNF4 protein for 30 min, followed by IA-rhodamine labeling for 1 h. The proteins were subjected to SDS / PAGE and visualized by in-gel fluorescence. Figure 3C ) and the gel was quantified by optical density to calculate the IC50 value. Figure 3C ) The gel shown is a representative gel of n=3.

[0019] Figures 4A-4F .BRD4 degraders based on RNF4 recruiters. Figure 4A )Structure of CCW 28-3, a RNF4 recruiter-based degrader linked to the BRD4 inhibitor JQ1. Figure 4B) Gel-based ABPP analysis of CCW 28-3 against pure human RNF4. CCW 28-3 was pre-incubated with pure RNF4 protein for 30 minutes and then labeled with IA-rhodamine for 1 hour. The proteins were subjected to SDS / PAGE and visualized by in-gel fluorescence. The gel was quantified by optical density to calculate the IC50 value. ( Figure 4C ) CCW 28-3 treatment in 231MFP breast cancer cells causes BRD4 degradation. 231MFP breast cancer cells were treated with vehicle DMSO or CCW 28-3 for 3 hours. Proteins were subjected to SDS / PAGE and Western blot analysis for BRD4 and GAPDH loading controls. ( Figure 4D , 4E) CCW 28-3 treatment in 231MFP breast cancer cells causes proteasome-, E1 inhibitor-, and BRD4 inhibitor-dependent BRD4 degradation. The vehicle DMSO or proteasome inhibitor bortezomib (BTZ) (10 μM), E1 inhibitor TAK-243 (10 μM), or BRD4 inhibitor JQ1 (10 μM) were preincubated for 30 minutes and then treated with MZ1 (1 μM) or CCW 28-3 (1 μM) for 3 hours. Proteins were subjected to SDS / PAGE and Western blot analysis for BRD4 and actin loading controls. ( Figure 4F )RNF4 wild-type and knockout Hela cells were treated with CCW 28-3 (10 μM) for 5 h and subjected to SDS / PAGE and Western blot analysis for BRD4, RNF4, and GAPDH. Figures 4B-4F ) in the imprint. Figures 4B-4F Data in (A) are from representative gels of n=3. Bar graphs are mean±sem, n=3-5 / group. Significance is indicated as: *p<0.05 compared to vehicle-treated controls; and *p<0.05 compared to CCW 28-3-treated groups in (B, DE) and ( Figure 4F ) compared with wild-type cells treated with CCW 28-3, #p<0.05.

[0020] Figure 5.Additional hits for RNF4 and a general assessment of the proteome-wide selectivity of RNF4 hits by gel-based ABPP. Gel-based ABPP analysis of DKM 2-76 and TRH 1-74, IA-rhodamine labeling for RNF4. The covalent ligand was pre-incubated with pure RNF4 protein for 30 minutes, followed by IA-rhodamine labeling (250nM) for 1 hour. The proteins were subjected to SDS / PAGE and visualized by intra-gel fluorescence. Gel-based ABPP screening of RNF4 hits YP 1-44 and TRH 1-23, IA-rhodamine labeling in the 231MFP breast cancer cell proteome. YP 1-44 and TRH 1-23 were pre-incubated with the proteome for 30 minutes, followed by IA-rhodamine labeling (250nM) for 1 hour. The proteins were subjected to SDS / PAGE and visualized by intra-gel fluorescence.

[0021] Figure 6 . isoTOP-ABPP analysis of CCW 28-3 in 231MFP breast cancer cells in situ. 231MFP cells were treated with DMSO vehicle or CCW 28-3 (10 μM) in situ for 1 hour, and then the proteome was labeled in vitro with IA-alkyne (100 μM) for 1 hour. Isotopic light (for DMSO treatment) or heavy (for compound treatment) TEV protease-cleavable biotin-azide tags were attached by CuAAC for isoTOP-ABPP analysis. Data are for three biological replicates.

[0022] Figure 7 CCW 28-3 was tested at lower concentrations in RNF4 wild-type and knockout Hela cells. RNF4 wild-type and knockout Hela cells were treated with DMSO vehicle or CCW 28-3 (5 or 1 μM) for 5 hours and subjected to SDS / PAGE and western blot analysis for BRD4 and GAPDH. Blots were quantified by densitometry. Data are from a representative gel of n=3. Bar graphs are mean ± sem, n = 3 / group. Significance is indicated as: *p < 0.05 compared to vehicle-treated controls; and #p < 0.05 compared to wild-type cells treated with CCW 28-3.

[0023] Figures 8A-8C . Nimbolide may impair the proliferation or survival of breast cancer cells. Fig. 8A ) Structure of azadirachtin. Azadirachtin has a cyclic enone that may react with cysteine. ( Figures 8B-8C) Proliferation of 231MFP and HCC38 breast cancer cells in serum-containing medium and cell survival in serum-free medium. Cells were treated with DMSO vehicle or azadirachtin and cell viability was assessed by Hoechst staining after 48 hours. Figures 8B-8C ) The data shown are mean ± sem, n = 6 / group. Significance is indicated as *p < 0.05 compared with vehicle-treated controls.

[0024] Figures 9A-9E .isoTOP-ABPP analysis of azadirachtin in the proteome of 231MFP breast cancer cells revealed RNF114 as a target. ( Fig. 9A ) Schematic diagram of isoTOP-ABPP, in which the 231MFP breast cancer cell proteome or cells were pretreated with DMSO or azadirachtin (10 μM, 30 min in vitro or 1.5 h in situ), and then the proteome was labeled in vitro with IA-alkyne (100 μM, 1 h), followed by the attachment of isotopically light (for DMSO treatment) or heavy (for azadirachtin treatment) TEV protease-cleavable biotin-azide tags by copper-catalyzed azide-alkyne cycloaddition (CuAAC). The control and treated proteomes were then combined in a 1:1 ratio, probe-labeled proteins were enriched with avidin, digested with trypsin, and probe-modified tryptic peptides were eluted by TEV protease, analyzed by LC-MS / MS, and the light to heavy probe-modified peptide ratio was quantified. ( Fig. 9B )like( Fig. 9A isoTOP-ABPP analysis of azadirachtin (10 μM) in the proteome of 231MFP breast cancer cells in vitro as described in (Fig. 2A). Three targets showing a light / heavy ratio > 5 included C308 of PTOV1, C8 of RNF114, and C123 of PFKP. Fig. 9C )like( Fig. 9A ) in situ analysis of azadirachtin (10 μM) in 231MFP breast cancer cells using isoTOP-ABPP analysis as described in ( Fig.9D ) RNF114 was stably knocked down in 231MFP cells using short hairpin RNA oligonucleotides. RNF114 knockdown in shRNF114 cells was confirmed by qPCR compared with shControl cells. Cell proliferation was assessed by Hoechst staining 48 hours after seeding the cells. ( Fig.9E)Sensitivity of 231MFP shControl and shRNF114 to azadirachtin. 231MFP shControl and shRNF114 cells were treated with DMSO vehicle or azadirachtin and cell proliferation was assessed by Hoechst staining after 48 hours. The percentage of proliferation with azadirachtin was normalized to the respective shControl or shRNF114 control group. ( Figures 9D-9E The data shown in ) are mean ± sem. Figure 9B-9E The data shown in ) are from n = 6 individuals / group. Fig.9D , 9E) The significance is indicated as *p<0.05 compared with the shControl group.

[0025] Figures 10A-10E .Azadirachtin covalently reacts with C8 of RNF114. ( Fig. 10A ) Azadirachtin targets an intrinsically disordered region within RNF114 as assessed by PONDR. Fig. 10B ) A route for the synthesis of alkyne-functionalized azadirachtin probes. Fig. 10C ) Azadirachtin probe labeling of the 231MFP breast cancer cell proteome. The 231MFP proteome was preincubated with DMSO or azadirachtin (10 μM, 30 min) and then labeled with the azadirachtin-alkyne probe (1 μM, 1 h), followed by rhodamine-azide attachment by CuAAC, SDS / PAGE, and in-gel fluorescence analysis. The bands that compete with azadirachtin correspond to the molecular weights of PTOV1 and RNF114. ( Fig. 10D ) Gel-based ABPP analysis of pure human RNF114 protein labeled with azadirachtin probe. In the top two panels, pure RNF114 protein was preincubated with DMSO vehicle or azadirachtin (100 μM, 30 minutes) and then labeled with azadirachtin probe (10 μM, 1 hour) in PBS. In the bottom two panels, pure wild-type and C8A mutant RNF114 proteins were labeled with azadirachtin probe (10 μM, 1 hour) in PBS containing 1 mg / ml BSA. For both experiments, ribonucleotide-alkyne labeling and silver staining of RNF114 are shown. ( Fig. 10E ) Pure RNF114 protein was labeled with azadirachtin (100 μM, 1 hour) and subjected to trypsin digestion and LC-MS / MS analysis. The azadirachtin-modified adduct on C8 of RNF114 is shown. The peptide sequence corresponds to residues 7-26 of SEQ ID NO: 2. ( Figures 10C-10D The data shown in ) are from n=3 individuals / group.

[0026] Figures 11A-11D .Azadirachtin inhibits RNF114 activity by disrupting substrate recognition. Fig.11A ) RNF114 ubiquitination assay using pure GST-Ube1, GST-UBE2D1, and RNF114 proteins, Flag-ubiquitin, and ATP in the presence or absence of p21, and western blot analysis against Flag-ubiquitin (left) or p21 (right). DMSO or azadirachtin (100 μM) was preincubated with RNF114, followed by the addition of E1 and E2 enzymes, Flag-ubiquitin, and ATP to initiate the reaction. Fig. 11B ) RNF114 autoubiquitination assay using DMSO or azadirachtin (100 μM) treatment of wild-type or C8A mutant RNF114. Fig. 11C ) In in vitro incubation of pure RNF114 and p21 proteins, pull-down of Flag-RNF114 and enrichment of p21 were inhibited by azadirachtin (100 μM). D) 231MFP cells were treated with azadirachtin (100 μM). p21 levels in DMSO control or azadirachtin-treated cells are shown. ( Figures 11A-11D The gel shown in ) is a representative image from n = 3 / group. Fig. 11C The data shown in ) are mean ± sem. Fig. 11C The data shown in ) are from n = 3 individuals / group. Fig. 11C ) is expressed as the same as ( Fig. 11C ) compared with the p21 / RNF114 group, or for ( Fig.11D ) compared to the vehicle-treated control group at each time point, *p<0.05.

[0027] Figures 12A-12G .Azadirachtin can be used to recruit RNF114 for BRD4 target protein degradation. Fig. 12A ) Pathways for the synthesis of XH1 and XH2, which are azadirachtin-based degraders consisting of azadirachtin as an RNF114 recruiter, a linker, and the BRD4 inhibitor JQ1. ( Fig. 12B , 12C) in XH1( Fig. 12B ) or XH2( Fig. 12C BRD4 levels in 231MFP breast cancer cells pretreated with DMSO vehicle or the proteasome inhibitor bortezomib (BTZ) (1 μM) 30 minutes before and during treatment with the treatment agent (100 nM) for 12 hours. Fig.12D ) BRD4 levels in 231MFP breast cancer cells treated with MZ1 versus XH2 for 12 hours. ( Figures 12E-12G) were treated with DMSO vehicle or E3 ligase inhibitors TAK-243 (10 μM) (E), JQ1 (1 μM) (F), or emetine (75 μM) ( Figure 12G ) BRD4 levels in 231MFP breast cancer cells pretreated for 30 minutes. Long and short BRD4 isoforms and GAPDH loading control were visualized by SDS / PAGE and Western blot analysis and quantified by densitometry ( Figures 12B-12G ). The gels shown in (BG) are representative images from n=3 / group. The data shown in (B, C, EG) are mean ± sem. Fig. 12B , 12C, 12E-12G) are indicated as: *p<0.05 compared with the vehicle-treated control group; and #p<0.05 compared with the XH2-treated group.

[0028] Figures 13A-13F .Chemoproteomics-enabled covalent ligand screening for the identification of more synthetically tractable covalent ligands targeting RNF114. Fig.13A ) Gel-based ABPP analysis of pure RNF114 protein competing with IA-alkyne (10 μM) or JNS27 (50 μM)-labeled azadirachtin. The structures of the IA-alkyne and JNS27 probes highlight the reactive parts in red. Gel-based ABPP analysis of wild-type and C8A mutant RNF114 proteins competing with JNS27-labeled azadirachtin (50 μM) is also shown. In these experiments, DMSO or azadirachtin was pre-incubated for 30 min before probe labeling for 1 h. ( Fig. 13B )EN62 was one of the top hits when screening a library of JNS27-tagged cysteine-reactive covalent ligands against RNF114. The structure of EN62 is shown with the acrylamide-reactive moiety highlighted in red. Gel-based ABPP analysis of JNS27-tagged EN62 against pure RNF114 is also shown. Fig. 13C ) RNF114 autoubiquitination assay using DMSO or EN62 (50 μM) treated wild-type or C8A mutant RNF114. Fig.13D ) In vitro IsoTOP-ABPP analysis of EN62 in the 231MFP breast cancer cell proteome. DMSO or EN62 (50 μM) was pre-incubated with the 231MFP proteome for 30 min, followed by IA-alkyne labeling (100 μM) for 1 h and then the isoTOP-ABPP method. Fig.13E ) Hoechst staining was used to assess 231MFP cell survival against EN62 after 48 hours. Fig.13F) Growth of 231MFP tumor xenografts in CB-17 female SCID mice treated with vehicle (18:1:1 saline:PEG40:ethanol) or EN62 (50 mg / kg ip, once daily, starting 17 days after s.c. injection of 231MFP cells). Figures 13A-13C The gel shown in ) is a representative image from n = 3 / group. Fig.13D The data shown in 13F) are mean ± sem, n = 3-8 / group. Figures 13E-13F ) are represented by *p<0.05 compared with vehicle-treated controls.

[0029] Fig.14 .Knockdown of PTOV1 and PFKP in 231MFP breast cancer cells. Stable knockdown of PTOV1 and PFKP was performed using shRNA oligonucleotides and expression was confirmed by qPCR. GFP targeting shRNA oligonucleotides was used in 231MFP shControl cells. Proliferation of 231MFP shControl, shPFKP, and shPTOV1 cells was assessed after 48 hours by Hoechst staining. Data shown are mean ± sem, n = 6 / group. Significance is indicated as *p < 0.05 compared to shControl cells.

[0030] Fig.15 p53 levels in 231MFP breast cancer cells treated with azadirachtin. p53 levels in 231MFP breast cancer cells treated with DMSO vehicle or azadirachtin (100 μM) were assessed by Western blot analysis and GAPDH levels as loading control. Gels represent n=3 / group. Blots were quantified by densitometry and normalized to loading control. Data shown in bar graphs are mean ± sem.

[0031] Figures 16A-16C .Gel-based ABPP screening of cysteine-reactive ligands against RNF114. Cysteine-reactive covalent ligands were screened against JNS27 labeling of pure human RNF114 protein. Covalent ligands (50 μM) were preincubated with RNF114 for 30 minutes and then labeled with JNS27 for 1 hour. Rhodamine-azide was then attached to the probe-labeled protein by CuAAC. Proteins were isolated by SDS / PAGE and visualized by in-gel fluorescence. Those proteins that showed inhibition of probe labeling were retested in the following dose-response study to identify hits that could reproducibly inhibit JNS27 labeling of RNF114.

[0032] Figures 17A-17C .Azadirachtin may impair the proliferation or survival of breast cancer cells. ( Figures 17A-17B )231MFP breast cancer cell proliferation in serum-containing medium ( Fig.17A ) and serum-free cell survival ( Fig. 17B ). Figures 17A-17B The data shown in are mean ± sem, n = 6 biologically independent samples / group. ( Fig. 17C ) Percentage of propidium iodide and Annexin-V-positive (PI+ / Annexin-V+) cells assessed by flow cytometry after treatment of 231MFP cells with DMSO vehicle or azadirachtin for 24 or 48 hours. Representative FACS data from n=3 biologically independent samples / group are shown. Fig.18D Quantification of the percentage of late apoptotic cells, defined as FITC+ / PI+ cells, is shown in FIG. Statistical significance was calculated using an unpaired two-tailed Student's t-test. Significance is expressed as a difference in the percentage of late apoptotic cells compared to vehicle-treated controls. Fig.17A For 100 and 10 μM, respectively, *p=7.75x10 -14 and 1.14x10 -13 ;exist Fig. 17B For 100 and 10 μM, respectively, *p = 3.88x10 -8 and 1.53x10 -7 .

[0033] Figures 18A-18E .Azadirachtin impairs the proliferation and survival of breast cancer cells and induces apoptosis. ( Figures 18A-18B ) Proliferation of HCC38 breast cancer cells in serum-containing medium ( Fig.18A ) and serum-free cell survival ( Fig.18B ). Cells were treated with DMSO vehicle or azadirachtin and cell viability was assessed 48 hours later. ( Fig. 18C ) shows the gating strategy used for flow cytometry data. Two gating steps were used - the first was gating by forward scatter and side scatter. The second gate was based on separation into quadrants by cell death dye (PI / Annexin). ( Figures 18D-18E ) In the treatment of 231MFP ( Fig.18D ) and HCC38( Fig.18E ) cells 24 or 48 h later, the percentage of propidium iodide and Annexin-V-positive (PI+ / Annexin-V+) cells was assessed by flow cytometry. Fig.18D Representative FACS data of 231MFP cells are shown in Fig. 17C , while data from HCC38 cells are shown in ( Fig.18E ) on the left side of the image. Figures 18D-18EThe bars in the graph are the percentages of late apoptotic cells defined as PI+ / Annexin-V+ cells. Figures 18A-18B and Figures 18D-18E The data shown are mean ± s.e.m. Figures 18A-18B In , n = 6 biologically independent samples / group, and in Figures 18D-18E n = 3 biologically independent samples / group. Statistical significance was calculated using an unpaired two-tailed Student's t-test. Significance is expressed as the difference between the control group treated with vehicle and the control group treated with vehicle. Fig.18A For 100 and 10 μM, respectively, *p = 1.64x10 -13 and 2.05x10 -13 ;exist Fig.18B For 100 and 10 μM, respectively, *p = 2.09x10 -11 and 7.07x10 -12 ;exist Fig.18D For 24 h data, *p = 9.05 x 10 for 10 and 100 μM, respectively -5 and 1.87x10 -5 ;exist Fig.18E For the 48-hour data, *p=0.00139, 0.000142 and 7.97x10 for 1, 10 and 100 μM, respectively. -9 ;exist Fig.18E For the 24-hour data, *p=0.00424, 0.0182 and 2.22x10 for 1, 10 and 100 μM, respectively. -11 ; and Fig.18E For the 48-hour data, *p=6.68x10 -6 ,4.70x10 -7 and 9.00x10 -11 .

[0034] Figures 19A-19D .isoTOP-ABPP analysis of azadirachtin in the proteome of 231MFP breast cancer cells revealed RNF114 as a target. ( Fig.19A )like Fig.19A isoTOP-ABPP analysis of azadirachtin (10 μM) in 231MFP breast cancer cells as described in the in situ analysis. The left panel shows the ratio of light to heavy isotope probe modified peptides, where the main target with the highest ratio is C8 of RNF114. The right panel shows representative MS1 light and heavy peaks of probe modified peptides with C8 of RNF114. ( Fig.19B) RNF114 knockdown by short interfering RNA (siRNA) targeting RNF114 was confirmed by Western blot analysis of RNF114 compared to siControl231MFP cells. GAPDH expression is shown as a loading control. The gel shown is a representative gel from n=3 biological replicates / group. ( Fig.19C )231MFP cell proliferation after 24 hours in siControl and siRNF114 cells. ( Fig.19D ) Effect of azadirachtin on 231MFP siControl and siRNF114 231MFP breast cancer cells Effect of azadirachtin on 231MFP siControl and siRNF114 231MFP breast cancer cells. Cells were treated with DMSO vehicle or azadirachtin for 24 hours and then proliferation was assessed. Data for siControl or siRNF114 groups were normalized relative to the corresponding DMSO vehicle control in each group. Individual biological independent sample data are shown, and lines represent mean values. Fig.19C The data shown are mean ± sem. Figures 19A-19B The data shown in are from n = 3 biologically independent samples / groups, while Figures 18D-18E Data were obtained from n = 5 biologically independent samples / group. Unpaired two-tailed Student's t-test was used to calculate Figures 18D-18E Statistical significance in . Fig.18D Significance is indicated as compared with siControl cells, *p = 4.52x10 -5 . Fig.18E The significance is expressed as compared to the corresponding azadirachtin treatment concentration in the siControl group, *p = 1.90x10 for 10, 6 and 3 μM, respectively. -5 , 2.72x10 -4 and 0.00101.

[0035] Figures 20A-20D . Elucidate the role of RNF114 in the effects mediated by azadirachtin. Fig. 20A ) RNF114 knockdown by 3 independent siRNAs targeting RNF114 was confirmed by Western blot analysis of RNF114 compared to siControl231MFP cells. GAPDH expression is shown as a loading control. ( Fig. 20B )231MFP cell proliferation in siControl and siRNF114 cells after 24 hours as assessed by Hoechst staining. Fig. 20C) Effect of azadirachtin on 231MFP siControl and siRNF114 231MFP breast cancer cells. Cells were treated with DMSO vehicle or azadirachtin for 24 hours and proliferation was assessed by Hoechst staining. Data for each of the siControl or siRNF114 groups were normalized to the corresponding DMSO vehicle control in each group. Individual biologically independent sample data are shown and lines represent mean values. ( Fig.20D ) Gel-based ABPP analysis of IA-rhodamine-labeled azadirachtin, JNS27, and iodoacetamide competition for recombinant human RNF114 protein. RNF114 protein was pretreated with DMSO vehicle or azadirachtin, JNS27, and iodoacetamide for 30 minutes, and then RNF114 was labeled with IA-rhodamine (100nM) for 30 minutes. RNF114 IA-rhodamine labeling was evaluated by SDS / PAGE and in-gel fluorescence. The data shown are from n=1 biological replicates. The data shown are from n=3 biological independent samples / groups. Fig. 20A and Fig.20D Data shown in are representative gels from n = 3 biologically independent samples / group. Fig. 20B The data shown in are mean ± s.e.m. Fig. 20B , n = 5 biologically independent samples / group. Fig. 20B , Fig. 20C Statistical significance was calculated using an unpaired two-tailed Student's t-test. Fig. 20B Significance is indicated as compared to siControl cells, for siRNF114-1, siRNF114-2, and siRNF114-3, *p = 4.52x10 -5 , 0.0429 and 0.00230. Fig. 20C Significance is indicated as compared to the corresponding concentration of azadirachtin treatment in siControl cells. *p = 1.90x10 for 10, 6, and 3 μM for siRNF114-1, respectively. -5 , 0.000272, 0.00101; for siRNF114-2, for 10, 6 and 3 μM, respectively, *p = 0.000626, 0.00139, 3.66x10 -5 ; and for siRNF114-3, *p=0.00134, 9.15x10 for 10, 6, and 3 μM, respectively. -5 , 0.00769. Significance in Figure 20F is indicated as *p=0.0188 compared to vehicle-treated controls.

[0036] Figures 21A-21G .Azadirachtin covalently reacts with C8 of RNF114. ( Fig.21A ) Azadirachtin targets an intrinsically disordered region within RNF114 as assessed by PONDR. Fig.21B ) A route for the synthesis of alkyne-functionalized azadirachtin probes. Fig. 21C ) Gel-based ABPP analysis of pure human RNF114 protein labeled with azadirachtin probe. In the top two panels, pure RNF114 protein was pre-incubated with DMSO vehicle or azadirachtin (100 μM, 30 minutes) and then labeled with azadirachtin probe (10 μM, 1 hour) in PBS. In the bottom two panels, pure wild-type and C8A mutant RNF114 proteins were labeled with azadirachtin probe (10 μM, 1 hour) in PBS containing 1 mg / ml BSA. ( Fig.21D ) Gel-based ABPP analysis of pure RNF114 protein competing with IA-alkyne (10 μM) or JNS27 (50 μM)-labeled azadirachtin. The structures of the IA-alkyne and JNS27 probes highlight the reactive parts in red. Gel-based ABPP analysis of wild-type and C8A mutant RNF114 proteins competing with JNS27-labeled azadirachtin (50 μM) is also shown. In these experiments, DMSO or azadirachtin was pre-incubated for 30 min before probe labeling for 1 h. ( Fig.21E ) Azadirachtin-alkyne labeling of Flag-RNF114 in 231MFP cells. 231MFP cells stably expressing Flag-tagged RNF114 were treated with DMSO vehicle or azadirachtin-alkyne for 2 hours. RNF114 was subsequently enriched from harvested cell lysates, and rhodamine-azide was then attached to the probe-labeled protein by CuAAC, followed by visualization of the azadirachtin-alkyne label by SDS / PAGE and in-gel fluorescence. Fig.21F ) Azadirachtin-alkyne labeling of endogenous RNF114 in 231MFP cells. 231MFP cells were treated with DMSO vehicle or azadirachtin-alkyne (50 μM) for 1.5 hours. Biotin-azide was attached to the probe-labeled proteins by CuAAC, and these proteins were then enriched with avidin. The resulting pull-down proteins were analyzed by SDS / PAGE and Western blot analysis for RNF114. Figures 21C-21F The gel shown in is a representative gel from n=3 biologically independent samples / group.

[0037] Figures 22A-22I .Azadirachtin inhibits RNF114 activity by disrupting substrate recognition. Figures 22A-22B) RNF114 ubiquitination assay using pure GST-Ube1, GST-UBE2D1 and RNF114 proteins, Flag-ubiquitin and ATP in the presence or absence of p21, and for Flag-ubiquitin ( Fig.22A ) or p21( Fig. 22B ) Western blot analysis. Fig. 22C ) RNF114 autoubiquitination assay using DMSO or azadirachtin (100 μM) treatment of wild-type or C8A mutant RNF114. Fig.22D ) In in vitro incubations of pure RNF114 and p21 proteins, pull-down of Flag-RNF114 and enrichment of p21 were inhibited by azadirachtin (100 μM). Fig.22E ) 231MFP cells were treated with azadirachtin (100 μM). p21 levels in DMSO control or azadirachtin-treated cells are shown. ( Fig.22F ) Tandem mass tag (TMT)-based quantitative proteomic profiles of 231MFP breast cancer cells treated with DMSO vehicle or azadirachtin (100 nM) for 12 hours. Proteins with significantly increased levels >2-fold are shown in red. ( Fig.22F The data shown in ) are for 6397 proteins quantified with 2 or more unique peptides in n=3 biologically independent samples / group. ( Figure 22G ) RNF114 ubiquitination assay using pure GST-Ube1, GST-UBE2D1, and RNF114 proteins, Flag-ubiquitin, and ATP in the presence of p21(CDKN1A), PEG10, or CTGF, and western blot analysis for Flag-ubiquitin. DMSO or azadirachtin (100 μM) was preincubated with RNF114, followed by addition of E1 and E2 enzymes, Flag-ubiquitin, and ATP to initiate the reaction. Fig.22H ) Expression of p21 (CDKN1A) and p57 (CDKN1C) in siControl and siCDKN1A / siCDKN1C 231MFP cells assessed by Western blot analysis, with actin as a loading control. ( Fig.22I ) 231MFP cell proliferation in siControl or siCDKN1A / siCDKN1C cells treated with DMSO vehicle or azadirachtin (6 μM) for 24 h. Figures 22A-22E and Figure 22G Data shown in are representative images from n=3 biologically independent samples / groups. Figures 22A-22D Quantification of the blots shown in Figures 23A-23D All three biologically independent samples / groups are shown in Fig.22H middle. Fig.22IThe data shown in are mean ± sem, n = 5 biologically independent samples / group. Fig.22E and Fig.22I Statistical significance was calculated using an unpaired two-tailed Student's t-test. Fig.22E *p=0.000799, 0.0295, 0.00962 and 0.0135 for 1 hour, 2 hours, 4 hours and 8 hours, respectively; Fig.22I Compared with the vehicle-treated siControl and siCDKN1A / siCDKN1C groups, p = 5.65x10 -8 and 0.0173. exist Fig.22I Significance is shown as compared to siControl cells treated with azadirachtin, #p=6.70x10 -5 .

[0038] Figures 23A-23I .Azadirachtin can be used to recruit RNF114 for BRD4 target protein degradation. Fig.23A ) Pathway for the synthesis of XH2, a azadirachtin-based degrader consisting of azadirachtin as an RNF114 recruiter, a linker, and the BRD4 inhibitor JQ1. ( Fig. 23B ) Gel-based ABPP analysis of XH2 against RNF114. RNF114 was pre-incubated with DMSO vehicle or XH2 for 30 minutes, then JNS27 labeling (50 μM) was performed for 1 hour, followed by rhodamine-azide attachment by CuAAC, SDS / PAGE, and in-gel fluorescence analysis. ( Figures 23C-23D )Use XH2( Fig.23C ) vs. MZ1( Fig.23D ) BRD4 expression in 231MFP breast cancer cells treated for 12 hours. Figures 23E-23F ) BRD4 expression in 231MFP breast cancer cells. Cells were treated with DMSO vehicle or the proteasome inhibitor bortezomib (BTZ) (1 μM) ( before or during treatment with MZ1 (1 μM) or XH2 (100 nM) for 12 h. Fig.23E ) or E1 ubiquitin activating enzyme inhibitor TAK-243 (10 μM) ( Fig.23F ) pretreated for 30 minutes. ( FIG24G ) Expression of RNF114 and loading control GAPDH in RNF114 wild-type (WT) and knockout (KO) HAP1 cells. ( Fig.23H) RNF114 and BRD4 expression in RNF114 wild-type (WT) or knockout (KO) HAP1 cells treated with DMSO vehicle, MZ1 (1 μM), or XH2 (100 nM) for 12 h. Fig.23I ) 231MFP breast cancer cells based on tandem mass tag (TMT) quantitative proteomic profiles, the breast cancer cells were treated with DMSO vehicle or XH2 (100nM) for 12 hours. The proteomic profiles were analyzed by SDS / PAGE and Western blot. Figures 23C-23H Long and short BRD4 isoforms were visualized in , quantified by densitometry, and normalized to a GAPDH loading control. Figures 23B-23H The gels shown in are representative images from n = 3 biologically independent samples / groups, and Figures 23C-23F and Fig.23H Quantification of the blots in is shown in Figures 25C-25F and Figure 25I. Fig.23I The data shown in are for 5797 proteins quantified with 2 or more unique peptides in triplicate treatments. Fig.23I Statistical significance in . DETAILED DESCRIPTION

[0039] I. Definitions

[0040] Abbreviations used herein have conventional meanings within the chemical and biological arts.Chemical structures and formulae described herein are constructed according to standard rules of chemical valency known in the chemical arts.

[0041] When substituents are described by a conventional chemical formula written from left to right, the substituents equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH 2 O- is equivalent to -OCH 2 -.

[0042] Unless otherwise indicated, the term "alkyl" by itself or as part of another substituent means a straight (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, monounsaturated, and or polyunsaturated, and may include monovalent, divalent, and polyvalent groups. An alkyl group may contain a specified number of carbons (e.g., C 1 -C 10means one carbon to ten carbons). Alkyl is an uncyclized chain. An unsaturated alkyl is an alkyl with one or more double or triple bonds. Alkoxy is an alkyl group connected to the rest of the molecule by an oxygen linker (-O-). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl group may contain more than one double bond and / or one or more triple bonds in addition to one or more double bonds. An alkynyl group may contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds. Unless otherwise stated, the term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl group. Unless otherwise stated, the term "alkenylene" by itself or as part of another substituent means a divalent radical derived from an alkene group.

[0043] Unless otherwise indicated, the term "heteroalkyl" itself or in combination with another term means a stable straight chain or branched chain or a combination thereof comprising at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si and S), and wherein the nitrogen atom and the sulfur atom may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. One or more heteroatoms (e.g., O, N, S, Si or P) may be placed at any internal position of the heteroalkyl or at the position where the alkyl is connected to the rest of the molecule. Heteroalkyl is an uncyclized chain. The heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si or P). The heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si or P). The heteroalkyl moiety may contain up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). Unless otherwise stated, the term "heteroalkenyl" by itself or in combination with another term means a heteroalkyl group containing at least one double bond. The heteroalkenyl group may optionally contain more than one double bond and / or one or more triple bonds in addition to one or more double bonds. Unless otherwise stated, the term "heteroalkynyl" by itself or in combination with another term means a heteroalkyl group containing at least one triple bond. The heteroalkynyl group may optionally contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds.

[0044] Similarly, unless otherwise indicated, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from a heteroalkylene. For heteroalkylene, heteroatoms may also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. For example, the formula -C(O) 2 R′- represents -C(O) 2 R′- and -R′C(O) 2 -Both. It is understood that when "heteroalkyl" is recited after reciting a specific heteroalkyl group such as -NR'R", the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Instead, the specific heteroalkyl group is recited to increase clarity. Therefore, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups such as -NR'R".

[0045] Unless otherwise stated, the terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, mean cyclic versions of "alkyl" and "heteroalkyl", respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom may occupy the position at which the heterocycle is attached to the rest of the molecule. "Cycloalkylene" and "heterocycloalkylene", alone or as part of another substituent, mean a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively.

[0046] In embodiments, the term "cycloalkyl" means a monocyclic, bicyclic, or polycyclic cycloalkyl ring system. In embodiments, the monocyclic ring system is a cycloalkyl group containing 3 to 8 carbon atoms, wherein such groups may be saturated or unsaturated, but not aromatic. In embodiments, the cycloalkyl group is fully saturated. In embodiments, a bridged monocyclic ring contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge between one carbon atom and three additional carbon atoms (i.e., of the form (CH 2 ) w In an embodiment, the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety via any carbon atom contained within the monocyclic cycloalkyl ring. In an embodiment, the polycyclic cycloalkyl is attached to the parent molecular moiety via any carbon atom contained within the base ring.

[0047] In an embodiment, cycloalkyl is cycloalkenyl. The term "cycloalkenyl" is used according to its common general meaning. In an embodiment, cycloalkenyl is a monocyclic, bicyclic or polycyclic cycloalkenyl ring system. In an embodiment, a monocyclic cycloalkenyl ring system is a cycloalkyl containing 3 to 8 carbon atoms, wherein such a group is unsaturated (i.e., contains at least one annular carbon-carbon double bond), but is not aromatic. In an embodiment, a bicyclic cycloalkenyl ring is a bridged monocyclic or fused bicyclic ring. In an embodiment, a bridged monocyclic ring contains a monocyclic cycloalkenyl ring in which two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge between a carbon atom and three additional carbon atoms (i.e., of the form (CH 2 ) w In an embodiment, the bridged or fused bicyclic cycloalkenyl is connected to the parent molecular moiety through any carbon atom contained in the monocyclic cycloalkenyl ring. In an embodiment, the polycyclic cycloalkenyl is connected to the parent molecular moiety through any carbon atom contained in the base ring.

[0048] In an embodiment, heterocycloalkyl is a heterocyclic radical. As used herein, the term "heterocyclic radical" means monocyclic, bicyclic or polycyclic heterocycles. Heterocyclic radical monocyclic heterocycle is a 3-, 4-, 5-, 6- or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N and S, wherein the ring is saturated and or unsaturated, but not aromatic. 3- or 4-membered rings contain 1 heteroatom selected from the group consisting of O, N and S. 5-membered rings can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. 6- or 7-membered rings contain zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. Heterocyclic radical monocyclic heterocycles are connected to the parent molecular moiety by any carbon atom or any nitrogen atom contained in the heterocyclic radical monocyclic heterocycle. Heterocyclic radical bicyclic heterocycles are connected to the parent molecular moiety by any carbon atom or any nitrogen atom contained in the monocyclic heterocyclic moiety of the bicyclic system. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring.

[0049] Unless otherwise stated, the term "halo" or "halogen", by itself or as part of another substituent, means a fluorine, chlorine, bromine, or iodine atom. In addition, terms such as "haloalkyl" are intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1 -C 4 )alkyl" includes but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

[0050] Unless otherwise indicated, the term "acyl" means -C(O)R, where R is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0051] Unless otherwise indicated, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which can be a monocyclic or fused together (i.e., fused ring aryl) or multiple rings (preferably, 1 to 3 rings) covalently linked. A fused ring aryl refers to multiple rings fused together, wherein at least one ring in the fused ring is an aryl ring. The term "heteroaryl" refers to an aryl (or ring) containing at least one heteroatom (such as N, O or S), wherein nitrogen atoms and sulfur atoms are optionally oxidized, and one or more nitrogen atoms are optionally quaternized. Therefore, the term "heteroaryl" includes fused ring heteroaryls (i.e., multiple rings fused together, wherein at least one ring in the fused ring is a heteroaromatic ring). Heteroaryls can be connected to the rest of the molecule through carbon atoms or heteroatoms. "Arylene" and "heteroarylene", alone or as part of another substituent, mean divalent groups derived from aryl and heteroaryl, respectively. The heteroaryl substituent can be -O- bonded to the ring heteroatom nitrogen.

[0052] Spirocycle is two or more rings in which adjacent rings are connected by a single atom. The single rings in the spirocycle can be the same or different. The single ring in the spirocycle can be substituted or unsubstituted, and can have substituents different from other single rings in the spirocycle set. The possible substituents of the single ring in the spirocycle are possible substituents of the same ring when it is not a part of the spirocycle (for example, substituents of cycloalkyl rings or heterocycloalkyl rings). When referring to a spirocycle system, a heterocyclic spirocycle means a spirocycle in which at least one ring is a heterocycle and each ring can be a different ring. When referring to a spirocycle system, a substituted spirocycle means that at least one ring is substituted and each substituent can be optionally different.

[0053] symbol Indicates the point at which a chemical part is attached to the rest of a molecule or chemical formula.

[0054] As used herein, the term "oxo" means an oxygen doubly bonded to a carbon atom.

[0055] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0056] Substituents for alkyl and heteroalkyl (including those commonly referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R", -SR', -halogen, -SiR'R"R'", -OC(O)R', -C(O)R', -CO 2 R′, -CONR′R″, -OC(O)NR′R″, -NR″C(O)R′, -NR′-C(O)NR″R″′, -NR″C(O) 2 R′, -NR-C(NR′R″R″′)=NR″″, -NR-C(NR′R″)=NR″′, -S(O)R′, -S(O) 2 R', -S(O) 2 NR′R″、-NRSO 2 R′, -NR′NR″R′″, -ONR′R″, -NR′C(O)NR″NR″′R″″, -CN, -NO 2 、-NR′SO 2 R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such groups. R, R', R", R"', and R"" each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy, or aralkyl. When a compound described herein contains more than one R group, each of the R groups is independently selected, for example, as each R' group, R" group, R"' group, and R"" group is independently selected when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they may be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. Based on the above discussion of substituents, one skilled in the art will understand that the term "alkyl" is intended to include groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl groups (e.g., -C(O)CH 3 、-C(O)CF 3 、-C(O)CH 2 OCH 3 wait).

[0057] Similar to the substituents described for alkyl, the substituents for aryl and heteroaryl are varied and are selected, for example, from the following: -OR', -NR'R", -SR', -halogen, -SiR'R"R"', -OC(O)R', -C(O)R', -CO 2 R′, -CONR′R″, -OC(O)NR′R″, -NR″C(O)R′, -NR′-C(O)NR″R″′, -NR″C(O) 2 R′, -NR-C(NR′R″R″′)=NR″″, -NR-C(NR′R″)=NR″″, -S(O)R′, -S(O) 2 R', -S(O) 2 NR′R″、-NRSO 2 R′, -NR′NR″R″′, -ONR′R″, -NR′C(O)NR″NR″′R″″, -CN, -NO 2 , -R′, -N 3 、-CH(Ph) 2 , fluorinated (C 1 -C 4 ) alkoxy and fluorinated (C 1 -C 4 )alkyl, -NR′SO 2 R", -NR'C(O)R", -NR'C(O)-OR", -NR'OR", in a number ranging from zero to the total number of open valences on the aromatic ring system; and wherein R', R", R"' and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound described herein contains more than one R group, each of the R groups is independently selected, for example, as each R' group, R" group, R"' group, and R"" group is independently selected when more than one of these groups is present.

[0058] The substituents of the ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene or heteroarylene) can be depicted as substituents on the ring rather than on a specific atom of the ring (commonly referred to as floating substituents). In this case, the substituent can be connected to any of the ring atoms (following the chemical valence rules), and in the case of a fused ring or spiro ring, the substituent depicted as being associated with a member of the fused ring or spiro ring (floating substituent on a single ring) can be a substituent on any of the fused rings or spiro rings (floating substituents on multiple rings). When the substituent is connected to the ring rather than a specific atom (floating substituent) and the subscript of the substituent is an integer greater than one, multiple substituents can be located on the same atom, the same ring, different atoms, different fused rings, different spiro rings, and each substituent can be optionally different. In the case where the connection point of the ring to the rest of the molecule is not limited to a single atom (floating substituent), the connection point can be any atom of the ring, and in the case of a fused ring or spiro ring, it can be any atom of any of the fused rings or spiro rings (following the chemical valence rules). In the case where a ring, fused ring or spiro ring contains one or more ring heteroatoms and the ring, fused ring or spiro ring is shown as having yet another floating substituent (including but not limited to a point of attachment to the rest of the molecule), the floating substituent may be bonded to the heteroatom. In the case where a ring heteroatom is shown as being bonded to one or more hydrogens in a structure or formula having a floating substituent (e.g., a ring nitrogen having two bonds to ring atoms and a third bond to a hydrogen), when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen while following the rules of chemical valence.

[0059] Two or more substituents can be optionally connected to form aryl, heteroaryl, cycloalkyl or heterocycloalkyl. This so-called ring-forming substituent is usually (although not necessarily) connected to the cyclic base structure. In one embodiment, the ring-forming substituent is connected to the adjacent members of the base structure. For example, two ring-forming substituents connected to the adjacent members of the cyclic base structure produce condensed ring structure. In another embodiment, the ring-forming substituent is connected to a single member of the base structure. For example, two ring-forming substituents connected to a single member of the cyclic base structure produce spirocyclic structure. In another embodiment, the ring-forming substituent is connected to the non-adjacent members of the base structure.

[0060] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0061] As used herein, "substituent" means a group selected from the following moieties:

[0062] (A) Oxo, halogen, -CCl 3 , -CBr 3 , -CF3 、-CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0063] (B) an alkyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group substituted with at least one substituent selected from the following:

[0064] (i) Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3, unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0065] (ii) an alkyl group, a heteroalkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group substituted with at least one substituent selected from the group consisting of:

[0066] (a) Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0067] (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl substituted with at least one substituent selected from the group consisting of oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2, -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0068] In the embodiments, as used herein, "substituent" means a group selected from the following moieties:

[0069] (A) Oxo, halogen, -CCl3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0070] (B) alkyl (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), cycloalkyl (e.g., C 3 -C 10 , C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), heterocycloalkyl (e.g., 3- to 10-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), aryl (e.g., C 6 -C 12 , C 6 -C 10 or phenyl) or heteroaryl (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered), substituted with at least one substituent selected from:

[0071] (i) Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0072] (ii) alkyl (e.g., C 1 -C 20 , C1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), cycloalkyl (e.g., C 3 -C 10 , C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), heterocycloalkyl (e.g., 3- to 10-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), aryl (e.g., C 6 -C 12 , C 6 -C 10 or phenyl) or heteroaryl (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered), substituted with at least one substituent selected from:

[0073] (a) Oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and

[0074] (b) alkyl (e.g., C 1 -C 20 , C 1 -C 12 , C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), heteroalkyl (e.g., 2-20 membered, 2-12 membered, 2-8 membered, 2-6 membered, 4-6 membered, 2-3 membered, or 4-5 membered), cycloalkyl (e.g., C 3 -C10 , C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), heterocycloalkyl (e.g., 3- to 10-membered, 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), aryl (e.g., C 6 -C 12 , C 6 -C 10 or phenyl) or heteroaryl (e.g., 5- to 12-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered), substituted with at least one substituent selected from the group consisting of oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2I. -OCH 2 F, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 Alkyl, C 1 -C 6 Alkyl or C 1 -C 4 alkyl), unsubstituted heteroalkyl (e.g., 2- to 8-membered heteroalkyl, 2- to 6-membered heteroalkyl, or 2- to 4-membered heteroalkyl), unsubstituted cycloalkyl (e.g., C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl or C 5 -C 6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, or 5- to 6-membered heterocycloalkyl), unsubstituted aryl (e.g., C 6 -C 10 Aryl, C 10 aryl, or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0075] As used herein, "size-limited substituent" or "size-limited substituent group" means a group selected from all substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 The substituted or unsubstituted heteroaryl group is an substituted or unsubstituted 5- to 10-membered heteroaryl group.

[0076] As used herein, "lower substituent" or "lower substituent group" means a group selected from all substituents described above for "substituent", wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 The aryl group is substituted or unsubstituted, and each substituted or unsubstituted heteroaryl group is a substituted or unsubstituted 5- to 9-membered heteroaryl group.

[0077] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 20-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5- to 10-membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C 1 -C 20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 20-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 8 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 The arylene group, and / or each substituted or unsubstituted heteroarylene group is a substituted or unsubstituted 5- to 10-membered heteroarylene group.

[0078] In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3-C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 In some embodiments, each substituted or unsubstituted alkylene group is a substituted or unsubstituted C 1 -C 8 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2- to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3- to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 Arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5- to 9-membered heteroarylene. In some embodiments, the compound is a chemical species described in the Examples section, Figures, or Tables below.

[0079] In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroalkylene, respectively). In embodiments, a substituted or unsubstituted moiety (e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroalkylene, respectively).

[0080] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, wherein if the substituted moiety is substituted with multiple substituents, each substituent may optionally be different. In embodiments, if the substituted moiety is substituted with multiple substituents, each substituent is different.

[0081] In embodiments, a substituted moiety (e.g., a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-restricted substituent, wherein if the substituted moiety is substituted with multiple size-restricted substituents, each size-restricted substituent may optionally be different. In embodiments, if the substituted moiety is substituted with multiple size-restricted substituents, each size-restricted substituent is different.

[0082] In an embodiment, a substituted moiety (e.g., a substituted alkyl, a substituted heteroalkyl, a substituted cycloalkyl, a substituted heterocycloalkyl, a substituted aryl, a substituted heteroaryl, a substituted alkylene, a substituted heteroalkylene, a substituted cycloalkylene, a substituted heterocycloalkylene, a substituted arylene, and / or a substituted heteroarylene) is substituted with at least one lower substituent, wherein if the substituted moiety is substituted with multiple lower substituents, each lower substituent may optionally be different. In an embodiment, if the substituted moiety is substituted with multiple lower substituents, each lower substituent is different.

[0083] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, size-restricted substituent, or lower substituent; wherein if the substituted moiety is substituted with multiple groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent may optionally be different. In embodiments, if the substituted moiety is substituted with multiple groups selected from substituents, size-restricted substituents, and lower substituents; each substituent, size-restricted substituent, and / or lower substituent is different.

[0084] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms, and individual isomers that can be defined as (R)- or (S)- or (D)- or (L)- of amino acids, based on absolute stereochemistry, are all included within the scope of the present disclosure. The compounds of the present disclosure do not include compounds that are too unstable to be synthesized and / or separated as known in the art. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefin bonds or other centers of geometric asymmetry, and unless otherwise indicated, it is intended that these compounds contain both E and Z geometric isomers.

[0085] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

[0086] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another isomeric form. It will be apparent to those skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present disclosure.

[0087] Unless otherwise stated, structures depicted herein are also intended to encompass all stereochemical forms of the structure; that is, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the compounds of the invention are within the scope of the present disclosure. Unless otherwise stated, structures depicted herein are also intended to encompass compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, having a molecule other than a deuterium or tritium replacing a hydrogen or ... 13 C- or 14 Compounds of the present invention having structures other than C-enriched carbon replacing carbon are within the scope of the present disclosure. The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes on one or more atoms constituting such compounds. For example, the compounds may be substituted with, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) and other radioactive isotopes. All isotopic variations of the compounds of the present disclosure, whether radioactive or non-radioactive, are encompassed within the scope of the present disclosure.

[0088] It should be noted that throughout the application, alternatives are written in Markush groups, such as in each amino acid position containing more than one possible amino acid. It is specifically contemplated that each member of a Markush group should be considered individually, thereby comprising another embodiment, and that a Markush group should not be understood as a single unit.

[0089] As used herein, the terms "bioconjugate reactive moiety" and "bioconjugate reactive group" refer to a moiety or group that is capable of forming a bioconjugate (e.g., a covalent linker) due to association between atoms or molecules of the bioconjugate reactive group. The association can be direct or indirect. For example, the conjugation between a first bioconjugate reactive group (e.g., -NH2, -COOH, N-hydroxysuccinimide, or -maleimide) provided herein and a second bioconjugate reactive group (e.g., a sulfhydryl, a sulfur-containing amino acid, an amine, an amine side chain containing an amino acid, or a carboxylate) can be performed directly, for example, via a covalent bond or a linker (e.g., a first linker of a second linker), or indirectly, for example, via a non-covalent bond (e.g., electrostatic interactions (e.g., ionic bonds, hydrogen bonds, halogen bonds), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (π effect), hydrophobic interactions, etc.). In embodiments, the bioconjugate or bioconjugate linker is formed using bioconjugate chemistry (i.e., association of two bioconjugate reactive groups) including, but not limited to, nucleophilic substitution (e.g., reaction of amines and alcohols with acyl halides, active esters), electrophilic substitution (e.g., enamine reaction), and addition of carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition). These and other useful reactions are discussed in, e.g., March, ADVANCED ORGANIC CHEMISTRY, 3rd ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Progress in Chemistry Series, Vol. 1, 198, American Chemical Society, Washington, DC, 1982. In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (e.g., a haloacetyl moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (eg, a pyridyl moiety) is covalently linked to a second bioconjugate reactive group (eg, a thiol group).In embodiments, a first bioconjugate reactive group (e.g., an N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (e.g., a maleimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., a sulfhydryl group). In embodiments, a first bioconjugate reactive group (e.g., a -sulfo-N-hydroxysuccinimide moiety) is covalently linked to a second bioconjugate reactive group (e.g., an amino group).

[0090] Useful bioconjugate reactive moieties for use in the bioconjugate chemistry herein include, for example: (a) carboxyl groups and their various derivatives, including but not limited to N-hydroxysuccinimide esters, N-hydroxybenzotriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyls, alkenyls, alkynyls, and aromatic esters; (b) hydroxyl groups that can be converted into esters, ethers, aldehydes, and the like. (c) alkyl halides, where the halide can subsequently be displaced by a nucleophilic group such as, for example, an amine, a carboxylate anion, a thiol anion, a carbonanion or an alkoxide ion, resulting in a new group covalently attached at the site of the halogen atom; (d) dienophiles, which are capable of participating in a Diels-Alder reaction, such as, for example, a maleimido or maleimide group; (e) aldehyde or ketone groups, which allow subsequent derivatization by formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes or by mechanisms such as Grignard addition or alkyllithium addition; (f) sulfonyl halides, which are used for subsequent reaction with amines, for example to form sulfonamides; (g) thiol groups, which can be converted into disulfides, reacted with acyl halides, or bonded to metals such as gold, or reacted with thiols; Maleimide reaction; (h) amine or sulfhydryl (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) olefins, which can undergo, for example, cycloadditions, acylations, Michael additions, etc.; (j) epoxides, which can react with, for example, amines and hydroxy compounds; (k) phosphoramidites and other standard functional groups useful for nucleic acid synthesis; (l) metal oxide silicon bonding; (m) metal bonding with reactive phosphorus groups (e.g., phosphine) to form, for example, phosphodiester bonds; (n) using copper-catalyzed cycloaddition click chemistry to attach azides to alkynes; (o) biotin conjugates can react with avidin or strepavidin to form avidin-biotin complexes or strepavidin-biotin complexes. The bioconjugate reactive group can be selected so that it does not participate in or interfere with the chemical stability of the conjugates described herein. Alternatively, reactive functional groups may be protected from participating in cross-linking reactions by the presence of protecting groups. In embodiments, the bioconjugate includes a molecular entity derived from the reaction of an unsaturated bond, such as maleimide, with a sulfhydryl group.

[0091] "Analog" or "analogue" is used according to its ordinary general meaning within chemistry and biology, and refers to a compound that is structurally similar but compositionally different from another compound (i.e., the so-called "reference" compound), for example in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or in the replacement of one functional group by another functional group, or in the absolute stereochemistry of one or more chiral centers of the reference compound. Thus, an analog is a compound that is similar or equivalent to the reference compound in function and appearance, but not similar or equivalent in structure or origin.

[0092] As used herein, the term "a" or "an" refers to one or more. In addition, as used herein, the phrase "substituted with [n]..." means that the specified group may be substituted with one or more of any or all of the named substituents. For example, when a group such as alkyl or heteroaryl is "substituted with an unsubstituted C 1 -C 20 alkyl or unsubstituted 2- to 20-membered heteroalkyl”, the group may contain one or more unsubstituted C 1 -C 20 alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl. In addition, where a portion is substituted with an R substituent, the group may be referred to as "R substituted". Where a portion is substituted with R, the portion is substituted with at least one R substituent, and each R substituent is optionally different. When a specific R group is present in the description of a chemical genus such as Formula (I), a Roman letter symbol may be used to distinguish each appearance of the specific R group. For example, where multiple R 13 In the case of a substituent, each R 13 Substituents can be divided into R 13A , R 13B , R 13C , R 13D etc., where R 13A , R 13B , R 13C , R 13D Each of the above is in R 13 and optionally different.

[0093] A "detectable agent" or "detectable moiety" is a substance, compound, element, molecule or composition detectable by appropriate means (e.g., spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging or other physical means). For example, useful detectable agents include 18 F. 32 P. 33 P.45 Water, 47 Sc、 52 Fe、 59 Fe、 62 Cu、 64 Cu、 67 Cu、 67 Ga、 68 Ga、 77 As、 86 Y、 90 Y、 89 Sr、 89 Zr、 94 Tc、 94 Tc、 99m Tc、 99 Bride, 105 Pd、 105 Rh、 111 Ag、 111 Through, 123 OF, 124 OF, 125 OF, 131 OF, 142 Pr、 143 Pr、 149 Pm、 153 Sm、 154-1581 Gd、 161 Tb、 166 Dy、 166 You、 169 Er、 175 Head, 177 Head, 186 Re、 188 Re、 189 Re、 194 They、 198 Shout, 199 Shout, 211 And、 211 Pb、 212 Bi、 212 Pb、 213 Bi、 223 Ra、 225 Ac, Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tb, Yb, Lu 32P, fluorophores (e.g., fluorescent dyes), electron-dense reagents, enzymes (e.g., enzymes commonly used in ELISA), biotin, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, single crystalline iron oxide nanoparticles, single crystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing gadolinium chelate ("Gd-chelate") molecules, gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma-emitting The invention relates to a radionuclide that emits radiation, a radionuclide that emits positrons, a radiolabeled glucose, a radiolabeled water, a radiolabeled ammonia, a biocolloid, a microbubble (e.g., a microbubble shell comprising albumin, galactose, a lipid and / or a polymer; a microbubble gas core comprising air, one or more heavy gases, perfluorocarbons, nitrogen, octafluoropropane, a perfluoroalkyl lipid microsphere, a perfluoroether, etc.), an iodinated contrast agent (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, iocolic acid), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores or haptens and proteins or other entities, which can be detected, for example, by incorporating a radiolabel into a peptide or antibody that specifically reacts with a target peptide. The detectable portion is a monovalent detectable agent or a detectable agent that can form a bond with another composition.

[0094] Radioactive substances (eg, radioisotopes) that can be used as imaging and / or labeling agents according to embodiments of the present disclosure include, but are not limited to: 18 F. 32 P. 33 P. 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y. 90 Y. 89 Sr. 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh,111 Ag, 111 In, 123 I. 124 I. 125 I. 131 I. 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-1581 Gd, 161 Tb, 166 Dy, 166 Ho, 169 2. 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At 211 Pb, 212 Bi, 212 Pb, 213 Bi, 223 Ra and 225 Ac. Paramagnetic ions that can be used as additional imaging agents according to embodiments of the present disclosure include, but are not limited to, transition ions and lanthanide metals (e.g., metals with atomic numbers 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.

[0095] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art. Thus, where a group may be substituted by one or more of a plurality of substituents, such substitutions are selected so as to conform to the principles of chemical bonding and to yield compounds that are not inherently unstable and / or that would be unstable under environmental conditions (such as aqueous, neutral, and several known physiological conditions) as known to those of ordinary skill in the art. For example, heterocycloalkyl or heteroaryl groups are connected to the rest of the molecule via ring heteroatoms in accordance with the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0096] One of ordinary skill in the art will understand that when a variable (e.g., a moiety or linker) of a compound or genus of compounds (e.g., a genus described herein) is described by the name or formula of an independent compound with all filled valences, the unfilled valence or valences of the variable will be determined by the context in which the variable is used. For example, when a variable of a compound described herein is connected (e.g., bonded) to the rest of the compound by a single bond, the variable should be understood to represent the monovalent form of the independent compound (i.e., capable of forming a single bond due to the unfilled valences) (e.g., in one embodiment, if a variable is named "methane", but it is known that the variable is connected to the rest of the compound by a single bond, one of ordinary skill in the art will understand that the variable is actually the monovalent form of methane, i.e., methyl or -CH 3 Similarly, for linker variables (e.g., L as described herein) 1 , L 2 or L 3 ), one of ordinary skill in the art would understand that the variable is a divalent form of the independent compound (e.g., in one embodiment, if a variable is designated as "PEG" or "polyethylene glycol" but the variable is attached to the rest of the compound by two separate bonds, one of ordinary skill in the art would understand that the variable is a divalent form of PEG (i.e., capable of forming two bonds through two unfilled valencies), rather than the independent compound PEG).

[0097] The term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (neat or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or similar salts. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include acid addition salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic functional groups and acidic functional groups that allow these compounds to be converted into base addition salts or acid addition salts. Therefore, the compounds of the present disclosure can exist in the form of salts (such as having pharmaceutically acceptable acids). The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, mesylates, nitrates, maleates, acetates, citrates, fumarates, propionates, tartrates (e.g., (+)-tartrates, (-)-tartrates or mixtures thereof, including racemic mixtures), succinates, benzoates, and salts of amino acids such as glutamic acid and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art. The neutral form of the compound is preferably regenerated by contacting the salt with an alkali or acid and separating the parent compound in a conventional manner. The parent form of the compound can be different from various salt forms in some physical properties, such as solubility in polar solvents.

[0098] In addition to salt forms, the present disclosure also provides compounds in the form of prodrugs. Prodrugs of compounds described herein are those compounds that are susceptible to undergoing chemical changes under physiological conditions to provide compounds of the present disclosure. Prodrugs of compounds described herein can be transformed in vivo after administration. In addition, prodrugs can be converted into compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment (such as, for example, when contacted with a suitable enzyme or chemical reagent).

[0099] Some compounds of the present disclosure can exist in non-solvated form and solvated form (including hydrated form). Generally speaking, the solvated form is equivalent to the non-solvated form and is included in the scope of the present disclosure. Some compounds of the present disclosure can exist in multiple crystals or amorphous forms. Generally speaking, all physical forms are equivalent for the purposes contemplated by the present disclosure, and are intended to be within the scope of the present disclosure.

[0100] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that facilitate administration of active agents to subjects and facilitate absorption by subjects, and the substances can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to patients. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose or starch), fatty acid esters, carboxymethyl cellulose, polyvinyl pyrrolidone and pigments, etc. Such preparations can be sterilized and, if necessary, can be mixed with adjuvants (such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring substances and / or aromatic substances, etc.), which do not react harmfully with the compounds of the present disclosure. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0101] The term "preparation" is intended to include the formulation of an active compound with encapsulating material in the form of a carrier providing a capsule in which the active ingredient, with or without other carriers, is surrounded by the carrier in which it is associated. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0102] As used herein, the term "about" means a range of values ​​that includes a specified value, which a person of ordinary skill in the art would consider to be reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extends to + / -10% of a specified value. In embodiments, about includes a specified value.

[0103] "Contacting" is used according to its ordinary general meaning and refers to the process of bringing at least two different species (e.g., chemical compounds including biomolecules or cells) into close enough proximity to react, interact, or physically touch. However, it should be understood that the resulting reaction product can be produced directly by the reaction between the added reagents, or by intermediates that can be produced in the reaction mixture from one or more of the added reagents. The term "contacting" can include allowing two species to react, interact, or physically touch, wherein the two species can be a compound as described herein and a protein or enzyme. In some embodiments, contacting includes allowing a compound as described herein to interact with a protein or enzyme involved in a signaling pathway.

[0104] As defined herein, the terms "activation / activate / activating", "activator", etc., with respect to protein-inhibitor interactions, mean that the activity or function of the protein is positively affected (e.g., increased) relative to the activity or function of the protein in the absence of the activator. In an embodiment, activation means positively affecting (e.g., increasing) the concentration or level of the protein relative to the concentration or level of the protein in the absence of the activator. The term may refer to activation or activating, sensitizing or upregulating the amount of a protein that is reduced in a signal transduction or enzymatic activity or a disease. Thus, activation may at least partially comprise partially or completely increasing stimulation, increasing or initiating activation, sensitizing or upregulating signal transduction or enzyme activity or a protein associated with a disease (e.g., a protein that is reduced in a disease relative to a non-diseased control). Activation may at least partially comprise partially or completely increasing stimulation, increasing or initiating activation, sensitizing or upregulating the amount of a signal transduction or enzyme activity or a protein.

[0105] The terms "agonist", "activator", "up-regulator", etc. refer to a substance that can detectably increase the expression or activity of a given gene or protein. An agonist can increase expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the agonist. In some cases, expression or activity is 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times or more compared to expression or activity in the absence of the agonist.

[0106] As defined herein, the term "inhibition (inhibition / inhibit / inhibiting, etc.)" with respect to protein-inhibitor interactions means that the activity or function of the protein is negatively affected (e.g., reduced) relative to the activity or function of the protein in the absence of the inhibitor. In an embodiment, inhibition means that the concentration or level of the protein is negatively affected (e.g., reduced) relative to the concentration or level of the protein in the absence of the inhibitor. In an embodiment, inhibition refers to a reduction in the symptom of a disease or disease. In an embodiment, inhibition refers to a reduction in the activity of a specific protein target. Therefore, inhibition at least partially includes partially or completely blocking stimulation, reducing, preventing or delaying activation, desensitizing or downregulating the amount of signal transduction or enzyme activity or protein. In an embodiment, inhibition refers to a reduction in the activity of a target protein caused by a direct interaction (e.g., an inhibitor binds to a target protein). In an embodiment, inhibition refers to a reduction in the activity of a target protein caused by an indirect interaction (e.g., an inhibitor binds to a protein that activates the target protein, thereby preventing the target protein from activating).

[0107] Interchangeably, the terms "inhibitor", "repressor" or "antagonist" or "downregulator" refer to a substance that can detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to a control in the absence of the antagonist. In some cases, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or less compared to expression or activity in the absence of the antagonist.

[0108] The terms "RNF4" and "RING FINGER PROTEIN 4" refer to E3 ligase proteins (including homologs, isoforms and functional fragments thereof). The terms include any recombinant or naturally occurring RNF4 variants that maintain RNF4 activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% activity compared to wild-type RNF4). In an embodiment, the RNF4 protein encoded by the RNF4 gene has an amino acid sequence listed in Entrez 6047, UniProt P78317, RefSeq (protein) NP_002929, RefSeq (protein) NP_001171939 or RefSeq (protein) NP_001171938 or corresponding thereto. In an embodiment, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing this application. In an embodiment, RNF4 is human RNF4, such as RNF4 that causes human cancer. In an embodiment, RNF4 has the following sequence:

[0109]

[0110] The terms "RNF114" and "RING finger protein 114" and "ZNF228" and "ZNF313" refer to E3 ligase proteins (including homologs, isoforms and functional fragments thereof). The term includes any recombinant or naturally occurring form of RNF4 variants that maintain RNF114 activity (e.g., at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% activity compared to wild-type RNF114). In an embodiment, the RNF114 protein encoded by the RNF4 gene has an amino acid sequence listed in Entrez55905, UniProtQ9Y508 or RefSeq (protein) NP_061153 or corresponding thereto. In an embodiment, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing this application. In an embodiment, RNF114 is human RNF114, such as RNF114 that causes human cancer. In an embodiment, RNF114 has the following sequence:

[0111]

[0112] The terms "BRD4" and "bromodomain-containing protein 4" refer to proteins that associate with chromosomes during mitosis and play a key role in epigenetic memory transmission across cell division and transcriptional regulation. In an embodiment, the BRD4 protein encoded by the BRD4 gene has an amino acid sequence listed in Entrez23476, UniProtO60885, RefSeq (protein) NP_001317313.1, RefSeq (protein) NP_055114.1, or RefSeq (protein) NP_490597.1 or corresponding thereto. In an embodiment, the amino acid sequence or nucleic acid sequence is a sequence known at the time of filing this application. In an embodiment, BRD4 has the following sequence:

[0113]

[0114]

[0115] The term "expression" includes any step involved in the production of the polypeptide, including but not limited to transcription, post-transcriptional modification, translation, post-translational modification and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blot, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

[0116] The term "modulator" refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of a molecular target relative to the absence of the modulator. The term "modulate" is used according to its ordinary general meaning and refers to the action of changing or altering one or more properties. "Modulation" refers to the process of changing or altering one or more properties.

[0117] In the context of a substance or an activity or function of a substance associated with a disease, the term "associated" or "associated with..." means that the disease is caused (in whole or in part) by the substance or the activity or function of the substance, or the symptoms of the disease are caused (in whole or in part) by the substance or the activity or function of the substance.

[0118] As used herein, the term "abnormal" refers to different from normal. When used to describe enzymatic activity or protein function, abnormal refers to an activity or function that is greater or less than the average of a normal control or normal non-disease control sample. Abnormal activity can refer to the amount of activity that causes the disease, wherein returning the abnormal activity to a normal or non-disease associated amount (e.g., by administering a compound or using a method as described herein) results in a reduction in the disease or one or more disease symptoms.

[0119] As used herein, the term "signaling pathway" refers to a series of interactions between a cell and optional extracellular components (e.g., proteins, nucleic acids, small molecules, ions, lipids) that transmit changes in one component to one or more other components, which in turn can transmit changes to additional components, which are optionally propagated to other signaling pathway components.

[0120] In the present disclosure, "comprise / comprising", "containing", "having", etc. may have the meaning ascribed thereto in U.S. Patent Law and may mean "include / including", etc. "Consisting essentially of or consists essentially" also has the meaning ascribed thereto in U.S. Patent Law and the term is open ended, allowing for existence beyond what is recited as long as the basic or novel features recited are not altered by existence beyond what is recited, but excluding prior art embodiments.

[0121] The term "disease" or "condition" refers to a state or health condition in a patient or subject that can be treated with the compounds or methods provided herein. The disease can be cancer. The disease can be an autoimmune disease. The disease can be an inflammatory disease. The disease can be an infectious disease. In some other instances, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, etc., including solid and lymphoid cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioma, esophageal cancer, and liver cancer (including hepatocarcinoma), lymphoma (including B acute lymphoblastic lymphoma, Non-Hodgkin's Lymphoma (e.g., Burkitt's lymphoma, small cell lymphoma and large cell lymphoma), Hodgkin's lymphoma), leukemia (including AML, ALL and CML) or multiple myeloma.

[0122] As used herein, the term "cancer" refers to all types of cancers, tumors or malignancies found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas and sarcomas. Exemplary cancers that can be treated with the compounds or methods provided herein include brain cancer, gliomas, glioblastomas, neuroblastomas, prostate cancer, colorectal cancer, pancreatic cancer, medulloblastomas, melanomas, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, Hodgkin's Disease and non-Hodgkin's lymphoma. Exemplary cancers that can be treated with the compounds or methods provided herein include thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, gastric cancer and uterine cancer. Additional examples include thyroid cancer, bile duct cancer, pancreatic cancer, malignant melanoma of the skin, colon adenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, malignant pancreatic islet tumor, malignant carcinoid, urinary bladder cancer, precancerous skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumor, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0123] The term "leukemia" refers to a progressive, malignant disease of the blood-forming organs and is generally characterized by the unregulated proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemias are usually clinically classified based on: (1) the duration and character of the disease - acute or chronic; (2) the type of cells involved; myeloid (myeloid), lymphoid (lymphoid), or monocytic; and (3) the increase or non-increase in the number of abnormal cells in the blood - leukemic or non-leukemic (meta-leukemic). Exemplary leukemias that can be treated with the compounds or methods provided herein include, e.g., acute non-lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemicleukemia, a leukocytic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblasticleukemia, hemocytoblastic leukemia, leukemia), histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia leukemia), stem cell leukemia, subleukemic leukemia and undifferentiated cell leukemia.

[0124] As used herein, the term "lymphoma" refers to a group of cancers that affect hematopoietic and lymphoid tissues. It begins in lymphocytes (blood cells found primarily in lymph nodes, spleen, thymus, and bone marrow). The two main types of lymphoma are non-Hodgkin's lymphoma and Hodgkin's disease. Hodgkin's disease accounts for approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphoma (NHL) can be classified based on the growth rate of the cancer and the cell types involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the cell types involved, there are B cell and T cell NHL. Exemplary B cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodular (monocytoid B cell) lymphoma, splenic lymphoma, diffuse large cell B lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B lymphoblastic lymphoma. Exemplary T cell lymphomas that can be treated with the compounds or methods provided herein include, but are not limited to, cutaneous T cell lymphoma, peripheral T cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T lymphoblastic lymphoma.

[0125] The term "sarcoma" generally refers to a tumor composed of material similar to embryonic connective tissue and usually consists of tightly packed cells embedded in a fibrous or homogeneous substance. Sarcomas that can be treated with the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, green carcinosarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, sarcoma), angiosarcoma, leukosarcoma, malignant mesothelioma sarcoma, extraperiosteal sarcoma, reticular cell sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

[0126] The term "melanoma" is understood to refer to tumors of the melanocyte system of the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0127] The term "cancer" refers to a malignant new growth composed of epithelial cells that tends to infiltrate surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds or methods provided herein include, for example, medullary thyroid cancer, familial medullary thyroid cancer, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenocarcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid cell tumor, basal cell-like carcinoma, basosquamous cell carcinoma, bronchioloalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, brain-like carcinoma, cholangiocarcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, uterine body carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, scirrhous carcinoma, embryonal carcinoma, medullary carcinoma, epidermoid carcinoma, adenoid epithelial cell carcinoma, explant carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatinous carcinoma, fibrocarcinoma, colloid carcinoma, fibrocar ... carcinoma), colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, adrenal carcinoma, embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare), lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucoepidermoid carcinoma, myxoid carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, thorn cell carcinoma, pultaceous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, potato carcinoma, spheroid cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma ectaticatelangiectaticum), carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or villous carcinoma.

[0128] As used herein, the terms "metastasis," "metastatic," and "metastatic cancer" are used interchangeably and refer to the spread of a proliferative disease or disorder (e.g., cancer) from one organ to another non-adjacent organ or part of the body."Metastatic cancer" is also referred to as "stage IV cancer."

[0129] The term "treating" or "treatment" refers to any indicator of successful treatment or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as elimination; relief; alleviation of symptoms or making an injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; or making the end point of degeneration less declining; improving the patient's physical or mental health. The treatment or improvement of symptoms can be based on objective or subjective parameters; including the results of a physical examination, a neuropsychiatric examination, and / or a psychiatric assessment. The term "treatment" and its conjugations may include preventing an injury, pathology, condition, or disease. In an embodiment, treatment is prevention. In an embodiment, treatment does not include prevention. As used herein (and well understood in the art), "treatment" or "treatment" also broadly includes any method for obtaining a beneficial or desired result (including a clinical result) in a subject's condition. Beneficial or desired clinical results may include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, alleviation of the extent of the disease, stabilization (i.e., non-exacerbation) of the disease state, prevention of disease transmission or spread, delay or slowing of disease progression, improvement or alleviation of the disease state, reduction of disease recurrence, and alleviation (whether partial or total, and whether detectable or undetectable). In other words, as used herein, "treatment" includes any cure, improvement, or prevention of the disease. Treatment can prevent the occurrence of the disease; inhibit the spread of the disease; alleviate the symptoms of the disease (e.g., eye pain, seeing halos, red eyes, extremely high intraocular pressure), completely or partially remove the root cause of the disease, shorten the duration of the disease, or a combination of these things. As used herein, "treatment" includes preventive treatment. The method of treatment includes administering a therapeutically effective amount of an active agent to a subject. The administration step may consist of a single administration, or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of the active agent, the activity of the composition used in the treatment, or a combination thereof. It should also be understood that the effective dose of the medicament for treatment or prevention can increase or decrease during a specific treatment or prevention regimen. By standard diagnostic assays known in the art, the variation of dosage can be produced and become apparent. In some cases, chronic administration may be required. For example, the composition is administered to a subject in an amount sufficient to treat the patient, and continues for a sufficient duration. In an embodiment, treatment (treating or treatment) is not a preventive treatment.

[0130] The term "prevention" refers to reducing the occurrence of disease symptoms in a patient. As noted above, prevention can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would occur in the absence of treatment.

[0131] "Patient" or "subject in need thereof" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient is a human.

[0132] "Effective amount" is an amount sufficient to achieve the stated purpose of the compound (e.g., to achieve the effect of its administration, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce signal transduction pathways, or to reduce one or more symptoms of a disease or condition) relative to the absence of the compound. An example of an "effective amount" is an amount sufficient to facilitate treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of one or more symptoms, or eliminating one or more symptoms. The "preventive effective amount" of a drug is the amount of the drug that will have the expected preventive effect when administered to a subject, such as preventing or delaying the onset (or recurrence) of damage, disease, pathology, or condition or reducing the likelihood of onset (or recurrence) of damage, disease, pathology, or condition or its symptoms. A complete preventive effect does not necessarily occur by administering a single dose, and may occur after administering only a series of doses. Therefore, the preventive effective amount may be administered in the form of one or more administrations. As used herein, "activity reduction amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of an antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amount will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, Gennaro, ed., Lippincott, Williams & Wilkins).

[0133] For any compound described herein, the therapeutically effective amount can be initially determined according to a cell culture assay. The target concentration will be the concentration of one or more active compounds that can achieve the methods described herein, as measured using methods described herein or known in the art. As is well known in the art, the therapeutically effective amount for humans can also be determined according to animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective for animals. The dose in the human body can be adjusted by monitoring the effectiveness of the compound and by adjusting the dose up or down as described above. It is entirely within the ability of ordinary technicians to adjust the dose based on the methods described above and other methods to achieve maximum efficacy in humans.

[0134] As used herein, the term "therapeutically effective amount" refers to the amount of a therapeutic agent sufficient to improve a condition as described above. For example, for a given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. The therapeutic efficacy can also be expressed as a "fold" increase or decrease. For example, a therapeutically effective amount can have an effect of at least 1.2 times, 1.5 times, 2 times, 5 times, or more relative to a control.

[0135] The dosage can vary according to the needs of the patient and the compound employed. In the context of the present disclosure, the dosage administered to the patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature and extent of any adverse side effects. It is within the skill of the practitioner to determine the appropriate dosage for a particular situation. Typically, treatment begins with a smaller dose that is smaller than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect in these cases is achieved. The amount and interval of administration can be adjusted individually to provide an effective level of the administered compound for the specific clinical indication being treated. This will provide a treatment regimen commensurate with the severity of the individual disease state.

[0136] As used herein, the term "administer" means oral administration to a subject, administration in the form of a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or implantation of a slow release device (e.g., a mini-osmotic pump). Administered by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palate, gums, nose, vagina, rectum or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial administration. Other modes of delivery include, but are not limited to, use of liposome formulations, intravenous infusions, transdermal patches, etc. In an embodiment, administration does not include administration of any activating agent other than the narrated activating agent.

[0137] By "co-administration," it is meant that the compositions described herein are administered simultaneously, just before, or just after administration of one or more additional therapies. The compounds provided herein can be administered alone or can be co-administered to a patient. Co-administration is intended to include administration of the compound (more than one compound) alone or in combination, either simultaneously or sequentially. Thus, the formulations can also be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered transdermally, by topical routes, or formulated into application sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, pectins, paints, powders, and aerosols.

[0138] As used herein, "cell" refers to a cell that performs metabolic functions or other functions sufficient to maintain or replicate its genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of intact membranes, specific dye staining, the ability to produce offspring, or the ability to combine with a second gamete to produce living offspring in the case of gametes." Stem cell" is a cell characterized by the ability to self-renew by mitosis and the potential to differentiate into tissues or organs. Among mammalian stem cells, embryonic stem cells (ES cells) and somatic stem cells (e.g., HSC) can be distinguished. Embryonic stem cells are retained in blastocysts and produce embryonic tissues, while somatic stem cells are retained in adult tissues for the purpose of tissue regeneration and repair.

[0139] "Control" or "control experiment" is used according to its ordinary general meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment, except that the experimental procedures, reagents or variables are omitted. In some examples, the control is used as a standard of comparison in evaluating the effects of the experiment. In some embodiments, the control is a measure of the activity of the protein in the absence of a compound as described herein (including the embodiments and examples).

[0140] "Anti-cancer agent" and "anticancer agent" are used in their ordinary general sense and refer to a composition, compound, drug, antagonist, inhibitor, modulator, peptide, protein, nucleic acid, or molecule with anti-tumor properties or the ability to inhibit cell growth or proliferation. In some embodiments, the anti-cancer agent is a chemotherapeutic agent. In some embodiments, the anti-cancer agent is an agent identified herein as having utility in a method for treating cancer. In some embodiments, the anti-cancer agent is an agent approved by the FDA or similar regulatory agency in a country other than the United States for the treatment of cancer. Examples of anticancer agents include, but are not limited to, antiandrogens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK (e.g., MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g., XL518, CI-1040, PD035901, selumetinib / AZD6244, GSK1120212 / trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733, PD318088, AS703026, BAY869766), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards (e.g., chloroethylamine, cyclophosphamide, chlorambucil, melphalan), ethyleneimine, and methylmelamine (e.g., hexamethyltriazine), melamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin), triazenes (decarbazine), antimetabolites (e.g., 5-thiopurine, folinic acid, capecitabine, fludarabine, gemcitabine (gemcitabine), pemetrexed, raltitrexed, folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin, etc.), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate (etoposide phosphate), etc.),phosphate), teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamicin, daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g., cisplatin, oxaliplatin, latin), carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), adrenocortical hormone inhibitors (e.g., mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors of mitogen-activated protein kinase signaling (e.g., U0126 , PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY43-9006, wortmannin or LY294002), mTOR inhibitors, antibodies (e.g., rituximab), 5-aza-2′-deoxycytidine, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec.RTM.), geldanamycin, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), bortezomib, trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogens, antiestrogens; antisense oligonucleotides; apoptosis gene regulators; apoptosis regulators; arginine deaminase; BCR / ABL antagonists; β-lactam derivatives; bFGF inhibitors; bicalutamide; camptothecin derivatives; casein kinase inhibitors (ICOS); clomifene analogs; cytarabine daclizumabdacliximab; dexamethasone; estrogen agonist; estrogen antagonist; etanidazole; etoposide phosphate; exemestane; fadrozole; finasteride; fludarabine; fluororubicin hydrochloride; gadoliniumtexaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; immunopotentiating peptides; insulin-like growth factor-1 receptor inhibitors; interferon agonists; interferons; interleukins; letrozole; leukemia inhibitory factor; interleukin α; leuprorelin + estrogen + progesterone; leuprorelin; matrix lytic factor inhibitors; matrix metalloproteinase inhibitors; MIF inhibitors; mifepristone; mismatched double-stranded RNA; monoclonal antibodies body; mycobacterial cell wall extract; nitric oxide modulators; oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogen activator inhibitors; platinum complexes; platinum compounds; prednisone; proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitors; enzymatic nucleic acids; signal transduction inhibitors; signal transduction modulators; single-chain Antigen binding proteins; stem cell inhibitors; stem cell division inhibitors; stromelysin inhibitors; synthetic mucopolysaccharides; tamoxifen methyl iodide; telomerase inhibitors; thyroid stimulating hormone; translation inhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists; steroids (e.g., dexamethasone), finasteride, aromatase inhibitors, gonadotropin-releasing hormone agonists (GnRH) (such as goserelin or leuprolide), adrenal cortical steroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., caproate), diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), immunostimulants (e.g., bacillus Calmette-Guérin (BCG), levamisole, interleukin-2, α-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR and anti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonal antibody-Pseudomonas exotoxin conjugate, etc.), radioimmunotherapy (e.g., with 111 In, 90 Y or 131I etc. conjugated anti-CD20 monoclonal antibodies), triptolide, homoharringtonine, dactinomycin, doxorubicin, epirubicin, topotecan, itraconazole, vindesine, cerivastatin, vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan, clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib, gefitinib, EGFR inhibitors, therapies or therapeutic agents targeting epidermal growth factor receptor (EGFR) (e.g., gefitinib, TM ), erlotinib (Tarceva TM ), cetuximab (Erbitux TM ), lapatinib (Tykerb TM ), panitumumab (Vectibix TM ), vandetanib (Caprelsa TM)、afatinib / BIBW2992、CI-1033 / canertinib、neratinib / HKI-272、CP-724714、TAK-285、AST-1306、ARRY334543、ARRY-380、AG-1478、dacomitinib / PF299804、OSI-420 / desmethylerlotinib、AZD 8931, AEE788, pelitinib / EKB-569, CUDC-101, WZ8040, WZ4002, WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib, sunitinib, dasatinib, pyrrolobenzodiazepines (e.g., tomay mycin), carboplatin, CC-1065 and CC-1065 analogs (including amino-CBI), nitrogen mustards (e.g., chlorambucil and melphalan), dolastatin and dolastatin analogs (including auristatin: for example, monomethyl auristatin E), anthracycline antibiotics (e.g., doxorubicin, daunorubicin, etc.), duocarmycin and duocarmycin analogs, enediynes (e.g., neocarcinostatisin, etc.), ocarzinostatin and calicheamicin), leptomycin derivatives, maytansinoids and maytansinoid analogs (e.g., mertansine), methotrexate, mitomycin C, paclitaxel, vinca alkaloids (e.g., vinblastine and vincristine), epothilones (e.g., epothilone B), camptothecin and its clinical analogs topotecan and irinotecan, etc.

[0141] The "specificity" of a compound refers to the ability of the compound to produce a specific effect (such as inhibition) on a specific molecular target while having little or no effect on other proteins in the cell.

[0142] The term "electrophilic chemical moiety" or "electrophile moiety" is used according to its ordinary general chemical meaning and refers to a chemical group (eg, a monovalent chemical group) that is electrophilic.

[0143] The term "irreversible covalent bond" is used in accordance with its common general meaning in the art and refers to an association produced between atoms or molecules (e.g., an electrophilic chemical moiety and a nucleophilic moiety) where the probability of dissociation is low. In embodiments, an irreversible covalent bond is not easily dissociated under normal biological conditions. In embodiments, an irreversible covalent bond is formed by a chemical reaction between two substances (e.g., an electrophilic chemical moiety and a nucleophilic moiety).

[0144] As used herein, the term "capable of binding" refers to a moiety (e.g., a compound described herein) that is capable of measurably binding to a target (e.g., an E3 ubiquitin ligase binder that is capable of forming a covalent bond with a cysteine ​​of an E3 ubiquitin ligase). In embodiments, when a moiety is capable of binding to a target, the moiety is capable of binding with a Kd of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM.

[0145] As used herein, the term "target protein degrader" refers to an agent (e.g., compound or composition) that can induce protein degradation on a target protein (e.g., a protein of interest). Typically, a target protein degrader can recruit E3 ligases to a specific protein target, thereby ubiquitinating and degrading the target in a proteasome-dependent manner. Since functional inhibition of the target is not necessary for the efficacy of the degrader, this strategy has the potential to target and degrade any protein for which a ligand is present in the proteome (e.g., a target protein binder or a target protein degrader).

[0146] The term "target protein binding agent" refers to a portion capable of binding to a protein (e.g., a target protein). In an embodiment, a target protein binding agent is a molecule or substance that forms a complex with a protein (e.g., a target protein). In an embodiment, a target protein binding agent is a monovalent form of a molecule or substance that forms a complex with a protein (e.g., a target protein).

[0147] The term "binding agent linker" refers to a covalent linker that binds a target protein binding agent and an E3 ubiquitin ligase binding agent.

[0148] As used herein, the term "E3 ubiquitin ligase binder" refers to a monovalent agent (e.g., a monovalent compound described herein) that is capable of measurably binding to an E3 ubiquitin ligase (E3 ligase) (e.g., RNF4 or RNF114). For example, an E3 ubiquitin ligase binder is a portion or monovalent form of a compound having the formula: Where R 2 ,z2,R 1 ,z1,L 3 and R 4 As stated in this article; Where R 7 、z7、R 5 , R 2 ,z2,L 3 , R 4 , R 6 , R 1 and z1 as described herein; or Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described in this article.

[0149] As used herein, the term "covalent cysteine ​​modifier moiety" refers to a monovalent electrophilic moiety capable of measurably binding to a cysteine ​​amino acid. In embodiments, the covalent cysteine ​​modifier moiety binds via an irreversible covalent bond. In embodiments, the covalent cysteine ​​modifier moiety is capable of binding with a Kd of less than about 10 μM, 5 μM, 1 μM, 500 nM, 250 nM, 100 nM, 75 nM, 50 nM, 25 nM, 15 nM, 10 nM, 5 nM, 1 nM, or about 0.1 nM.

[0150] II.Compounds

[0151] In one aspect, a target protein degrader is provided, comprising 1) a target protein binder and 2) an E3 ubiquitin ligase binder, wherein the E3 ubiquitin ligase is human RNF4 or human RNF114. In an embodiment, the E3 ubiquitin ligase is human RNF4. In an embodiment, the E3 ubiquitin ligase is human RNF114. In an embodiment, the E3 ubiquitin ligase binder is capable of forming a covalent bond with the cysteine ​​of the E3 ubiquitin ligase. In an embodiment, the target protein binder and the E3 ubiquitin ligase binder are covalently bonded via a binder linker.

[0152] In an embodiment, the E3 ubiquitin ligase binder is part of a compound having the formula:

[0153] In an embodiment, the E3 ubiquitin ligase binder is a monovalent compound having the formula:

[0154] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula:

[0155] R 1 are independently halogen, -CX 1 3 、-CHX 1 2 、-CH 2 X 1 、-CN、-OR 1D 、-C(O)R 1C 、-C(O)-OR 1C 、-C(O)NR 1A R 1B 、-N(O) m1 、-SO n1 R 1D 、-SO v1 NR 1A R 1B 、-NR 1A R 1B 、-NHC(O)NR 1A R 1B 、-NR 1A SO 2 R 1D 、-NR 1A C(O)R 1C 、-NR 1A C(O)OR 1C 、-NR 1A OR 1C 、-OCX 1 3 、-OCH 2 X 1 、-OCHX 1 2 、-N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a bond to a binder linker; two R 1 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 2 are independently halogen, -CX 2 3 、-CHX 2 2 、-CH 2 X 2 、-CN、-OR 2D 、-C(O)R 2C、-C(O)-OR 2C 、-C(O)NR 2A R 2B 、-N(O) m2 、-SO n2 R 2D 、-SO v2 NR 2A R 2B 、-NR 2A R 2B 、-NHC(O)NR 2A R 2B 、-NR 2A SO 2 R 2D 、-NR 2A C(O)R 2C 、-NR 2A C(O)OR 2C 、-NR 2A OR 2C 、-OCX 2 3 、-OCH 2 X 2 、-OCHX 2 2 、-N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a bond to a binder linker; two R 2 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 3 For the bond, -N(R 3 )-、-C(O)-、-C(O)N(R 3 )-、-N(R 3 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. R 3 are independently hydrogen, oxo, halogen, -CX 3 3 、-CHX 3 2 、-CH 2 X 3、-CN、-OR 3D 、-C(O)R 3C 、-C(O)-OR 3C 、-C(O)NR 3A R 3B 、-N(O) m3 、-SO n3 R 3D 、-SO v3 NR 3A R 3B 、-NR 3A R 3B 、-NHC(O)NR 3A R 3B 、-NR 3A SO 2 R 3D 、-NR 3A C(O)R 3C 、-NR 3A C(O)OR 3C 、-NR 3A OR 3C 、-OCX 3 3 、-OCH 2 X 3 、-OCHX 3 2 、-N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a bond to a binder linker. 4 are independently hydrogen, oxo, halogen, -CX 4 3 、-CHX 4 2 、-CH 2 X 4 、-CN、-OR 4D 、-C(O)R 4C 、-C(O)-OR 4C 、-C(O)NR 4A R 4B 、-N(O) m4 、-SO n4 R 4D 、-SO v4 NR 4A R 4B 、-NR 4A R 4B 、-NHC(O)NR 4A R4B 、-NR 4A SO 2 R 4D 、-NR 4A C(O)R 4C 、-NR 4A C(O)OR 4C 、-NR 4A OR 4C 、-OCX 4 3 、-OCH 2 X 4 、-OCHX 4 2 、-N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E. E is an electrophilic moiety. z1 is an integer from 0 to 4. z2 is an integer from 0 to 5. Each R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C and R 4D are independently hydrogen, -CX 3 、-CN、-COOH、-CONH 2 、-CHX 2 、-CH 2 X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R bonded to the same nitrogen atom 1A and R 1B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 2A and R 2B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 3A and R 3BThe substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; R 4A and R 4B The substituents may be optionally linked to form a substituted or unsubstituted heterocycloalkyl or a substituted or unsubstituted heteroaryl; each X, X 1 , X 2 , X 3 and X 4 R is independently -F, -Cl, -Br or -I. n1. n2. n3 and n4 are independently integers from 0 to 4. m1, m2, m3, m4, v1, v2, v3 and v4 are independently 1 or 2. Only one R 1 or an R 2 or an R 3 is a bond to the binding agent linker. 1 is a bond to the binding agent linker. 2 is a bond to the binding agent linker. 3 is a bond to the binding agent linker. 1 is independently a bond to a binding agent linker. 2 is independently a bond to a binding agent linker. 3 is independently a bond to the binding agent linker. 1 or an R 2 or an R 3 is the bond to the binder linker.

[0156] In an embodiment, R 3 are independently hydrogen, halogen, -CX 3 3 、-CHX 3 2 、-CH 2 X 3 、-CN、-OR 3D 、-C(O)R 3C 、-C(O)-OR 3C 、-C(O)NR 3A R 3B 、-N(O) m3 、-SO n3 R 3D 、-SO v3 NR 3A R 3B 、-NR 3A R 3B 、-NHC(O)NR 3A R 3B 、-NR3A SO 2 R 3D 、-NR 3A C(O)R 3C 、-NR 3A C(O)OR 3C 、-NR 3A OR RC 、-OCX 3 3 、-OCH 2 X 3 、-OCHX 3 2 、-N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a bond to a binder linker. 3A , R 3B , R 3C , R 3D , X 3 , n3, m3 and v3 are as described herein and are included in the embodiments.

[0157] In an embodiment, R 4 are independently hydrogen, halogen, -CX 4 3 、-CHX 4 2 、-CH 2 X 4 、-CN、-OR 4D 、-C(O)R 4C 、-C(O)-OR 4C 、-C(O)NR 4A R 4B 、-N(O) m4 、-SO n4 R 4D 、-SO v4 NR 4A R 4B 、-NR 4A R 4B 、-NHC(O)NR 4A R 4B 、-NR 4A SO 2 R 4D 、-NR 4A C(O)R 4C 、-NR 4A C(O)OR 4C 、-NR 4A OR4C 、-OCX 4 3 、-OCH 2 X 4 、-OCHX 4 2 、-N 3 、-SF 5 R is an electrophilic moiety, wherein R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. 4A , R 4B , R 4C , R 4D , X 4 , n4, m4 and v4 are as described herein and are included in the embodiments.

[0158] In an embodiment, R 1 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a bond to a binder linker; two R 1 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 2 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a bond to a binder linker; two R 2 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. 3 For the bond, -N(R 3 )-、-C(O)-、-C(O)N(R 3 )-、-N(R 3 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. In embodiments, R 3 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R 4 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or E. E is an electrophilic moiety. z1 is an integer from 0 to 4. z2 is an integer from 0 to 5. Only one R 1 and an R 2 is a bond to the binding agent linker. 1 is a bond to the binding agent linker. 2 is the bond to the binder linker.

[0159] In an embodiment, the E3 ubiquitin ligase binder is part of a compound having the formula:

[0160] In an embodiment, the E3 ubiquitin ligase conjugate is a monovalent compound having the formula:

[0161] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula:

[0162] R 1 , R 2 , L 3 , z1, z2 and R 4 As described in this article.

[0163] R 5 and R 6 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a bond to a binder linker. 7 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or a bond to a binder linker; two R 7 The substituents may be optionally linked to form a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. The symbol z7 is an integer from 0 to 10; in an embodiment, only one R 1 , R 2 , R 5 , R 6 or R 7 is independently a bond to a binding agent linker. 1 is independently a bond to a binding agent linker. 2 is independently a bond to a binding agent linker. 3 is independently a bond to a binding agent linker. 5 is independently a bond to a binding agent linker. 6 is independently a bond to a binding agent linker. 7 is independently a bond to a binding agent linker.

[0164] In an embodiment, the E3 ubiquitin ligase binder is part of a compound having the formula: R 1 , R 2 , R 3 , R 4 , R 5, R 6 and R 7 As described herein. 8 , R 9 and R 10 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or a bond to a binder linker. Only one R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 7 , R 8 , R 9 or R 10 is a bond to the binder linker; and It is a single bond or a double bond.

[0165] In an embodiment, the E3 ubiquitin ligase binder is a monovalent compound having the formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described in this article.

[0166] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described in this article.

[0167] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described in this article.

[0168] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: R 1 , R 3 , R 4 , R 5 , R 6 , R7 , R 8 , R 9 , R 10 , z1 and z7 are as described herein. 2w are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or substituted or unsubstituted heteroaryl (e.g., 5-10, 5-9, or 5-6 members), or a bond to a binder linker. The symbol z3 is an integer from 0 to 3. Only one R 1 , R 2w , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is a bond to the binder linker; and It is a single bond or a double bond.

[0169] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: R 1 , R 2w , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , z1, z3 and z7 are as described in this article.

[0170] In an embodiment, R 3 is independently a bond to a binding agent linker. 8 is independently a bond to a binding agent linker. 9 is independently a bond to a binding agent linker. 10 is independently a bond to a binding agent linker.

[0171] In an embodiment, R 2ware independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , R 21 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), R 21 - substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), R 21- substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), R 21 - substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R 21 - substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl), R 21 - a substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered) or a bond to a binding linker.

[0172] In an embodiment, R 2w are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl, or a bond to a binding agent linker.

[0173] In an embodiment, the substituted R 2w (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 2w is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 2w When substituted, it is substituted with at least one substituent. 2w When substituted, it is substituted with at least one substituent of limited size. 2w When substituted, it is substituted with at least one lower substituent.

[0174] In an embodiment, R 2w are independently hydrogen or substituted or unsubstituted C 1 -C 4 In the embodiment, R 2w are independently hydrogen. 2w are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 2w is independently unsubstituted C 1 -C 4 In the embodiment, R 2wis independently unsubstituted methyl. 2w is independently unsubstituted ethyl. 2w is independently unsubstituted n-propyl. 2w is independently unsubstituted isopropyl. 2w is independently unsubstituted n-butyl. 2w is independently unsubstituted tert-butyl.

[0175] In an embodiment, R 3 are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 3 is independently unsubstituted C 1 -C 4 In the embodiment, R 3 is independently unsubstituted methyl. 3 is independently unsubstituted ethyl. 3 is independently unsubstituted n-propyl. 3 is independently unsubstituted isopropyl. 3 is independently unsubstituted n-butyl. 3 is independently unsubstituted tert-butyl.

[0176] In an embodiment, z3 is 0. In an embodiment, z3 is 1. In an embodiment, z3 is 2. In an embodiment, z3 is 3.

[0177] In an embodiment, R 7 are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 7 is independently unsubstituted C 1 -C 4 In the embodiment, R 7 is independently unsubstituted methyl. 7 is independently unsubstituted ethyl. 7 is independently unsubstituted n-propyl. 7 is independently unsubstituted isopropyl. 7 is independently unsubstituted n-butyl. 7 is independently unsubstituted tert-butyl.

[0178] In an embodiment, R 8 are independently hydrogen, halogen, -CCl3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6, C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bond to a binding agent linker.

[0179] In an embodiment, R 8 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl, or a bond to a binding agent linker.

[0180] In an embodiment, the substituted R 8 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 8 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 8 When substituted, it is substituted with at least one substituent. 8 When substituted, it is substituted with at least one substituent of limited size. 8 When substituted, it is substituted with at least one lower substituent.

[0181] In an embodiment, R 8 are independently hydrogen or substituted or unsubstituted C 1 -C 4 In the embodiment, R 8 are independently hydrogen. 8 are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 8 is independently unsubstituted C 1 -C 4 In the embodiment, R 8 is independently unsubstituted methyl. 8 is independently unsubstituted ethyl. 8 is independently unsubstituted n-propyl. 8 is independently unsubstituted isopropyl.8 is independently unsubstituted n-butyl. 8 is independently unsubstituted tert-butyl.

[0182] In an embodiment, R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bond to a binding agent linker.

[0183] In an embodiment, R 9 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl, or a bond to a binding agent linker.

[0184] In an embodiment, the substituted R 9 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 9 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 9 When substituted, it is substituted with at least one substituent. 9 When substituted, it is substituted with at least one substituent of limited size. 9 When substituted, it is substituted with at least one lower substituent.

[0185] In an embodiment, R 9 are independently hydrogen or substituted or unsubstituted C 1 -C 4 In the embodiment, R 9 are independently hydrogen. 9 are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 9 is independently unsubstituted C 1 -C 4 In the embodiment, R9 is independently unsubstituted methyl. 9 is independently unsubstituted ethyl. 9 is independently unsubstituted n-propyl. 9 is independently unsubstituted isopropyl. 9 is independently unsubstituted n-butyl. 9 is independently unsubstituted tert-butyl.

[0186] In an embodiment, R 10 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bond to a binding agent linker.

[0187] In an embodiment, R 10 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl, or a bond to a binding agent linker.

[0188] In an embodiment, the substituted R 10 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 10 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 10 When substituted, it is substituted with at least one substituent. 10 When substituted, it is substituted with at least one substituent of limited size. 10 When substituted, it is substituted with at least one lower substituent.

[0189] In an embodiment, R 10 are independently hydrogen or substituted or unsubstituted C 1 -C 4 In the embodiment, R 10are independently hydrogen. 10 are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 10 is independently unsubstituted C 1 -C 4 In the embodiment, R 10 is independently unsubstituted methyl. 10 is independently unsubstituted ethyl. 10 is independently unsubstituted n-propyl. 10 is independently unsubstituted isopropyl. 10 is independently unsubstituted n-butyl. 10 is independently unsubstituted tert-butyl.

[0190] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described herein. In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula:

[0191] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: Where R 1 , R 2w , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , z1, z3 and z7 are as described herein. In an embodiment, the E3 ubiquitin ligase binder is a monovalent form of the formula: In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula:

[0192] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described herein. In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula:

[0193] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: Where R 1 , R 2w , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , z1, z3 and z7 are as described herein. In an embodiment, the E3 ubiquitin ligase binder is a monovalent form of the formula: In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula:

[0194] In an embodiment, the E3 ubiquitin ligase binder is part of a monovalent compound having the formula: Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described herein. In embodiments, the E3 ubiquitin ligase binder is part of a monovalent compound having the formula: In an embodiment, the E3 ubiquitin ligase binder is part of a monovalent compound having the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula:

[0195] In an embodiment, the E3 ubiquitin ligase binder is part of a monovalent compound having the formula: Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described herein. In embodiments, the E3 ubiquitin ligase binder is part of a monovalent compound having the formula: In an embodiment, the E3 ubiquitin ligase binder is part of a monovalent compound having the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula:

[0196] In an embodiment, the E3 ubiquitin ligase binder is part of a compound having the formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described in this article.

[0197] In an embodiment, the E3 ubiquitin ligase binder is a monovalent compound having the formula: Where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described herein. In embodiments, the E3 ubiquitin ligase binder is a monovalent compound having the formula: In an embodiment, the E3 ubiquitin ligase binder is a monovalent compound having the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula: In an embodiment, the E3 ubiquitin ligase binder has the formula:

[0198] In an embodiment, the E3 ubiquitin ligase binder is a monovalent compound having the formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 As described in this article.

[0199] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: Where L 3 and R 4 As described in this article.

[0200] In an embodiment, the E3 ubiquitin ligase binder is part of a compound having the formula: Where L 3 and R 4 As described in this article.

[0201] In an embodiment, the E3 ubiquitin ligase binder is a monovalent compound having the formula: Where L 3 and R 4 As described in this article.

[0202] In embodiments, the E3 ubiquitin ligase binder is in the monovalent form of the formula: Where L 3 and R 4 As described in this article.

[0203] In an embodiment, the E3 ubiquitin ligase binder has the formula: Where L 3 and R 4 As described in this article.

[0204] In an embodiment, the E3 ubiquitin ligase binder has the formula: Where L 3 and R 4 As described in this article.

[0205] In an embodiment, the E3 ubiquitin ligase binder has the formula: Where L 3 and R 4 As described in this article.

[0206] In an embodiment, the E3 ubiquitin ligase binder has the formula: Where L 3 and R 4 As described in this article.

[0207] In an embodiment, the E3 ubiquitin ligase binder has the formula: Where L 3 and R 4 As described in this article.

[0208] In an embodiment, the E3 ubiquitin ligase binder has the formula: Where L 3 and R 4 As described in this article.

[0209] In an embodiment, R 1 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0210] In an embodiment, R 1Independently being halogen, -CCl 3 、-CBr 3 、-CF 3 、-CI 3 、-CHCl 2 、-CHBr 2 、-CHF 2 、-CHI 2 、-CH 2 Cl、-CH 2 Br、-CH 2 F、-CH 2 I、-CN、-OH、-NH 2 、-COOH、-CONH 2 、-NO 2 、-SH、-SO 3 H、-SO 4 H、-SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H、-NHC(O)H、-NHC(O)OH、-NHOH、-OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 、-OCHCl 2 、-OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl、-OCH 2 Br、-OCH 2 I、-OCH 2 F、-N 3 、-SF 5, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl.

[0211] In an embodiment, the substituted R 1 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 1 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 1 When substituted, it is substituted with at least one substituent. 1 When substituted, it is substituted with at least one substituent of limited size. 1 When substituted, it is substituted with at least one lower substituent.

[0212] In an embodiment, R 1 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 11 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 11 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 11 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 11 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 11 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 11 - substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered) or a bond to a binder linker; two R 1 The substituents may be optionally linked to form 11-substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 11 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 11 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 11 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0213] In an embodiment, R 1 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 11 -substituted or unsubstituted C 1 -C 8 Alkyl, R 11 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 11 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 11 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 11 -substituted or unsubstituted C 6 -C 10 Aryl or R 11 -substituted or unsubstituted 5- to 10-membered heteroaryl or a bond to the binder linker; two R 1 The substituents may be optionally linked to form 11 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 11 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 11 -substituted or unsubstituted C 6 -C 10 Aryl or R 11 -substituted or unsubstituted 5- to 10-membered heteroaryl.

[0214] In an embodiment, R 1 are independently halogen. 1 are independently unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0215] In an embodiment, R 1 are independently halogen. 1 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0216] R 11 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0217] In an embodiment, R 11 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0218] In an embodiment, R 11 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl.

[0219] In an embodiment, the substituted R 11 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 11 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 11 When substituted, it is substituted with at least one substituent. 11 When substituted, it is substituted with at least one substituent of limited size. 11 When substituted, it is substituted with at least one lower substituent.

[0220] In an embodiment, R 11 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 12 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 12 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 12 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 12-substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 12 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 12 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). 11 is an unsubstituted alkyl group (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0221] In an embodiment, R 11 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 12 -substituted or unsubstituted C 1 -C 8 Alkyl, R 12 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 12 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 12 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 12 -substituted or unsubstituted C 6 -C 10 Aryl or R 12 -substituted or unsubstituted 5- to 10-membered heteroaryl. 11 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0222] R 12 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0223] In an embodiment, R 12 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 The alkyl radicals may be alkyl, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0224] In an embodiment, R 12 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C 3 -C 8 Cycloalkyl, unsubstituted 3- to 8-membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl or unsubstituted 5- to 10-membered heteroaryl.

[0225] In an embodiment, R 2 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0226] In an embodiment, R 2 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl.

[0227] In an embodiment, the substituted R 2 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, a substituent of limited size or a lower substituent; wherein if the substituted R 2 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 2 When substituted, it is substituted with at least one substituent. 2 When substituted, it is substituted with at least one substituent of limited size. 2 When substituted, it is substituted with at least one lower substituent.

[0228] In an embodiment, R 2 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 21 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 21 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 21 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 21 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 21 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 21 -substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); two R 2 The substituents may be optionally linked to form 21 -substituted or unsubstituted cycloalkyl (e.g., C3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 21 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 21 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 21 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0229] In an embodiment, R 2 are independently halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 21 -substituted or unsubstituted C 1 -C 8 Alkyl, R 21 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 21 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 21 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 21 -substituted or unsubstituted C 6 -C 10 Aryl or R 21 -substituted or unsubstituted 5- to 10-membered heteroaryl or a bond to the binder linker; two R 2 The substituents may be optionally linked to form 21 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 21 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 21 -substituted or unsubstituted C 6 -C 10 Aryl or R 21 -substituted or unsubstituted 5- to 10-membered heteroaryl.

[0230] In an embodiment, R 2 are independently halogen, -CF 3 、-NO 2 , by R 21 -substituted or unsubstituted C 1 -C 3 Alkyl, unsubstituted 2-membered to 3-membered heteroalkyl or a bond to a binder linker; two R 2 The substituents may be optionally linked to form an unsubstituted phenyl group.

[0231] In an embodiment, R 2 are independently halogen, -CF 3 、-NO 2 , by R 21 -substituted or unsubstituted C 1 -C 3 Alkyl, unsubstituted 2-membered to 3-membered heteroalkyl or a bond to a binder linker; two R 2The substituents may be optionally linked to form an unsubstituted phenyl group; and R 21 is independently -OH.

[0232] In an embodiment, R 2 are independently halogen. 2 In the embodiment, R 2 is independently -Br. In an embodiment, R 2 In an embodiment, R 2 is independently -F. In an embodiment, R 2 Independently -CF 3 In an embodiment, R 2 Independently -NO 2 In an embodiment, R 2 Independently 21 -substituted C 1 -C 4 In the embodiment, R 2 Independently 21 -substituted C 1 -C 4 Alkyl, where R 21 In the embodiment, R 2 independently -CH 2 OH. In the embodiment, R 2 is independently unsubstituted C 1 -C 4 In the embodiment, R 2 is independently unsubstituted methyl. 2 is independently unsubstituted ethyl. 2 is independently unsubstituted n-propyl. 2 is independently unsubstituted isopropyl. 2 is independently unsubstituted n-butyl. 2 is independently unsubstituted tert-butyl. 2 is independently an unsubstituted 2- to 4-membered heteroalkyl. 2 Independently -OCH 3 In an embodiment, R 2 Independently -OCH 2 CH 3 In an embodiment, R 2 are independently a bond to a binding agent linker. 2 The substituents may be optionally linked to form an unsubstituted phenyl group.

[0233] R 21 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0234] In an embodiment, R 21 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0235] In an embodiment, R 21 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl.

[0236] In an embodiment, the substituted R 21 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 21 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 21 When substituted, it is substituted with at least one substituent. 21 When substituted, it is substituted with at least one substituent of limited size. 21 When substituted, it is substituted with at least one lower substituent.

[0237] In an embodiment, R 21 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 22 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 22 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 22 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 22 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 22 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 22 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered). 21 is an unsubstituted alkyl group (e.g., C 1 -C 8 , C1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0238] In an embodiment, R 21 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 22 -substituted or unsubstituted C 1 -C 8 Alkyl, R 22 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 22 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 22 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 22 -substituted or unsubstituted C 6 -C 10 Aryl or R 22 -substituted or unsubstituted 5- to 10-membered heteroaryl.

[0239] R 22 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 B x 、-CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0240] In an embodiment, R 22 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0241] In an embodiment, R 22 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 The alkyl radicals may be alkyl, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0242] In an embodiment, R 22 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C 3 -C 8 Cycloalkyl, unsubstituted 3- to 8-membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl or unsubstituted 5- to 10-membered heteroaryl.

[0243] In the embodiment, L 3 For the bond, -N(R 3 )-、-C(O)-、-C(O)N(R 3 )-、-N(R 3 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6), substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0244] In the embodiment, L 3 For the bond, -N(R 3 )-、-C(O)-、-C(O)N(R 3 )-、-N(R 3 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted arylene, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroarylene.

[0245] In an embodiment, the substituted L 3 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted L 3 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when L 3 When substituted, it is substituted with at least one substituent. 3 When substituted, it is substituted with at least one substituent of limited size. 3 When substituted, it is substituted with at least one lower substituent.

[0246] In the embodiment, L 3 For the bond, -N(R 3 )-、-C(O)-、-C(O)N(R3 )-、-N(R 3 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, via R 3 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 3 -substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 3 -substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 3 -substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R 3 - substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenylene) or R 3 - substituted or unsubstituted heteroarylene (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0247] In the embodiment, L 3 For the bond, -N(R 3 )-、-C(O)-、-C(O)N(R 3 )-、-N(R 3 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, via R 3 -substituted or unsubstituted C 1 -C 8 Alkylene, R 3 -substituted or unsubstituted 2- to 8-membered heteroalkylene, 3 -substituted or unsubstituted C 3 -C 8 Cycloalkylene, R 3 -substituted or unsubstituted 3- to 8-membered heterocycloalkylene, 3 -substituted or unsubstituted C6 -C 10 Arylene or R 3 -substituted or unsubstituted 5- to 10-membered heteroarylene.

[0248] In the embodiment, L 3 -N(R 3 )-. In the embodiment, L 3 -N(R 3 )-;R 3 Independently 31 -substituted methyl, unsubstituted phenyl or unsubstituted 5- to 6-membered heteroaryl; and R 31 is independently unsubstituted phenyl or unsubstituted 5- to 6-membered heteroaryl. 3 for In the embodiment, L 3 for In the embodiment, L 3 -CH 2 NH-.

[0249] In an embodiment, R 3 Independently 31 Substituted or unsubstituted C 1 -C 4 In the embodiment, R 3 Independently 31 Substituted C 1 -C 4 In the embodiment, R 3 Independently 31 In the embodiment, R 3 Independently 31 In the embodiment, R 3 Independently 31 In the embodiment, R 3 Independently 31 In the embodiment, R 3 are independently halogen. 3 is independently -F. In an embodiment, R 3 In the embodiment, R 3 is independently -Br. In an embodiment, R 3 In an embodiment, R 3 Independently 31 In the embodiment, R 3 Independently 31 In the embodiment, R 3 Independently In an embodiment, R 31 are independently C(O)H, -COOH or R 32 is a substituted or unsubstituted 2- to 6-membered heteroalkyl group. 31 is independently -C(O)H. In an embodiment, R 31 In the embodiment, R 31 Independently 32 substituted 2- to 6-membered heteroalkyl. 31 is independently an unsubstituted 2- to 6-membered heteroalkyl. 31 Independently In an embodiment, R 31 Independently 32 In the embodiment, R 31 is independently unsubstituted phenyl. 32 are independently oxo.

[0250] In an embodiment, R 3 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0251] In an embodiment, R 3 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0252] In an embodiment, R 3 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl.

[0253] In an embodiment, the substituted R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 3 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 3 When substituted, it is substituted with at least one substituent. 3 When substituted, it is substituted with at least one substituent of limited size. 3 When substituted, it is substituted with at least one lower substituent.

[0254] In an embodiment, R 3 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 31 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 31 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 31 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 31 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 31 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 31 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0255] In an embodiment, R 3 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 、-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 31 -substituted or unsubstituted C 1 -C 8 Alkyl, R 31 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 31 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 31 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 31 -substituted or unsubstituted C 6 -C 10 Aryl or R 31 -substituted or unsubstituted 5- to 10-membered heteroaryl.

[0256] R 31 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0257] In an embodiment, R 31 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0258] In an embodiment, R 31 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl.

[0259] In an embodiment, the substituted R 31 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 31 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 31 When substituted, it is substituted with at least one substituent. 31 When substituted, it is substituted with at least one substituent of limited size. 31 When substituted, it is substituted with at least one lower substituent.

[0260] In an embodiment, R 31 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 32 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 32 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 32 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C4 -C 6 or C 5 -C 6 ), by R 32 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 32 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 32 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0261] In an embodiment, R 31 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH2 F, -N 3 、-SF 5 , by R 32 -substituted or unsubstituted C 1 -C 8 Alkyl, R 32 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 32 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 32 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 32 -substituted or unsubstituted C 6 -C 10 Aryl or R 32 -substituted or unsubstituted 5- to 10-membered heteroaryl.

[0262] R 32 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0263] In an embodiment, R 32 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl (e.g., C1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0264] In an embodiment, R 32 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 The alkyl radicals may be alkyl, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0265] In an embodiment, R 32 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C 3 -C 8 Cycloalkyl, unsubstituted 3- to 8-membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl or unsubstituted 5- to 10-membered heteroaryl.

[0266] In an embodiment, R 4 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bond to a binding agent linker.

[0267] In an embodiment, R 4 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl, or a bond to a binding agent linker.

[0268] In an embodiment, the substituted R 4 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 4 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 4 When substituted, it is substituted with at least one substituent. 4 When substituted, it is substituted with at least one substituent of limited size. 4 When substituted, it is substituted with at least one lower substituent.

[0269] In an embodiment, R 4are independently hydrogen or substituted or unsubstituted C 1 -C 4 In the embodiment, R 4 are independently hydrogen. 4 are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 4 is independently unsubstituted C 1 -C 4 In the embodiment, R 4 is independently unsubstituted methyl. 4 is independently unsubstituted ethyl. 4 is independently unsubstituted n-propyl. 4 is independently unsubstituted isopropyl. 4 is independently unsubstituted n-butyl. 4 is independently unsubstituted tert-butyl. 4 is independently E, wherein E is as described herein, included in the Examples.

[0270] In an embodiment, R 4 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 41 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 41 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 41 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 41 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 41 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 41 -substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered) or E.

[0271] In an embodiment, R 4 are independently hydrogen, oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 41 -substituted or unsubstituted C 1 -C 8 Alkyl, R 41 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 41 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 41 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 41 -substituted or unsubstituted C 6 -C 10 Aryl or R 41 -substituted or unsubstituted 5- to 10-membered heteroaryl or E.

[0272] R 41 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0273] In an embodiment, R 41 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0274] In an embodiment, R 41 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl.

[0275] In an embodiment, the substituted R 41 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 41 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 41 When substituted, it is substituted with at least one substituent. 41 When substituted, it is substituted with at least one substituent of limited size. 41 When substituted, it is substituted with at least one lower substituent.

[0276] In an embodiment, R 41 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 42 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 42 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 42 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 42 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 42 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 42 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0277] In an embodiment, R 41 are independently oxo, halogen, -CCl3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 42 -substituted or unsubstituted C 1 -C 8 Alkyl, R 42 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 42 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 42 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 42 -substituted or unsubstituted C 6 -C 10 Aryl or R 42-substituted or unsubstituted 5- to 10-membered heteroaryl.

[0278] R 42 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0279] In an embodiment, R 42 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3, -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0280] In an embodiment, R 42 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C 3 -C8 Cycloalkyl, unsubstituted 3- to 8-membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl or unsubstituted 5- to 10-membered heteroaryl.

[0281] In embodiments, E is a covalent cysteine ​​modifier moiety.

[0282] In an embodiment, E is R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 17 In the embodiment, X 17 In the embodiment, X 17 It is -Cl.

[0283] In an embodiment, E is R 15 , R 16 and R 17 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3、-SF 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 17 In the embodiment, X 17 In the embodiment, X 17 It is -Cl.

[0284] In an embodiment, R 15 , R 16 and R 17 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0285] In an embodiment, R 18 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0286] In an embodiment, R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl.

[0287] In an embodiment, R 15 , R 16 and R 17 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted aryl, substituted (e.g., substituted with a substituent, a size-restricted substituent, or a lower substituent) or unsubstituted heteroaryl.

[0288] In an embodiment, the substituted R 15(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 15 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 15 When substituted, it is substituted with at least one substituent. 15 When substituted, it is substituted with at least one substituent of limited size. 15 When substituted, it is substituted with at least one lower substituent.

[0289] In an embodiment, the substituted R 16 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 16 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 16 When substituted, it is substituted with at least one substituent. 16 When substituted, it is substituted with at least one substituent of limited size. 16 When substituted, it is substituted with at least one lower substituent.

[0290] In an embodiment, the substituted R 17 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 17 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 17 When substituted, it is substituted with at least one substituent. 17 When substituted, it is substituted with at least one substituent of limited size. 17 When substituted, it is substituted with at least one lower substituent.

[0291] In an embodiment, the substituted R 18(e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 18 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 18 When substituted, it is substituted with at least one substituent. 18 When substituted, it is substituted with at least one substituent of limited size. 18 When substituted, it is substituted with at least one lower substituent.

[0292] In an embodiment, R 15 , R 16 , R 17 and R 18 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0293] In an embodiment, R 15 , R 16 and R 17 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0294] In an embodiment, E is And R 15 , R 16 , R 17 and R 18 are independently hydrogen.

[0295] In an embodiment, E is And R 15 , R 16 and R 17 In an embodiment, E is And R 17 is independently -Cl.

[0296] In an embodiment, -L 3 -R 4 for: In an embodiment, -L 3 -R 4 for: In an embodiment, -L 3 -R 4 for: In an embodiment, -L 3 -R 4 for:

[0297] In an embodiment, z1 is an integer from 0 to 2. In an embodiment, z2 is an integer from 0 to 2. In an embodiment, z1 is 0. In an embodiment, z1 is 1. In an embodiment, z1 is 2. In an embodiment, z1 is 3. In an embodiment, z1 is 4. In an embodiment, z2 is 0. In an embodiment, z2 is 1. In an embodiment, z2 is 2. In an embodiment, z2 is 3. In an embodiment, z2 is 4. In an embodiment, z2 is 5.

[0298] In an embodiment, z2 is 1 and R 2 is the bond to the binder linker.

[0299] In an embodiment, R 7 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bond to a binding agent linker.

[0300] In an embodiment, R 7 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl, or a bond to a binding agent linker.

[0301] In an embodiment, the substituted R 7 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 7 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 7 When substituted, it is substituted with at least one substituent. 7 When substituted, it is substituted with at least one substituent of limited size. 7 When substituted, it is substituted with at least one lower substituent.

[0302] In an embodiment, R 1 , R 2 and R 7 are independently halogen, -CCl 3, -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 51 -substituted or unsubstituted C 1 -C 8 Alkyl, R 51 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 51 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 51 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 51 -substituted or unsubstituted C 6 -C 10 Aryl or R 51-substituted or unsubstituted 5- to 10-membered heteroaryl or a bond to the binder linker; two R 1 Substituent or two R 2 Substituent or two R 7 The substituents may be optionally linked to form 51 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 51 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 51 -substituted or unsubstituted C 6 -C 10 Aryl or R 51 -substituted or unsubstituted 5- to 10-membered heteroaryl.

[0303] In an embodiment, R 7 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 51 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 51 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 51 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 51 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 51 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 51 - substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered) or a bond to a binder linker; two R 7 The substituents may be optionally linked to form 51 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 51 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 51 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 51 - substituted or unsubstituted heteroaryl (eg, 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0304] In an embodiment, R 7 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 51 -substituted or unsubstituted C 1 -C 8 Alkyl, R 51 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 51 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 51 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 51-substituted or unsubstituted C 6 -C 10 Aryl or R 51 -substituted or unsubstituted 5- to 10-membered heteroaryl or a bond to the binder linker; two R 7 The substituents may be optionally linked to form 51 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 51 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 51 -substituted or unsubstituted C 6 -C 10 Aryl or R 51 -substituted or unsubstituted 5- to 10-membered heteroaryl.

[0305] In an embodiment, R 5 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bond to a binding agent linker.

[0306] In an embodiment, R 5 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl, or a bond to a binding agent linker.

[0307] In an embodiment, the substituted R 5 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 5 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 5 When substituted, it is substituted with at least one substituent. 5 When substituted, it is substituted with at least one substituent of limited size. 5 When substituted, it is substituted with at least one lower substituent.

[0308] In an embodiment, R 5 are independently hydrogen or substituted or unsubstituted C 1 -C 4 In the embodiment, R 5 are independently hydrogen. 5 are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 5 is independently unsubstituted C 1 -C 4 In the embodiment, R 5 is independently unsubstituted methyl. 5 is independently unsubstituted ethyl. 5 is independently unsubstituted n-propyl. 5 is independently unsubstituted isopropyl. 5 is independently unsubstituted n-butyl. 5 is independently unsubstituted tert-butyl.

[0309] In an embodiment, R 6 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkyl (e.g., 3-8, 3-6, 4-6, 4-5, or 5-6 members), substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroaryl (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bond to a binding agent linker.

[0310] In an embodiment, R 6 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkyl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted aryl, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroaryl, or a bond to a binding agent linker.

[0311] In an embodiment, the substituted R 6 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl and / or substituted heteroaryl) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted R 6 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when R 6When substituted, it is substituted with at least one substituent. 6 When substituted, it is substituted with at least one substituent of limited size. 6 When substituted, it is substituted with at least one lower substituent.

[0312] In an embodiment, R 6 are independently hydrogen or substituted or unsubstituted C 1 -C 4 In the embodiment, R 6 are independently hydrogen. 6 are independently substituted or unsubstituted C 1 -C 4 In the embodiment, R 6 is independently unsubstituted C 1 -C 4 In the embodiment, R 6 is independently unsubstituted methyl. 6 is independently unsubstituted ethyl. 6 is independently unsubstituted n-propyl. 6 is independently unsubstituted isopropyl. 6 is independently unsubstituted n-butyl. 6 is independently unsubstituted tert-butyl.

[0313] In an embodiment, R 5 and R 6 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 51 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 51 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 51 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 51 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 51 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 51 -substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered) or a bond to the binding linker.

[0314] In an embodiment, R 5 and R 6 are independently hydrogen, halogen, -CCl3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 51 -substituted or unsubstituted C 1 -C 8 Alkyl, R 51 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 51 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 51 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 51 -substituted or unsubstituted C 6 -C 10 Aryl or R 51- a substituted or unsubstituted 5- to 10-membered heteroaryl group or a bond to the binding agent linker.

[0315] R 51 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl or unsubstituted heteroaryl.

[0316] In an embodiment, R 51 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0317] In an embodiment, R 51 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C 3 -C8 Cycloalkyl, unsubstituted 3- to 8-membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl or unsubstituted 5- to 10-membered heteroaryl.

[0318] In an embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N3 、-SF 5 , by R 51 -substituted or unsubstituted C 1 -C 8 Alkyl, R 51 - substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 51 -substituted or unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 51 -substituted or unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 51 -substituted or unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), 51 -substituted or unsubstituted aryl (e.g., C 6 -C 10 or phenyl) or R 51 - substituted or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered); or a bond to a binder linker; wherein only one R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is a bond to the binding agent linker; and R 51 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkyl (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkyl (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkyl (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted aryl (e.g., C 6 -C 10or phenyl) or unsubstituted heteroaryl (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered).

[0319] In an embodiment, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3 、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , by R 51-substituted or unsubstituted C 1 -C 8 Alkyl, R 51 -substituted or unsubstituted 2- to 8-membered heteroalkyl, 51 -substituted or unsubstituted C 3 -C 8 Cycloalkyl, R 51 -substituted or unsubstituted 3- to 8-membered heterocycloalkyl, 51 -substituted or unsubstituted C 6 -C 10 Aryl or R 51 -substituted or unsubstituted 5- to 10-membered heteroaryl; or a bond to a binder linker; wherein only one R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10 is a bond to the binding agent linker; and R 51 are independently oxo, halogen, -CCl 3 , -CBr 3 , -CF 3 、-CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 、-CHI 2 、-CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 、-NO 2 、-SH、-SO 3 H, -SO 4 H, -SO 2 NH 2 、-NHNH 2 、-ONH 2 、-NHC(O)NHNH 2 、-NHC(O)NH 2 、-NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 、-OCF 3 ,-OCBr 3、-OCI 3 ,-OCHCl 2 , -OCHBr 2 、-OCHI 2 、-OCHF 2 、-OCH 2 Cl, -OCH 2 Br, -OCH 2 I. -OCH 2 F, -N 3 、-SF 5 , unsubstituted C 1 -C 8 alkyl, unsubstituted 2- to 8-membered heteroalkyl, unsubstituted C 3 -C 8 Cycloalkyl, unsubstituted 3- to 8-membered heterocycloalkyl, unsubstituted C 6 -C 10 aryl or unsubstituted 5- to 10-membered heteroaryl.

[0320] In an embodiment, the binding agent linker is L 11 -L 12 -L 13 -L 14 .L 11 Directly attaches to the E3 ubiquitin ligase binder.

[0321] L 11 For the bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or a bioconjugate linker.

[0322] L 12 , L 13 and L 14 are independently a bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O)2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or a bioconjugate linker.

[0323] In the embodiment, L 11 For the bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bioconjugate linker.

[0324] In the embodiment, L 11 -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2-, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or a bioconjugate linker.

[0325] In the embodiment, L 11 -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenyl) or a substituted or unsubstituted heteroarylene (e.g., 5-10 membered, 5-9 membered, or 5-6 membered) or a bioconjugate linker.

[0326] In an embodiment, L11 is -N(R 61 )-、C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2-, -S(O)-, -O-, -S-, -NHC(O)NH-, R 61 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 61 -substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 61 -substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 61 -substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R 61 - substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenyl) or R 61 - substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered) or a bioconjugate linker. 11 -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), unsubstituted cycloalkylene (e.g., C 3 -C 8 , C3 -C 6 , C 4 -C 6 or C 5 -C 6 ), unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), unsubstituted arylene (e.g., C 6 -C 10 or phenyl) or an unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered) or a bioconjugate linker.

[0327] In the embodiment, L 11 -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, R 61 -substituted or unsubstituted C 1 -C 20 Alkylene, R 61 -substituted or unsubstituted 2- to 20-membered heterocyclylene, R 61 -substituted or unsubstituted C 3 -C 8 Cycloalkylene, R 61 -substituted or unsubstituted 3- to 8-membered heterocycloalkylene, 61 -substituted or unsubstituted C 6 -C 10 Arylene, R 61 - a substituted or unsubstituted 5- to 10-membered heteroarylene group or a bioconjugate linker. 11 -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, unsubstituted heteroarylene, or a bioconjugate linker.

[0328] In an embodiment, L 11 -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted arylene, or substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroarylene, or a bioconjugate linker.

[0329] In an embodiment, the substituted L 11 (e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted L 11 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when L 11 When substituted, it is substituted with at least one substituent. 11 When substituted, it is substituted with at least one substituent of limited size. 11 When substituted, it is substituted with at least one lower substituent.

[0330] In an embodiment, L 12 , L 13 and L 14 are independently a bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61)C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, R 61 -substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 or C 1 -C 2 ), by R 61 -substituted or unsubstituted heteroalkylene (e.g., 2- to 8-membered, 2- to 6-membered, 4- to 6-membered, 2- to 3-membered, or 4- to 5-membered), 61 -substituted or unsubstituted cycloalkylene (e.g., C 3 -C 8 , C 3 -C 6 , C 4 -C 6 or C 5 -C 6 ), by R 61 -substituted or unsubstituted heterocycloalkylene (e.g., 3- to 8-membered, 3- to 6-membered, 4- to 6-membered, 4- to 5-membered, or 5- to 6-membered), R 61 - substituted or unsubstituted arylene (e.g., C 6 -C 10 or phenyl) or R 61 - a substituted or unsubstituted heteroarylene (e.g., 5- to 10-membered, 5- to 9-membered, or 5- to 6-membered) or a bioconjugate linker.

[0331] In the embodiment, L 12 , L 13 and L 14 are independently a bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, R 61 -substituted or unsubstituted C 1 -C 20 Alkylene, R 61 -substituted or unsubstituted 2- to 20-membered heteroalkylene,61 -substituted or unsubstituted C 3 -C 8 Cycloalkylene, R 61 -substituted or unsubstituted 3- to 8-membered heterocycloalkylene, 61 -substituted or unsubstituted C 6 -C 10 Arylene, R 61 - a substituted or unsubstituted 5- to 10-membered heteroarylene group or a bioconjugate linker. 12 , L 13 and L 14 are independently a bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, unsubstituted heteroarylene, or a bioconjugate linker.

[0332] In an embodiment, L 12 are independently a bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted alkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heteroalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted cycloalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted heterocycloalkylene, substituted (e.g., substituted with at least one substituent, size-restricted substituent, or lower substituent) or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or a bioconjugate linker.

[0333] In an embodiment, the substituted L 12(e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroarylene) is substituted with at least one substituent, size-limited substituent or lower substituent; wherein if the substituted L 12 is substituted by a plurality of groups selected from substituents, size-restricted substituents and lower substituents; each substituent, size-restricted substituent and / or lower substituent may optionally be different. In an embodiment, when L 12 When substituted, it is substituted with at least one substituent. 12 When substituted, it is substituted with at least one substituent of limited size. 12 When substituted, it is substituted with at least one lower substituent.

[0334] In an embodiment, L 13 are independently a bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O) 2 -, -S(O)-, -O-, -S-,...

Claims

1. A target protein degrader, comprising 1) a target protein binder and 2) an E3 ubiquitin ligase binder, wherein the E3 ubiquitin ligase is human RNF4 or human RNF114; wherein the target protein binder and the E3 ubiquitin ligase binder are covalently bonded via a binder linker; wherein the target protein binding agent is and Wherein the E3 ubiquitin ligase binder is in the monovalent form of the following formula: in R 1 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -NO2, unsubstituted alkyl or unsubstituted heteroalkyl; R 2 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -NO2, unsubstituted alkyl, unsubstituted heteroalkyl, or a bond to a binder linker; L 3 -N(R 3 )- or -N(H)-; R 3 is a substituted or unsubstituted alkyl group; R 4 is E; E is: R 15 , R 16 and R 17 are independently hydrogen or unsubstituted alkyl; X 17 It is a halogen; z1 is an integer from 0 to 4; z2 is an integer from 0 to 5; or Wherein the E3 ubiquitin ligase binder is in the monovalent form of the following formula: R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or unsubstituted alkyl; R 3 is a bond to the binding agent linker; and It is a single bond or a double bond. 2 . The target protein degrader according to claim 1 , wherein the E3 ubiquitin ligase binder is capable of forming a covalent bond with the cysteine ​​of the E3 ubiquitin ligase.

3. The target protein degrader according to claim 1, wherein the E3 ubiquitin ligase is human RNF4.

4. The target protein degrader according to claim 1, wherein the E3 ubiquitin ligase binder is in a monovalent form of the following formula:

5. The target protein degrading agent according to claim 4, in R 3 For R 31 -Substituted or unsubstituted C1-C8 alkyl; R 31 independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, R 32 -substituted or unsubstituted C1-C8 alkyl, 32 -substituted or unsubstituted 2- to 8-membered heteroalkyl, or R 32 -substituted or unsubstituted C6-C 10 aryl; and R 32 independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, unsubstituted C1-C8 alkyl, or unsubstituted 2- to 8-membered heteroalkyl.

6. The target protein degradation agent according to claim 5, wherein R 2 Independently halogen, -CF3, -NO2, unsubstituted C1-C3 alkyl, unsubstituted 2- to 3-membered heteroalkyl, or a bond to a binder linker.

7. The target protein degradation agent according to claim 5, wherein z2 is 1 and R 2 is the bond to the binder linker.

8. The target protein degradation agent according to claim 5, wherein R 1 are independently halogen.

9. The target protein degrading agent according to claim 5, wherein z1 is 0.

10. The target protein degradation agent according to claim 5, wherein L 3 -N(R 3 )-;R 3 For R 31 -substituted methyl; and R 31 is independently unsubstituted phenyl.

11. The target protein degradation agent according to claim 5, wherein E is and R 15 , R 16 and R 17 For hydrogen.

12. The target protein degradation agent according to claim 5, wherein E is And X 17 is independently -Cl.

13. The target protein degrader according to claim 1, wherein the E3 ubiquitin ligase binder is in a monovalent form of the following formula:

14. The target protein degrader according to claim 13, wherein the E3 ubiquitin ligase binder is in a monovalent form of the following formula:

15. The target protein degrader according to claim 13, wherein the E3 ubiquitin ligase binder is in a monovalent form of the following formula:

16. The target protein degrader according to claim 13, wherein the E3 ubiquitin ligase binder is in a monovalent form of the following formula:

17. The target protein degrader according to claim 13, wherein the E3 ubiquitin ligase binder has the following formula:

18. The target protein degrader according to claim 13, wherein the E3 ubiquitin ligase binder has the following formula:

19. The target protein degradation agent according to claim 1, wherein the binding agent linker is L 11 -L 12 -L 13 -L 14 ; L 11 directly linked to the E3 ubiquitin ligase binder; L 11 -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or a bioconjugate linker; and L 12 , L 13 and L 14 are independently a bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)-, -O-, -S-, -NHC(O)NH-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, or a bioconjugate linker.

20. The target protein degradation agent according to claim 19, wherein L 11 -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O)2-, -S(O)-, -O-, -S-, -NHC(O)NH-, via R 61 -substituted or unsubstituted C1-C 20 Alkylene, R 61 -substituted or unsubstituted 2- to 20-membered heterocyclylene, R 61 -substituted or unsubstituted C3-C8 cycloalkylene, R 61 -substituted or unsubstituted 3- to 8-membered heterocycloalkylene, 61 -substituted or unsubstituted C6-C 10 Arylene, R 61 - a substituted or unsubstituted 5- to 10-membered heteroarylene group or a bioconjugate linker; L 12 , L 13 and L 14 are independently a bond, -N(R 61 )-、-C(O)-、-C(O)N(R 61 )-、-N(R 61 )C(O)-, -N(H)-, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -S(O)2-, -S(O)-, -O-, -S-, -NHC(O)NH-, via R 61 -substituted or unsubstituted C1-C 20 Alkylene, R 61 -substituted or unsubstituted 2- to 20-membered heterocyclylene, R 61 -substituted or unsubstituted C3-C8 cycloalkylene, R 61 -substituted or unsubstituted 3- to 8-membered heterocycloalkylene, 61 -substituted or unsubstituted C6-C 10 Arylene, R 61 - a substituted or unsubstituted 5- to 10-membered heteroarylene group or a bioconjugate linker; R 61 are independently oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, -SF 5、 unsubstituted C1-C8 alkyl, unsubstituted 2-membered to 8-membered heteroalkyl, unsubstituted C3-C8 cycloalkyl, unsubstituted 3-membered to 8-membered heterocycloalkyl, unsubstituted C6-C 10 aryl or unsubstituted 5- to 10-membered heteroaryl. The target protein degrader according to claim 1 , wherein the target protein binding agent is capable of binding to a target protein associated with a disease. The target protein degrader according to claim 1 , wherein the target protein binding agent binds to BRD4.

23. The target protein degradation agent according to claim 1, which has the following formula:

24. The target protein degradation agent according to claim 1, which has the following formula:

25. A pharmaceutical composition comprising the target protein degrading agent according to any one of claims 1 to 24 and a pharmaceutically acceptable excipient.

26. Use of the target protein degrader according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing cellular protein levels.

27. The use according to claim 26, further comprising the following steps: A) ubiquitinating a cellular protein contacted with a target protein degrader, thereby forming a ubiquitinated cellular protein; B) contacting the ubiquitinated cellular protein with the proteasome, thereby forming a ubiquitinated cellular protein-proteasome complex; and C) Proteolysis of cellular proteins by the proteasome.

28. The use according to claim 26, wherein the E3 ubiquitin ligase binder contacts the E3 ubiquitin ligase cysteine ​​residue.

29. The use according to claim 28, wherein the E3 ubiquitin ligase binder covalently binds to the E3 ubiquitin ligase cysteine ​​residue.

30. The use according to claim 28, wherein the E3 ubiquitin ligase is human RNF4.

31. The use according to claim 30, wherein the cysteine ​​residue is C132 of human RNF4.

32. The use according to claim 30, wherein the cysteine ​​residue is C135 of human RNF4.

33. The use according to claim 28, wherein the E3 ubiquitin ligase is human RNF114.

34. The use according to claim 33, wherein the cysteine ​​residue is C8 of human RNF114.

35. The use according to claim 26, wherein the E3 ubiquitin ligase binder contacts an amino acid of the E3 ubiquitin ligase that lacks a stable secondary or tertiary conformational structure in the absence of the E3 ubiquitin ligase binder.

36. The use according to claim 35, wherein the amino acid contacted with the E3 ubiquitin ligase binding agent adopts a stable secondary or tertiary conformational structure when contacted with the E3 ubiquitin ligase binding agent.

37. Use of a target protein degrader or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22 in the preparation of a medicament for treating cancer in a subject in need thereof.

38. Use of a target protein degrader or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 in the preparation of a medicament for reducing cellular protein levels, comprising contacting the cellular protein with the target protein degrader, thereby forming a target protein degrader-cellular protein complex.

39. The use according to claim 38, wherein the E3 ubiquitin ligase binding agent contacts the E3 ubiquitin ligase cysteine ​​residue.

40. The use according to claim 39, wherein the E3 ubiquitin ligase binder covalently binds to a cysteine ​​residue of the E3 ubiquitin ligase.

41. The use according to claim 39, wherein the E3 ubiquitin ligase is human RNF4.

42. Use according to claim 41, wherein the cysteine ​​residue is C132 of human RNF4.

43. The use according to claim 41, wherein the cysteine ​​residue is C135 of human RNF4.

44. The use according to claim 39, wherein the E3 ubiquitin ligase is human RNF114.

45. Use according to claim 44, wherein the cysteine ​​residue is C8 of human RNF114.

46. ​​The use according to claim 38, wherein the E3 ubiquitin ligase binder contacts an amino acid of the E3 ubiquitin ligase that lacks a stable secondary or tertiary conformational structure in the absence of the E3 ubiquitin ligase binder.

47. The use according to claim 46, wherein the amino acid contacted with the E3 ubiquitin ligase binding agent adopts a stable secondary or tertiary conformational structure when contacted with the E3 ubiquitin ligase binding agent.

48. The use according to claim 38, wherein prior to contacting, the target protein degrading agent is synthesized by covalently reacting an E3 ubiquitin ligase binder, a binder linker, and a target protein binder to produce a target protein degrading agent.

49. The use according to claim 48, wherein the E3 ubiquitin ligase binder is identified from candidate E3 ubiquitin ligase binders prior to synthesis.

50. The use according to claim 49, wherein the E3 ubiquitin ligase binder is identified by a method comprising the steps of: i) contacting the E3 ubiquitin ligase protein with a mixture of candidate E3 ubiquitin ligase binders, thereby forming an E3 ubiquitin ligase protein-E3 ubiquitin ligase binder complex; and ii) identifying a candidate E3 ubiquitin ligase binder from the E3 ubiquitin ligase protein-E3 ubiquitin ligase binder complex as an E3 ubiquitin ligase binder.

51. The use according to claim 50, wherein the candidate E3 ubiquitin ligase binder comprises a covalent cysteine ​​modifier moiety, and the candidate E3 ubiquitin ligase binder is identified as an E3 ubiquitin ligase binder by detecting covalent binding of the E3 ubiquitin ligase binder to an E3 ubiquitin ligase protein to form an E3 ubiquitin ligase protein-E3 ubiquitin ligase binder complex.

52. The use according to claim 51, wherein the detection of the E3 ubiquitin ligase protein-E3 ubiquitin ligase binder complex comprises the use of a detectable label or mass spectrometry.

53. The use of claim 38, wherein the target protein binding agent is identified prior to synthesis.

54. The use according to claim 53, wherein the target protein binding agent is identified by a method comprising the steps of: i) contacting the cellular protein with a mixture of candidate target protein binding agents, thereby forming a cellular protein-target protein binding agent complex; and ii) identifying a target protein binding agent that forms a cellular protein-target protein binding agent complex.

55. The use according to claim 54, wherein the candidate target protein binding agent that forms the cellular protein-target protein binding agent complex is identified as the target protein binding agent by detecting the cellular protein-target protein binding agent complex.

56. The use according to claim 55, wherein the detection of the cellular protein-target protein binding agent complex comprises the use of a detectable label or mass spectrometry.

57. The use of claim 38, wherein prior to synthesis, the E3 ubiquitin ligase binder is modified to remove the covalent cysteine ​​modifier moiety.

58. A method for preparing an E3 ubiquitin ligase-E3 ubiquitin ligase binder-cellular protein complex, the method comprising: A) contacting the E3 ubiquitin ligase with an E3 ubiquitin ligase binder, thereby forming an E3 ubiquitin ligase-E3 ubiquitin ligase binder complex; as well as B) contacting the E3 ubiquitin ligase-E3 ubiquitin ligase binder complex with the cellular protein, thereby forming the E3 ubiquitin ligase-E3 ubiquitin ligase binder-cellular protein complex; Wherein the E3 ubiquitin ligase binder is in the monovalent form of the following formula: in R 1 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -NO2, unsubstituted alkyl or unsubstituted heteroalkyl; R 2 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -NO2, unsubstituted alkyl or unsubstituted heteroalkyl; L 3 -N(R 3 )- or -N(H)-; R 3 is a substituted or unsubstituted alkyl group; R 4 is E; E is: R 15 , R 16 and R 17 are independently hydrogen or unsubstituted alkyl; X 17 It is a halogen; R 5 and R 6 are independently hydrogen or unsubstituted alkyl; R 7 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, unsubstituted alkyl or unsubstituted heteroalkyl; z1 is an integer from 0 to 4; z2 is an integer from 0 to 5; and z7 is an integer from 0 to 10; or Wherein the E3 ubiquitin ligase binder is in the monovalent form of the following formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or unsubstituted alkyl; and It is a single bond or a double bond.

59. The method of claim 58, wherein the E3 ubiquitin ligase binding agent covalently bonds to a cysteine ​​of the E3 ubiquitin ligase.

60. The method of claim 58, wherein the E3 ubiquitin ligase is human RNF4.

61. A method for preparing a cellular protein-E3 ubiquitin ligase binder-E3 ubiquitin ligase complex, the method comprising: A) contacting the cellular protein with an E3 ubiquitin ligase binder, thereby forming a cellular protein-E3 ubiquitin ligase binder complex; as well as B) contacting the cellular protein-E3 ubiquitin ligase binder complex with the E3 ubiquitin ligase, thereby forming a cellular protein-E3 ubiquitin ligase binder-E3 ubiquitin ligase complex; Wherein the E3 ubiquitin ligase binder is in the monovalent form of the following formula: in R 1 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -NO2, unsubstituted alkyl or unsubstituted heteroalkyl; R 2 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -NO2, unsubstituted alkyl or unsubstituted heteroalkyl; L 3 -N(R 3 )- or -N(H)-; R 3 is a substituted or unsubstituted alkyl group; R 4 is E; E is: R 15 , R 16 and R 17 are independently hydrogen or unsubstituted alkyl; X 17 It is a halogen; R 5 and R 6 are independently hydrogen or unsubstituted alkyl; R 7 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, unsubstituted alkyl or unsubstituted heteroalkyl; z1 is an integer from 0 to 4; z2 is an integer from 0 to 5; and z7 is an integer from 0 to 10; or Wherein the E3 ubiquitin ligase binder is in the monovalent form of the following formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or unsubstituted alkyl; and It is a single bond or a double bond.

62. The method of claim 61, wherein the E3 ubiquitin ligase binding agent covalently bonds to a cysteine ​​of the E3 ubiquitin ligase.

63. The method of claim 61, wherein the E3 ubiquitin ligase is human RNF4.

64. A method of inhibiting the formation of a cellular protein-E3 ubiquitin ligase complex, the method comprising contacting the E3 ubiquitin ligase with an E3 ubiquitin ligase binding agent, and thereby inhibiting the formation of the cellular protein-E3 ubiquitin ligase complex; Wherein the E3 ubiquitin ligase binder is in the monovalent form of the following formula: in R 1 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -NO2, unsubstituted alkyl or unsubstituted heteroalkyl; R 2 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -NO2, unsubstituted alkyl or unsubstituted heteroalkyl; L 3 -N(R 3 )- or -N(H)-; R 3 is a substituted or unsubstituted alkyl group; R 4 is E; E is: R 15 , R 16 and R 17 are independently hydrogen or unsubstituted alkyl; X 17 It is a halogen; R 5 and R 6 are independently hydrogen or unsubstituted alkyl; R 7 are independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, unsubstituted alkyl or unsubstituted heteroalkyl; z1 is an integer from 0 to 4; z2 is an integer from 0 to 5; and z7 is an integer from 0 to 10; or Wherein the E3 ubiquitin ligase binder is in the monovalent form of the following formula: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently hydrogen or unsubstituted alkyl; and It is a single bond or a double bond.

65. The method of claim 64, wherein the E3 ubiquitin ligase binding agent covalently bonds to a cysteine ​​of the E3 ubiquitin ligase.

66. The method of claim 64, wherein the E3 ubiquitin ligase binder contacts the E3 ubiquitin ligase at an amino acid of the E3 ubiquitin ligase, and the E3 ubiquitin ligase is capable of contacting a cellular protein in the absence of the E3 ubiquitin ligase binder to form a cellular protein-E3 ubiquitin ligase complex.

67. The method of claim 64, wherein the E3 ubiquitin ligase is human RNF4.

68. The method of claim 65, wherein the E3 ubiquitin ligase is RNF4 and the cysteine ​​is C132 of human RNF4.

69. The method of claim 65, wherein the E3 ubiquitin ligase is RNF4 and the cysteine ​​is C135 of human RNF4.

70. The method of any one of claims 58 to 69, wherein the E3 ubiquitin ligase binding agent is in a monovalent form of the formula:

71. The method of claim 70, wherein the E3 ubiquitin ligase binding agent contacts an amino acid of the E3 ubiquitin ligase that lacks a stable secondary or tertiary conformational structure in the absence of the E3 ubiquitin ligase binding agent.

72. The method of claim 71, wherein the amino acid contacted with the E3 ubiquitin ligase binding agent adopts a stable secondary or tertiary conformational structure when contacted with the E3 ubiquitin ligase binding agent.

73. The method of any one of claims 58 to 66, wherein the E3 ubiquitin ligase is human RNF114.

74. The method of any one of claims 65 to 66, wherein the E3 ubiquitin ligase is human RNF114 and the cysteine ​​is C8 of human RNF114.

75. The method of claim 73, wherein the cellular protein is p21.

76. The method of claim 73, wherein the E3 ubiquitin ligase binding agent is in the monovalent form of the formula:

77. The method of claim 76, wherein the E3 ubiquitin ligase binding agent contacts an amino acid of the E3 ubiquitin ligase that lacks a stable secondary or tertiary conformational structure in the absence of the E3 ubiquitin ligase binding agent.

78. The method of claim 77, wherein the amino acid contacted with the E3 ubiquitin ligase binding agent adopts a stable secondary or tertiary conformational structure when contacted with the E3 ubiquitin ligase binding agent.

79. The method of claim 73, wherein the E3 ubiquitin ligase binder is in the monovalent form of the formula:

80. The method of claim 79, wherein the E3 ubiquitin ligase binding agent contacts an amino acid of the E3 ubiquitin ligase that lacks a stable secondary or tertiary conformational structure in the absence of the E3 ubiquitin ligase binding agent.

81. The method of claim 80, wherein the amino acid contacted with the E3 ubiquitin ligase binding agent adopts a stable secondary or tertiary conformational structure when contacted with the E3 ubiquitin ligase binding agent.

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