Modified proteins and proteolytic agents

Abstract

Provided herein are compounds, pharmaceutical compositions, and methods for binding to or degrading a target protein. Also provided herein are compounds having a DNA damage binding protein 1 (DDB1) binding moiety. Some such embodiments include a linker. Some such embodiments include a target protein binding moiety. Also provided herein are ligand-DDB1 complexes. Also provided herein are in vivo modified DDB1 proteins.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the benefits under International Application PCT / CN2020 / 092941 filed on 28 May 2020 and International Application PCT / CN2021 / 081554 filed on 18 March 2021, which are incorporated herein by reference in their entirety.

[0002] Sequence List This application includes a sequence listing filed electronically in ASCII format and incorporated herein by reference. The name of the ASCII copy prepared on 7 May 2021 is 54922-705_603_SL.txt and it is 2,261 bytes in size. [Background technology]

[0003] A ligand is needed to bind to or modify a protein. In the medical field, selective degradation of target proteins is required. [Overview of the project]

[0004] This specification describes modified proteins and protein-ligand complexes. Modified proteins and protein-ligand complexes of some embodiments are useful for bioengineering applications such as the selective degradation of target proteins, molecular glues, or antimicrobial agents.

[0005] This specification describes ligands that can bind to DD1. DDB1-binding ligands are useful for bioengineering applications such as the selective degradation of target proteins, molecular glues, or antimicrobial agents.

[0006] In some embodiments herein, ligand-DNA damage-binding protein 1 (DDB1) complexes are disclosed, which are formed by directly binding the DDB1 protein to a ligand containing a DDB1 binding moiety. In some embodiments, the DDB1 binding moiety is bound to a binding region on the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes a β-propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein includes the upper surface of the BPC domain. In some embodiments, the binding region on the DDB1 protein includes one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033. In some embodiments, one or more of the following DDB1 residues—ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033—are involved in the binding of the DDB1 protein to its ligand. In some embodiments, the binding between the DDB1 binding site and the DDB1 protein is non-covalent.In some embodiments, the binding of the DDB1 protein to the ligand has a binding affinity with an equilibrium dissociation constant (Kd) of less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, less than 60 μM, less than 50 μM, less than 45 μM, less than 40 μM, less than 35 μM, less than 30 μM, less than 25 μM, less than 20 μM, less than 15 μM, less than 14 μM, less than 13 μM, less than 12 μM, less than 11 μM, less than 10 μM, less than 9 μM, less than 8 μM, less than 7 μM, less than 6 μM, less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, or less than 1 μM. In some embodiments, the binding of the DDB1 protein to the ligand has a binding affinity with a Kd of less than 20 μM, a Kd of 20 - 100 μM, or a Kd of less than 100 μM. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is a covalent bond. In some embodiments, the DDB1 ligand is a small molecule. In some embodiments, the DDB1 ligand is synthetic. In some embodiments, the DDB1 binding moiety has the formula (II):

[0007]

Chemical Formula

[0008] [ka] Formula (IIa) The structure includes F 2 is a heteroaryl compound. In some embodiments, F 2is a 5-membered or 6-membered ring heteroaryl. In some embodiments, F 2 These are triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl. In some embodiments, the DDB1 binding moiety is formula (IIb):

[0009] [ka] Equation (IIb) The structure includes, in the formula, A 4 and A 5 Each of them is independently CR 12 , S, N, or O, A 4 Or A 5 At least one of them is N, O, or S. In some embodiments, A 4 is N, and A 5 is S. In some embodiments, the DDB1 coupling portion is

[0010] [ka] The structure includes, where the wavy line indicates an optional binding site to the linker or target protein binding site. In some embodiments, R 12 At each instance, L is independently selected from -NO2, halogen, methyl, halomethyl, phenyl, isopropyl, cyclopropyl, SO2CH3, or -CN. In some embodiments, L 2 -NR c C(=O)- or C(=O)NR c In some embodiments, R c is H, CH3, isopropyl, or cyclopropyl. In some embodiments, q is 1 or 2. In some embodiments, s is 1 or 2. In some embodiments, the DDB1 binding moiety comprises one of the compounds B-1 to B-176 shown in Table 1. In some embodiments, the DDB1 binding moiety is

[0011] [ka]

[0012] [ka]

[0013] [ka]

[0014] [ka]

[0015] [ka]

[0016] [ka] or comprising pharmaceutically acceptable salts thereof. In some embodiments, the DDB1 binding moiety is

[0017] [ka] or comprising pharmaceutically acceptable salts thereof. In some embodiments, the DDB1 binding moiety is

[0018] [ka]

[0019] [ka] or comprising pharmaceutically acceptable salts thereof. In some embodiments, the DDB1 binding moiety is

[0020] [ka] or pharmaceutically acceptable salts thereof. In some embodiments, the DDB1 binding moiety comprises the peptides listed in Table 3. In some embodiments, the DDB1 binding moiety comprises one of SEQ ID NOs: 1-7 (e.g., SEQ ID NOs: 1, 2, 3, 4, 5, 6, or 7), or a pharmaceutically acceptable salt thereof. In some embodiments, the DDB1 binding moiety is covalently linked to a linker. In some embodiments, the linker is a bond. In some embodiments, the linker is not a bond. In some embodiments, the linker is not merely a bond. Some embodiments include a DDB1 binding moiety to which a linker is bound. In some embodiments, the DDB1 binding moiety to which a linker is bound comprises one of the compounds BL-1-B-71 shown in Table 2. In some embodiments, the linker is further linked to a target protein binding moiety. In some embodiments, the target protein binding moiety binds to a target protein. In some embodiments, the target protein binding moiety comprises one of the compounds A-1-A-69 shown in Table 4. In some embodiments, the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently linked to a target protein binding moiety via a linker. In some embodiments, the heterobifunctional compound comprises any of compounds D-1 to D-130 shown in Table 5. In some embodiments, the complex is formed in vivo. In some embodiments, the complex is formed in vitro.

[0021] In some embodiments of this specification, in vivo modified proteins are disclosed, comprising a DDB1 protein that is directly bound to a ligand containing a DNA damage-binding protein 1 (DDB1) binding moiety. In some embodiments, the DDB1 binding moiety binds to a binding region on the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes a β-propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein includes the upper surface of the BPC domain. In some embodiments, the binding region on the DDB1 protein includes one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033. In some embodiments, the DDB1 protein is directly bound to the ligand through a non-covalent interaction between the DDB1 protein and the ligand. In some embodiments, the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033 are involved in non-covalent interactions between the DDB1 protein and its ligand.In some embodiments, the binding of the DDB1 protein to the ligand occurs when the equilibrium dissociation constant (Kd) is less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, less than 60 μM, less than 50 μM, less than 45 μM, less than 40 μM, less than 35 μM, less than 30 μM, less than 25 μM, and less than 20 μM. The binding affinity includes Kd less than 15 μM, Kd less than 14 μM, Kd less than 13 μM, Kd less than 12 μM, Kd less than 11 μM, Kd less than 10 μM, Kd less than 9 μM, Kd less than 8 μM, Kd less than 7 μM, Kd less than 6 μM, Kd less than 5 μM, Kd less than 4 μM, Kd less than 3 μM, Kd less than 2 μM, or Kd less than 1 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity of Kd less than 20 μM, Kd between 20 and 100 μM, or Kd less than 100 μM. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand comprises a targeted proteolytic inducer. In some embodiments, the ligand is synthetic. In some embodiments, the ligand and / or DDB1 binding moiety includes the structures described herein. In some embodiments, the DDB1 binding moiety is covalently linked to the linker. In some embodiments, the linker is a binding. In some embodiments, the linker is not merely a binding. In some embodiments, the linker is further connected to the target protein binding moiety. In some embodiments, the target protein binding moiety binds to the target protein. In some embodiments herein, ligands comprising a DNA damage-binding protein 1 (DDB1) binding moiety are disclosed. In some embodiments, the DDB1 binding moiety is covalently connected to the target protein via a linker. In some embodiments, the DDB1 binding moiety binds to the DDB1 protein. In some embodiments, the DDB1 binding moiety binds to a binding region on the DDB1 protein. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent. In some embodiments, the binding between the DDB1 protein and the ligand includes binding affinities of Kd less than 20 μM, Kd between 20 and 100 μM, or Kd less than 100 μM.In some embodiments, the ligand is a small molecule. In some embodiments, the ligand comprises a targeted proteolysis inducer. In some embodiments, the ligand is synthetic. In some embodiments, the DDB1 binding moiety has the formula (II):

[0022]

Chemical Formula

[0023] [ka] Formula (IIa) The structure includes F 2 is a heteroaryl compound. In some embodiments, F 2 is a 5-membered or 6-membered ring heteroaryl. In some embodiments, F 2 These are triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl. In some embodiments, the DDB1 binding moiety is formula (IIb):

[0024] [ka] Equation (IIb) The structure includes, in the formula, A 4 and A 5Each of them is independently CR 12 , S, N, or O, A 4 Or A 5 At least one of them is N, O, or S. In some embodiments, A 4 is N, and A 5 is S. In some embodiments, the DDB1 coupling portion is

[0025] [ka] The structure includes, where the wavy line indicates an optional binding site to the linker or target protein binding site. In some embodiments, R 12 At each instance, L is independently selected from -NO2, halogen, methyl, halomethyl, phenyl, isopropyl, cyclopropyl, SO2CH3, or -CN. In some embodiments, L 2 -NR c C(=O)- or -C(=O)NR c - In some embodiments, R c is H, CH3, isopropyl, or cyclopropyl. In some embodiments, q is 1 or 2. In some embodiments, s is 1 or 2. In some embodiments, the DDB1 binding moiety comprises one of the compounds B-1 to B-176 shown in Table 1. In some embodiments, the DDB1 binding moiety is

[0026] [ka]

[0027] [ka]

[0028] [ka]

[0029] [ka]

[0030] [ka]

[0031] [ka] or comprising pharmaceutically acceptable salts thereof. In some embodiments, the DDB1 binding moiety is

[0032] [ka] or comprising pharmaceutically acceptable salts thereof. In some embodiments, the DDB1 binding moiety is

[0033] [ka]

[0034] [ka] or comprising pharmaceutically acceptable salts thereof. In some embodiments, the DDB1 binding moiety is

[0035] [ka] or comprising pharmaceutically acceptable salts thereof. In some embodiments, the linker is -(CH2) p2 NH(CH2) p1 NH-, -(CH2) p2 NH(CH2) p1 C(=O)NH-, -(CH2) p2 NH(CH2) p1 NHC(=O)-, -(CH2) p2 NH(CH2CH2)(OCH2CH2) p1 NH-, -(CH2) p2 NH(CH2CH2)(OCH2CH2)p1 C(=O)NH-, or -(CH2) p2 NH(CH2CH2)(OCH2CH2) p1 The ligand is NHC(=O)-, where p1 is 1 to 15 and p2 is 0 to 15. In some embodiments, the target protein binding moiety binds to the target protein. In some embodiments, the target protein binding moiety comprises one of the compounds A-1 to A-69 shown in Table 4. In some embodiments, the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected to the target protein binding moiety via a linker. In some embodiments, the heterobifunctional compound comprises one of the compounds D-1 to D-130 shown in Table 5. In some embodiments, the heterobifunctional compound is a target protein degradation inducer. In some embodiments, in vivo contact between the ligand and the target protein results in the degradation of the target protein.

[0036] In some embodiments of this specification, a method for degrading a target protein in a subject is disclosed, comprising administering to the subject a heterobifunctional ligand comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently linked to a target protein binding moiety via a linker. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the administration is intravenous. In some embodiments, the administration is intramuscular. In some embodiments, the administration is intracochlear. In some embodiments, the administration is subcutaneous. In some embodiments, the administration includes injection. In some embodiments, the administration is oral. In some embodiments, the administration is sublingual. In some embodiments, the administration is buccal. In some embodiments, the administration is rectal. In some embodiments, the administration is vaginal. In some embodiments, the administration is intraocular. In some embodiments, the administration is intraaural. In some embodiments, the administration is intranasal. In some embodiments, the administration is inhalation. In some embodiments, the administration is spraying. In some embodiments, the administration is cutaneous. In some embodiments, the administration is topical. In some embodiments, the administration is transdermal. In some embodiments, the administration is systemic. In some embodiments, the administration of the ligand to the subject includes administering an effective amount of ligand sufficient to degrade the target protein. In some embodiments, after the administration of the ligand to the subject, the target protein is ubiquitinated to form a ubiquitinated target protein. In some embodiments herein, a method for degrading a target protein in a sample is disclosed, comprising the step of contacting the target protein with a ligand containing a DNA damage-binding protein 1 (DDB1) binding moiety covalently attached to the target protein binding moiety via a linker. In some embodiments, the sample is a biological sample. In some embodiments, the biological sample includes tissue, cells, or body fluids. In some embodiments, the contact is performed in vitro. In some embodiments, the contact is performed in vivo. In some embodiments,After contact with a ligand, the target protein is ubiquitinated to form a ubiquitinated target protein. In some embodiments, the ubiquitinated target protein is degraded. In some embodiments, the degradation of the target protein is specific to the target protein. In some embodiments, the degradation of the target protein involves proteasomal degradation. In some embodiments, the target protein is degraded by a proteasome. In some embodiments, the ligand binds to the DDB1 protein to form a ligand-DDB1 complex. In some embodiments, the ligand binds directly to the DDB1 protein via the DDB1 binding moiety of the ligand. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is covalent. In some embodiments, the target protein is ubiquitinated by a ubiquitin E3 ligase complex containing the DDB1 protein. In some embodiments, the ligand (e.g., DDB1 ligand) recruits the ubiquitin E3 ligase complex to the target protein via the DDB1 binding moiety. In some embodiments, the ligand is a small molecule. In some embodiments, the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently linked to a target protein binding moiety via a linker. In some embodiments, the heterobifunctional compound induces target protein degradation. In some embodiments, the ligand includes the ligands described herein. In some embodiments, the target protein is a transcription factor, CBP, p300, kinase, receptor, TRK, TrkA, TrkB, TrkC, cyclin-dependent kinase, CDK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, CDK13, cyclin, cyclin A, cyclin B, cyclin C, cyclin D, cyclin D1, cyclin D2, cyclin D3, cyclin E, cyclin H, cyclin K, cyclin T, cyclin T1, p25, p35, B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, partner in the apoptotic pathway, BclIBax,C5a receptor, HMG-CoA reductase, PDE type V phosphodiesterase, PDE type IV phosphodiesterase, PDE I, PDE II, PDE III, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclooxygenase 1, cyclooxygenase 2, receptor, 5HT receptor, dopamine receptor, G protein, Gq, histamine receptor, 5-lipoxygenase, tryptase, serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH, trypanosoma protein, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAK, STAT, RXR, RAR, HIV 1 protease, HIV 1 Integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance, protein P-glycoprotein, MRP, tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Ca+ channel, VCAM, integrin, VLA-4 integrin, selectin, CD40, CD40L, neurokinin, neurokinin receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras, Raf, Mek, Erk, interleukin-1 convertase, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus 1 protease, cytomegalovirus protease, poly-ADP ribose polymerase, vascular endothelial growth factor, oxytocin receptor, microsomal transport protein inhibitor, bile acid transport inhibitor, 5-α reductase inhibitor, angiotensin II, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y, neuropeptide Y receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase, AMP deaminase, purine receptor, P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7, farnesyltransferase, geranylgeranyltransferase, NGF receptor, beta-amyloid, tyrosine kinase,Flk-IIKDR, Vitronectin receptor, Integrin receptor, Her2 neu, Telomerase inhibitor, Cytosolic phospholipase A2, EGF receptor tyrosine kinase, Ecdysone 20-monooxygenase, GABAergic chloride channel ion channel, Acetylcholinesterase, Voltage-sensitive sodium channel protein, Calcium release channel, Chloride channel, Acetyl-CoA carboxylase, Adenylosuccinate synthase, Protoporphyrinogen oxidase, Enoylpyruvinyl schimate phosphate, Synthase, HSP, Hsp90, Kinase, MDM, MDM2, Human BET bromodomain-containing protein, HDAC, Lysine methyltransferase, Angiogenic protein, Immunomodulatory protein, AHR, VEGFR, 3 It contains one of the following: Alk, Abl, Janus kinase, JAK2, Met, B Raf, phosphatase, FKBP, thyroid hormone receptor, acyl protein thioesterase-1, acyl protein thioesterase-2, HIV protein, HIV protease, HIV integrase, HCV protein, or HCV protease.

[0037] This specification discloses a method of treatment comprising administering to a subject suffering from an infection a therapeutically effective amount of a heterobifunctional compound comprising a DNA damage-binding protein 1 (DDB1) binding moiety covalently linked to a target protein binding moiety. In some embodiments, the infection includes a viral infection, and the target protein includes a viral protein. In some embodiments, the compound includes a ligand as described herein. In some embodiments, administration results in ubiquitination and degradation of the target protein. In some embodiments, the subject is human.

[0038] In some embodiments herein, a method for modulating the DNA damage-binding protein 1 (DDB1) protein is disclosed, comprising the step of contacting the DDB1 protein with a compound containing a DDB1 binding moiety. In some embodiments, the DDB1 binding moiety comprises the structure of formula (II), the structure of formula (IIa), or the structure of formula (IIb), or salts thereof. In some embodiments, the compound comprises the compounds in Table 1, or salts thereof. In some embodiments, the compound comprises the peptides in Table 3, or peptides having an amino acid sequence that is at least 70% identical, at least 75% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to the peptides in Table 3. In some embodiments, contacting the compound with the DDB1 protein comprises contacting the compound with the DDB1 protein in vitro. In some embodiments, contacting the compound with the DDB1 protein comprises delivering the compound to cells expressing the DDB1 protein. In some embodiments, contacting the compound with the DDB1 protein comprises contacting the compound with the DDB1 protein in vivo. In some embodiments, contacting the compound with the DDB1 protein includes administering the compound to a subject. In some embodiments, the subject is human. In some embodiments, the compound binds to the DDB1 protein. In some embodiments, contact increases the amount of DDB1 protein compared to the baseline amount. In some embodiments, contact decreases the amount of DDB1 protein compared to the baseline amount. In some embodiments, contact increases the activity of the DDB1 protein compared to the baseline activity. In some embodiments, contact decreases the activity of the DDB1 protein compared to the baseline activity.

[0039] In some embodiments herein, a method is disclosed for bringing a DNA damage-binding protein 1 (DDB1) protein into close proximity to a target protein, comprising the step of contacting the DDB1 protein and the target protein with a compound comprising a DDB1-binding moiety and a target protein-binding moiety. In some embodiments, the compound comprises a ligand as described herein. In some embodiments, the contact is performed in vitro. In some embodiments, the contact is performed in vivo. In some embodiments, contacting the compound with the DDB1 protein and the target protein includes delivering the compound to cells expressing the DDB1 protein and the target protein. In some embodiments, contacting the compound with the DDB1 protein and the target protein includes administering the compound to a subject. In some embodiments, the subject is human. In some embodiments, the compound binds to the DDB1 protein and the target protein. In some embodiments, contact increases the amount of target protein compared to a baseline amount. In some embodiments, contact decreases the amount of target protein compared to a baseline amount. In some embodiments, contact increases the activity of the target protein compared to its baseline activity. In some embodiments, contact decreases the activity of the target protein compared to its baseline activity.

[0040] Reference All published documents, patents, and patent applications referenced herein are incorporated herein by reference for the specific purposes identified herein. [Brief explanation of the drawing]

[0041] [Figure 1A] This figure shows the three-dimensional conformation of proteins, including the DNA damage-binding protein 1 (DDB1) protein, according to some embodiments described herein. [Figure 1B] This figure shows the ligand-bound DDB1 protein in several embodiments. [Figure 2A]This figure shows the SPR sensorgram of the heterobifunctional compound D-2 that binds to DDB1. [Figure 2B] This figure shows the SPR sensorgram of the heterobifunctional compound D-7 that binds to DDB1. [Figure 2C] This figure shows the SPR sensorgram of the heterobifunctional compound D-13 that binds to DDB1. [Figure 2D] This figure shows the SPR sensorgram of the heterobifunctional compound D-48 that binds to DDB1. [Figure 2E] This figure shows the SPR sensorgram of the heterobifunctional compound D-49 that binds to DDB1. [Figure 3A] This figure shows immunoblots of P300 and CBP proteins expressed in LNCaP cells after treatment with heterobifunctional compound D-2 or D-13 at specified concentrations for 8 hours. [Figure 3B] This figure shows immunoblots of P300 and CBP proteins expressed by LNCaP cells after treatment with the heterobifunctional compound D-7 at a specified concentration for 8 hours. [Figure 4] The figure shows immunoblots of P300 and CBP proteins expressed in LNCaP cells after treatment with heterobifunctional compounds D-2 or D-13 at various time points. [Figure 5A] This figure shows an immunoblot of the P300 protein expressed in Calu-1 cells after treatment with the heterobifunctional compound D-2, either in the presence or absence of bortezomib (BTZ), MG-132, or MLN4924. [Figure 5B] This figure shows immunoblots of P300 protein expressed in Calu-1 cells after treatment with the heterobifunctional compound D-13, in or out of the presence of BTZ, MG-132, MLN4924, or BL11. [Figure 6] This figure shows a graph of LNCaP cell viability against the concentrations of GNE-781, D-2, or D-7. [Figure 7A]This figure shows immunoblots of CDK4 and CDK6 proteins expressed in Calu-1 cells after treatment with heterobifunctional compounds D-44, D-45, D-46, D-47, D-48, or D-49 at specified concentrations for 16 hours. [Figure 7B] This figure shows immunoblots of CDK4 and CDK6 proteins expressed in Calu-1 cells after treatment with the heterobifunctional compound D-45, D-47, D-48, or D-49 at specified concentrations for 16 hours. [Figure 8] This figure shows immunoblots of CDK4 and CDK6 proteins expressed in Calu-1 cells after treatment with heterobifunctional compounds D-48 or D-49 at various time points. [Figure 9] This figure shows immunoblots of cyclins and cyclin-dependent kinases expressed in Calu-1 cells after treatment with heterobifunctional compounds D-118, D-119, or D-120 at specified concentrations for 16 hours. [Figure 10] This figure shows immunoblots of cyclins, cyclin-dependent kinases, and phospho-Rb expressed in Calu-1 cells after 16 hours of treatment with various amounts of heterobifunctional compounds D-49, D-108, D-110, D-111, D-122, D-123, D-124, D-125, or D-126. [Figure 11] This figure shows immunoblots of cyclins, cyclin-dependent kinases, and phospho-Rb expressed in Calu-1 cells after 16 hours of treatment with various amounts of heterobifunctional compounds D-49, D-124, D-128, D-129, and D-130. [Figure 12] This figure shows plots of cell viability for Calu-1, MDA-MB-453, and MIA PaCa-2 cell lines after treatment for 5 days with various amounts of compounds D-128, D-129, D-130, or palbociclib. [Figure 13]This is an immunoblot of cyclins, cyclin-dependent kinases, and phospho-Rb proteins after treatment with 5 μM heterobifunctional compound D-48 or D-49 over various time periods. [Figure 14] This figure shows immunoblots of cyclins, cyclin-dependent kinases, and phospho-Rb after treatment with 1.5 μM heterobifunctional compound D-129 over various time periods. [Modes for carrying out the invention]

[0042] This specification describes compounds and methods for binding to DNA damage-binding protein 1 (DDB1), for inducing subsequent cellular effects, and / or for inhibiting microorganisms such as viruses and bacteria. Compositions comprising a DDB1 binding moiety, a DDB1 binding moiety covalently connected to a linker, and / or a DDB1 binding moiety covalently connected via a linker to a target protein binding moiety are described. The compounds described herein may be useful for a variety of purposes, including, but are not limited to, 1) antiviral agents, 2) DDB1 protein level modifiers (e.g., increasing or decreasing DDB1 protein levels), 3) DDB1 function modifiers (e.g., DDB1 activators or inhibitors), or 4) molecular glues (e.g., increasing protein-protein interactions between DDB1 and another protein). Molecular glue functions may be useful for influencing the activity or protein levels of another protein.

[0043] An example of the DDB1 protein is included in the protein structure shown in Figure 1A. In some embodiments, the DDB1 protein contains 1140 amino acids and has a mass of 127 kDa. The DDB1 protein can function as a component of the E3 ubiquitin ligase complex, which may contain CUL4A and CUL4B. The DDB1 protein may function as a bridge or adapter and interact with other proteins such as DDB1 and CUL4-related factor (DCAF). DCAF may be a ubiquitin ligase substrate.

[0044] In some embodiments herein, ligand-DDB1 complexes are disclosed. In some embodiments, the ligand-DDB1 complex is formed by directly binding the DDB1 protein to the ligand non-covalently. In some embodiments, the ligand comprises a DDB1 binding moiety. In some embodiments, the ligand is a heterobifunctional compound comprising a DDB1 binding moiety that is covalently connected to a target protein binding moiety via a linker.

[0045] In some embodiments of this specification, modified proteins, such as in vivo modified proteins, are disclosed. In some embodiments, the modified protein comprises a DDB1 protein that is directly bound to a ligand. In some embodiments, the ligand comprises a DDB1 binding moiety. In some embodiments, the ligand is a heterobifunctional compound comprising a DDB1 binding moiety that is covalently attached to a target protein binding moiety via a linker.

[0046] In some embodiments herein, ligands are disclosed. In some embodiments, the ligand comprises a DDB1 binding moiety. In some embodiments, the DDB1 binding moiety is covalently bonded to a target protein via a linker.

[0047] In some embodiments herein, methods for degrading target proteins are disclosed. Some embodiments involve administering to a subject a ligand containing a DDB1 binding moiety that is covalently linked to a target protein binding moiety via a linker.

[0048] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple referents unless the context makes it clear. For example, a reference to “drug” includes multiple such drugs, and a reference to “cell” includes one or more cells (or more cells), and their equivalents known to those skilled in the art. When ranges relating to physical properties such as molecular weight, or chemical properties such as chemical formulas are used herein, all combinations of ranges and specific embodiments within them, and subcombinations, are intended to be inclusive. The term “about” when referring to a number or range means that the number or range expressed is an approximation within the range of experimental variability (or statistical experimental error), and for this reason, in some examples, it means that the number or range described varies by 1% to 15%. The term “comprising” (and related terms such as “comprise,” “comprises,” “having,” or “including”) is not intended to exclude, in other specific embodiments, any embodiment of any material composition, composition, method, or process described herein from “consist of” or “consist essentially of” the described feature.

[0049] Characterization of exemplary heterobifunctional compounds A non-limiting example of a ligand-binding DDB1 protein is shown in Figure 1B, which illustrates a model of docking of the DDB1 protein into a complex with a ligand containing compound B-1 in several embodiments. In this model, the ligand occupies the central lumen of the BPC domain of the DDB1 protein and is anchored toward the center of WD40-motiff via a salt bridge between the primary amine of LYS723 and the nitro group of the ligand, and via Coulomb interactions between the electron-deficient nitrogen of the nitro group and the lone pair of electrons of nearby water, and is aligned with the primary amine of LYS723 between the backbone carbonyl oxygen atoms of ARG722 and VAL360. In this model, the pi planes of the thiazole and amide are stationary on the VAL360 side chain, but the amide forms intermolecular hydrogen bonds with the ASN1005 side chain and intramolecular hydrogen bonds with the acetate. In this model, the sulfur of the thiophene is thought to be geometrically stabilized via steric-electronic interactions with the ASN1005 side chain. In this model, methyl acetate forms dispersion contact with the ARG722 side chain and ordered water. In this model, the benzene ring forms dispersion contact with the side chains of ALA381, LEU328, PRO358, and VAL1033. The docking model includes compound B-1, but other ligands may bind to the DDB1 protein in the same way as compound B-1.

[0050] The binding affinity of specific, non-limiting, and exemplary heterobifunctional compounds to DDB1 was determined by surface plasmon resonance (SPR) assay. In short, purified His-DDB1 protein was immobilized on a CM5 sensor chip by amine coupling to a density of 11,000–13,000 resonance units (RU). Sensorgrams were recorded in multi-cycle kinetic format for heterobifunctional compounds at different concentrations. All data were fitted to a steady-state affinity model using Biacore evaluation software, and the equivalent dissociation constant (K) was determined. DThe results showed that all exemplary heterobifunctional compounds bound to DDB1 in a concentration-dependent manner, with binding affinity (KD) ranging from 5 μM to 60 μM (see Figure 2, Table 6, and Table 7).

[0051] Experiments were conducted to confirm whether the heterobifunctional compounds described herein are capable of degrading target proteins. Specific and exemplary heterobifunctional compounds were characterized in LNCaP cells and Calu-1 cells. LNCaP cells expressing P300 / CBP proteins were treated with the heterobifunctional compounds disclosed herein (D-2, D-13, or D-7) at specified concentrations for 8 hours. Cells were collected, lysed, and subjected to immunoblotting with antibodies specific to P300 or CBP proteins. Bincrine was included as a loading control. DMSO treatment was used as a negative control. After treatment with D-2, D-13, or D-7, P300 and CBP protein levels in LNCaP cells were significantly reduced in a concentration-dependent manner (Figures 3A and 3B). These results highlight the degradation of targeted proteins by three non-limiting examples of heterobifunctional degradation-inducing compounds. In addition, LNCaP cells were treated with 500 nM D-2 for a specified period. Subsequently, changes in P300 and CBP protein levels were measured by immunoblotting. Significant degradation of P300 and CBP was easily detected as early as 2–4 hours after compound administration (Figure 4).

[0052] Heterobifunctional compound-mediated degradation of p300 and CBP was dependent on the ubiquitin-proteasome system and culin E3 ligase. D-2 or D-13-induced degradation was impaired by co-administration of proteasome inhibitors, namely MG-132 or bortezomib (BTZ), or a culin RING E3 ubiquitin ligase (CRL) negylation inhibitor, namely MLN4924, as demonstrated in Figures 5A and 5B. Binding to DDB1 also played a role in the ability of heterobifunctional compounds to induce protein degradation of P300 and CBP. As demonstrated in Figure 5B, D-13-mediated degradation could be partially neutralized by co-administration of an excess DDB1 ligand, namely BL-11, which competes with DDB1 binding. These findings suggest that, overall, heterobifunctional compounds induce degradation of P300 / CBP proteins through mechanisms specifically mediated by DDB1, culin E3 ligase, and the proteasome.

[0053] Targeting CBP / P300 to the bromodomain or lysine acetyltransferase domain using ligands has been shown to impair cancer cell proliferation and survival. LNCaP cells seeded in 96-well plates were treated with 10 μM GNE-781 or selected heterobifunctional compounds after 12 3-fold serial dilutions. Cell viability was determined 3 days after treatment using the CellTiter-Glo kit (Promega). Cell viability was normalized to the mean of three replicas of untreated cells. Dose-dependent responses were analyzed according to least-squares nonlinear regression using GraphPad Prism software. Heterobifunctional compounds suppressed LNCaP cell viability in a dose-dependent manner, as exemplified by D-2 or D-7 (Figure 6). These results demonstrate that downregulation of the CBP / P300 protein by using the heterobifunctional compounds described herein induces antiproliferative activity. Compared to the p300 / CBP inhibitor GNE-781, the exemplified heterobifunctional p300 / CBP degradation inducer compounds D-2 and D-7 induced a more potent inhibitory effect on LNCaP cell proliferation. Overall, the heterobifunctional degradation inducer compounds described herein have the potential to be more potent than target protein inhibitors in inducing cellular effects such as inhibition of cell proliferation or viability.

[0054] Additional heterobifunctional compounds were designed and their ability to target and degrade CDK4 and CDK6 as two more target proteins was examined. Calu-1 cells expressing CDK4 / 6 proteins were treated with the heterobifunctional compounds disclosed herein (D-44 to D-49) at specified concentrations for 16 hours. Cells were collected, lysed, and subjected to immunoblotting with antibodies specific to CDK4 protein, CDK6 protein, or phosphorylated Rb protein. Tubulin was included as a loading control. DMSO treatment was used as a negative control. After treatment with various heterobifunctional compounds, CDK4 and CDK6 protein levels in Calu-1 cells were significantly reduced in a concentration-dependent manner, and downstream Rb phosphorylation was also reduced accordingly (Figures 7A and 7B). Palbociclib, i.e., a CDK4 / 6 inhibitor, or BL-11, i.e., a linker, bound to the DDB1 ligand which does not have a CDK4 / 6 binding site, but had no significant effect on CDK4 protein levels (Figure 7B). In addition, Calu-1 cells were treated with 1 μM D-48 or D-48 for a specified period. Subsequently, changes in CDK4 and CDK6 protein levels were measured by immunoblotting. Significant degradation of CDK4 and CDK6 was detected 16 hours after compound administration (Figure 8). These experiments highlight the degrading ability of heterobifunctional compounds derived from DDB1 binders to numerous different target proteins, including but not limited to epigenetic target proteins such as CBP and p300, and kinases such as CDK4 and CDK6.

[0055] Figures 10, 11, 13, and 14 show Western blots of various proteins, including cyclin D1, cyclin D2, cyclin D3, CDK4, CDK6, or phospho-Rb, after treatment with heterobifunctional compounds. Some heterobifunctional compounds were more potent or effective than others in reducing the expression of the proteins shown in these figures. For example, some heterobifunctional compounds were effective at lower doses than others. These data suggest that the heterobifunctional compounds described herein may be effective for binding, inhibiting, or degrading target proteins. These compounds may be effective against a wide range of cell types.

[0056] Figure 12 and Table 8 include cell viability data after treatment with heterobifunctional compounds D-128, D129, or D-130. These heterobifunctional compounds were more potent or effective than palbociclib in reducing the viability of various different cell types. For example, D-128, D129, or D-130 were effective at lower doses than palbociclib. The data demonstrate that the heterobifunctional compounds described herein may be effective in inhibiting cell viability. These compounds may be effective against a large number of cell types.

[0057] definition As used in this specification and the appended claims, unless otherwise specified, the following terms have the meanings set forth below:

[0058] "Amino" represents the -NH2 radical.

[0059] "Cyano" represents the -CN radical.

[0060] "Nitro" represents the -NO2 radical.

[0061] "Oxa" represents -O- (radical).

[0062] "Oxo" represents the O radical.

[0063] "Thioxo" represents the S radical.

[0064] "Imino" represents the NH radical.

[0065] "Oxymo" represents the N-OH radical.

[0066] "Hydrazino" represents the N-NH2 radical.

[0067] "Alkyl" refers to a linear or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, without unsaturation, and having 1 to 15 carbon atoms (e.g., C1-C1). 15 Alkyl represents 1 to 13 carbon atoms (e.g., C1-C1). In one embodiment, alkyl represents 1 to 13 carbon atoms. 13 It contains alkyl. In one embodiment, the alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In another embodiment, the alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In another embodiment, the alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In another embodiment, the alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In another embodiment, the alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In another embodiment, the alkyl contains 1 carbon atom (e.g., C1 alkyl). In another embodiment, the alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is bonded to the remainder of the molecule by a single bond. Unless otherwise specified herein, alkyl groups are substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, R a , -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR a -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a ) is arbitrarily replaced by one or more of the following: R aEach of these is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0068] "Alkoxy" refers to a radical bonded via the oxygen atom of a -O-alkyl group, where alkyl is an alkyl chain as defined above.

[0069] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0070] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" represent substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, each having one or more skeletal chain atoms selected from atoms other than carbon. Exemplary skeletal chain atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof, where nitrogen, phosphorus, and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Where given, the numerical range represents the total chain length. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the remainder of the molecule may occur via either a heteroatom or carbon in the heteroalkyl chain, heteroalkenyl chain, or heteroalkynyl chain. Unless otherwise specified herein, the heteroalkyl group, heteroalkenyl group, or heteroalkynyl group may be optionally substituted with one or more substituents, such as those described herein.

[0071] "Alkenyl" represents a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having 2 to 12 carbon atoms. In some embodiments, the alkenyl contains 2 to 8 carbon atoms. In other embodiments, the alkenyl contains 2 to 4 carbon atoms. The alkenyl is bonded to the remainder of the molecule by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), buto-1-enyl, pento-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specified herein, the alkenyl group is substituted with the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, R a , -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR a -OC(O)-N(R a)2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a ) is arbitrarily replaced by one or more of the following: R a Each of these is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0072] "Alkynyl" refers to a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms. In some embodiments, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 6 carbon atoms. In other embodiments, the alkynyl contains 2 to 4 carbon atoms. The alkynyl is bonded to the remainder of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specified herein, the alkynyl group is substituted with the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, R a , -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR a -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a ) is arbitrarily replaced by one or more of the following: R aEach of these is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0073] An "alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, without unsaturation, and having 1 to 12 carbon atoms, with the remainder of the molecule bonded to a radical group, such as methylene, ethylene, propylene, and n-butylene. The alkylene chain is bonded to the remainder of the molecule via single bonds and to the radical group via single bonds. The bonding sites of the alkylene chain to the remainder of the molecule and the radical group are via one carbon in the alkylene chain or any two carbons in the chain. In some embodiments, the alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified herein, the alkylene chain may have the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, R a , -OR a , -SR a -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a ,-C(O)N(R a )2, -N(R a )C(O)OR a -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a(t is 1 or 2), -S(O) t Ure a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a ) is arbitrarily replaced by one or more of the following: R a Each of these is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyrylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0074] The term "aryl" represents a radical derived from monocyclic or polycyclic aromatic hydrocarbon ring systems by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon atoms consisting of 5 to 18 carbon atoms, and at least one of the multiple rings in the ring system is completely unsaturated, i.e., it contains a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. Examples of ring systems from which aryl groups are derived include, but are not limited to, benzene, fluorene, indan, indene, tetralin, and naphthalene. Unless otherwise specified herein, the term "aryl" or the prefix "ar-" (as in "aralkyl") is intended to include aryl radicals optionally substituted with one or more substituents, one or more substituents independently of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a)C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R a Each is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and R b These are, each independently and directly bonded, or linear or branched alkylene or alkenylene chains, R c These are linear or branched alkylene or alkenylene chains, and unless otherwise specified, the substituents described above are not substituted.

[0075] "Aralkyr" is formula -R c - Represents an aryl radical, where R c This refers to alkylene chains as defined above, such as methylene or ethylene. The alkylene chain portion of the aralkyl radical is optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl radical is optionally substituted as described above for aryl groups.

[0076] "Carbocyclyl" or "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, containing a system of fused or bridging rings, and having 3 to 15 carbon atoms. In some embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. Carbocyclyl is bonded to the remainder of the molecule by single bonds. Carbocyclyl can be saturated (containing only CC bonds) or unsaturated (containing one or more double or triple bonds). Fully saturated carbocyclyl radicals are also called "cycloalkyl." Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also called "cycloalkenyls." Examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic carbocyclyl radicals include adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norborneyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise specified herein, the term "carbocykyl" is intended to include a carbocykyl radical optionally substituted with one or more substituents, one or more substituents independently of alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralquinyl, optionally substituted carbocykyl, optionally substituted carbocykylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -OR a , -R b -OC(O)-R a , -R b-OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R aEach is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and R b These are, each independently and directly bonded, or linear or branched alkylene or alkenylene chains, and R c These are linear or branched alkylene or alkenylene chains, and the substituents are not substituted unless otherwise specified.

[0077] "Carbocyclylalkyl" is R c Formula -R is an alkylene chain as defined above. c - Represents the carbocyclyl radical. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0078] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodine substituent.

[0079] "Fluoroalkyl" refers to an alkyl radical as defined above, which is substituted with one or more fluororadicals as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted with alkyl as defined above.

[0080] "Heterocyclyl" or "heterocycloalkyl" represents a stable 3- to 18-membered non-aromatic ring radical containing 2- to 12 carbon atoms and 1- to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, heterocyclyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, optionally including fused or bridging ring systems. Heteroatoms in heterocyclyl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl radicals are partially or completely saturated. Heterocyclyls are bonded to the remainder of the molecule by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, decahydroisoquinolyl, imidazolinil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, quinuclidinil, thiazolidinil, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil. Unless otherwise specified herein, the term “heterocyclyl” is intended to include heterocyclyl radicals as defined above, which are optionally substituted by one or more substituents, where one or more substituents may be alkyl, alkenyl, alkynyl, halo, fluoroalkyl, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralquinyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R a , -R b -ORa , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R aEach is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and R b These are, each independently and directly bonded, or linear or branched alkylene or alkenylene chains, and R c These are linear or branched alkylene or alkenylene chains, and the substituents are not substituted unless otherwise specified.

[0081] An "N-heterocyclyl" or "N-bonded heterocyclyl" represents a heterocyclyl radical as defined above, containing at least one nitrogen atom, where the bond site of the heterocyclyl radical to the rest of the molecule is via the nitrogen atom in the heterocyclyl radical. N-heterocyclyl radicals are optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0082] A "C-heterocyclyl" or "C-bonded heterocyclyl" represents a heterocyclyl radical as defined above, containing at least one heteroatom, where the bond site of the heterocyclyl radical to the rest of the molecule is via a carbon atom in the heterocyclyl radical. C-heterocyclyl radicals are optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl.

[0083] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical containing 2- to 17 carbon atoms and 1- to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one of the rings is completely unsaturated, i.e., contains a delocalized (4n+2)π-electron system of the ring according to Hückel's theory. Heteroaryls include fused ring systems or bridging ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryls are bonded to the remainder of the molecule via any of the atoms of the ring. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrimidinyl, carbazolyl, sinnolinyl, cyclopenta[d]pyrimidinyl, and 6,7-dihydro-5H-s Clopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]sinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexa Hydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido(p yrido)[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyrimidinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,Examples include, but are not limited to, [3-d]pyridinyl and thiophenyl (i.e., thienyl). Unless otherwise specified herein, the term “heteroaryl” is intended to include heteroaryl radicals as defined above, which are optionally substituted with one or more substituents, and which may be alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, R, a , -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a(t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is either 1 or 2) is selected from R a Each is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), and R b These are, each independently and directly bonded, or linear or branched alkylene or alkenylene chains, R c These are linear or branched alkylene or alkenylene chains, and unless otherwise specified, the substituents described above are not substituted.

[0084] "N-heteroaryl" represents a heteroaryl radical as defined above, containing at least one nitrogen atom, where the bond site of the heteroaryl radical to the rest of the molecule is via the nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for the heteroaryl radical.

[0085] "C-heteroaryl" represents a heteroaryl radical as defined above, where the bond site of the heteroaryl radical to the rest of the molecule is via a carbon atom in the heteroaryl radical. The C-heteroaryl radical can be optionally substituted for the heteroaryl radical as described above.

[0086] In some embodiments, the compounds disclosed herein contain one or more chiral centers, thereby giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined as (R) or (S) from an absolute stereochemical standpoint. Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by this disclosure. Where the compounds described herein contain an alkene double bond, and unless otherwise specified, this disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomers are also intended to be included. The term “geometric isomer” refers to the E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-isomers, meta-isomers, and para-isomers around a benzene ring.

[0087] A "tautomer" refers to a molecule in which proton transfer is possible from one atom to another within the same molecule. The compounds presented herein exist as tautomers in some embodiments. Under conditions where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on various factors, including physical conditions, temperature, solvent, and pH. As some examples of tautomer equilibrium,

[0088] [ka] These are some examples.

[0089] In some embodiments, the compounds disclosed herein are used in various forms of enriched isotopes, for example, 2 H, 3 H, 11 C, 13 C, and / or 14 It is enriched in the contents of C. In a particular embodiment, the compound is deuterated at at least one position. Such a deuterated form can be produced by the procedure described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can increase the duration of action of a drug by improving metabolic stability or efficacy.

[0090] Unless otherwise specified, the structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, hydrogen exchange by deuterium or tritium, or 13 C or 14 Compounds having this structure, excluding carbon exchange by carbon-enriched carbon, are within the scope of this disclosure.

[0091] The compounds disclosed herein contain, by choice, one or more atoms constituting such compounds that contain atomic isotopes in an unnatural ratio. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), Iodine-125( 125 I) or carbon-14 ( 14 It may be labeled with isotopes such as C). 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S,34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotopic substitutions in I are intended. All isotopic variants of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0092] In one embodiment, the compounds disclosed herein are 2 Substituted with H atoms 1 It contains some or all of the H atoms. Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the following synthesis methods.

[0093] Deuterium-substituted compounds are synthesized using various methods, including those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0094] Deuterated starting materials are readily available and can be subjected to the synthesis methods described herein for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0095] "Pharmacologically acceptable salts" include both acid addition salts and base addition salts. Any pharmaceutically acceptable salt of any compound described herein is intended to encompass all pharmaceutically appropriate salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0096] "Pharmacologically acceptable acid addition salts" refer to salts that retain the bioeffects and properties of a free base, and these salts are not biologically or otherwise unwanted, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. Similarly, salts formed from organic acids such as aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanoates, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids are also included, such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacinates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, and methanesulfonates. Furthermore, salts of amino acids such as alginates, glucons, and galacturonic acids have also been considered (see, for example, Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a sufficient amount of the desired acid to produce the salt, according to methods and techniques familiar to those skilled in the art.

[0097] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the bioeffects and properties of a free acid and is not biologically or otherwise unwanted. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from metals or amines such as alkali metals, alkaline earth metals, or organic amines. Examples of salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and base ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydravamin, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. See Berge et al. above.

[0098] Modified or manipulated proteins In some embodiments of this specification, modified proteins, such as in vivo modified proteins, are disclosed. In some embodiments, the in vivo modified protein includes a DNA damage-binding protein 1 (DDB1) protein. In some embodiments, the DDB1 protein is bound to a ligand. In some embodiments, the ligand is a DDB1 ligand. In some embodiments, the DDB1 protein is directly bound to the ligand. In some embodiments, the binding of the DDB1 protein to the ligand is non-covalent. In some embodiments, the binding of the DDB1 protein to the ligand is covalent. The ligand may be any ligand described herein. In some embodiments, the ligand includes a DDB1 binding moiety, such as a DDB1 binding moiety described herein. In some embodiments, the DDB1 ligand is a heterobifunctional compound including a DDB1 binding moiety that is covalently connected to a target protein-binding moiety described herein via a linker. In some embodiments, the DDB1 protein is modified in vivo by binding to a ligand administered to a subject.

[0099] Modified proteins may include engineered proteins. In some embodiments herein, engineered DDB1 proteins, such as in vivo engineered DDB1 proteins, are disclosed. Engineered DDB1 proteins may be bound to ligands. Engineered DDB1 proteins may be bound to ligands in vivo. For example, when a ligand is administered to a subject, it may be bound to a DDB1 protein or an engineered DDB1 protein in vivo.

[0100] In some embodiments herein, in vivo modified proteins are disclosed. In some embodiments, the in vivo modified protein comprises a DDB1 protein directly bound to a ligand containing a DDB1 binding moiety. In some embodiments, the in vivo modified protein comprises a DDB1 protein directly bound to a ligand, the ligand containing a DDB1 binding moiety. In some embodiments, the in vivo modified protein comprises a DDB1 protein directly bound to a heterobifunctional compound, the heterobifunctional compound containing a DDB1 binding moiety covalently connected to a target protein binding moiety via a linker.

[0101] In some embodiments of this specification, in vivo modified proteins are disclosed. In some embodiments, the ligand includes a DDB1 binding moiety. In some embodiments, the ligand includes a linker. In some embodiments, the ligand includes a target protein binding moiety. In some embodiments, the DDB1 binding moiety is covalently connected to the linker. In some embodiments, the linker is further connected to the target protein binding moiety. In some embodiments, the DDB1 binding moiety is covalently connected to the target protein binding moiety via the linker. In some embodiments, the DDB1 binding moiety is covalently connected to the target protein binding moiety without a linker. In some embodiments, the target protein binding moiety binds to a target protein, such as a target protein described herein. In some embodiments, the ligand includes a compound described herein. For example, the ligand may include a DDB1 binding moiety disclosed herein, a linker disclosed herein, or a target protein binding moiety disclosed herein. In some embodiments, the linker is a bond. In some embodiments, the linker is not merely a bond. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand is a heterobifunctional compound including a DDB1 binding moiety that is covalently connected to the target protein binding moiety via a linker.

[0102] In some embodiments of this specification, in vivo modified proteins are disclosed. In some embodiments, the DDB1 binding region is bound to a binding region on the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes a β-propeller domain. In some embodiments, the β-propeller domain includes a β-propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein includes a BPC domain. In some embodiments, the binding region on the DDB1 protein includes the upper surface of the BPC domain. In some embodiments of this specification, in vivo modified proteins are disclosed. In some embodiments, the binding region on the DDB1 protein includes one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033. In some embodiments, the following DDB1 residues are present: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA8 41, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033 are involved in non-covalent binding between the DDB1 protein and its ligand.In vivo manipulated DDB1 proteins may include DDB1 proteins that bind to a ligand at any of the aforementioned residues.

[0103] In some embodiments of this specification, in vivo modified proteins are disclosed. In some embodiments, the binding region on the DDB1 protein includes ARG327 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes LEU328 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes PRO358 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ILE359 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes VAL360 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ASP361 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes GLY380 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ALA381 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes PHE382 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes SER720 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ARG722 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes LYS723 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes SER738 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ILE740 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes GLU787 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes TYR812 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes LEU814 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes SER815 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ALA834 of the DDB1 protein.In some embodiments, the binding region on the DDB1 protein includes VAL836 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ALA841 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ALA869 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes TYR871 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes SER872 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes MET910 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes LEU912 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes TYR913 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes LEU926 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes TRP953 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes SER955 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ALA956 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ASN970 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ALA971 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes PHE972 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes PHE1003 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes ASN1005 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes VAL1006 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes VAL1033 of the DDB1 protein.

[0104] In some embodiments, the binding of the DDB1 protein to the ligand includes one or more of the following: salt bridges, Coulomb interactions, hydrogen bonds, steric interactions, and dispersion contacts. In some embodiments, the binding of the DDB1 protein to the ligand includes salt bridges. In some embodiments, the binding of the DDB1 protein to the ligand includes Coulomb interactions. In some embodiments, the binding of the DDB1 protein to the ligand includes one or more hydrogen bonds. In some embodiments, the binding of the DDB1 protein to the ligand includes steric interactions. In some embodiments, the binding of the DDB1 protein to the ligand includes dispersion contacts.

[0105] In some embodiments, the DDB1 protein contains a BPC domain with a central lumen. In some embodiments, the ligand binds to the DDB1 protein in the central lumen of the BPC domain. In some embodiments, the DDB1 protein contains a WD40-motiff. In some embodiments, the WD40-motiff contains a center. In some embodiments, the ligand is anchored towards the center of the WD40-motiff. In some embodiments, the ligand is anchored towards the center of the WD40-motiff by a salt bridge. In some embodiments, the ligand contains a nitro group. In some embodiments, the salt bridge is between the primary amine of the amino acid in the DDB1 protein and the nitro group of the ligand. In some embodiments, the salt bridge is between the primary amine of the lysine (e.g., LYS723) in the DDB1 protein and the nitro group of the ligand.

[0106] In some embodiments, the ligand is anchored towards the center of the WD40-motiff by Coulomb interaction. In some embodiments, the ligand contains electron-deficient nitrogen. In some embodiments, the nitro group contains electron-deficient nitrogen. In some embodiments, the Coulomb interaction is between the electron-deficient nitrogen and the lone pair of water in the vicinity. In some embodiments, the water in the vicinity is aligned between the backbone carbonyl oxygen atoms of one or more amino acids in the DDB1 protein. In some embodiments, the water in the vicinity is aligned between the backbone carbonyl oxygen atoms of arginine (e.g., ARG722) in the DDB1 protein. In some embodiments, the water in the vicinity is aligned between the backbone carbonyl oxygen atoms of valine (e.g., VAL360) in the DDB1 protein. In some embodiments, the water in the vicinity is aligned between primary amines of lysine, such as LYS723. In some embodiments, the water in the vicinity is aligned between the backbone carbonyl oxygen atoms of arginine, the backbone carbonyl oxygen atoms of valine, and / or primary amines of lysine. In some embodiments, the surrounding water is aligned with the primary amine of LYS723 between the backbone carbonyl oxygen atoms of ARG722 and VAL360. In some embodiments, the ligand is anchored towards the center of the WD40-motiff by Coulomb interactions and salt bridges.

[0107] In some embodiments, the ligand comprises a thiazole. In some embodiments, the ligand comprises an amide. In some embodiments, the ligand comprises an acetate. In some embodiments, the ligand comprises one or more pi-faces. In some embodiments, the ligand comprises a pi-face of a thiazole. In some embodiments, the ligand comprises a pi-face of an amide. In some embodiments, the pi-faces of the thiazole and amide rest on an amino acid side chain. In some embodiments, the pi-faces of the thiazole and amide rest on a valine (e.g., VAL360) side chain. In some embodiments, the amide forms an intermolecular hydrogen bond with the amino acid side chain of the DDB1 protein. In some embodiments, the amide forms a hydrogen bond with the asparagine (e.g., ASN1005) side chain of the DDB1 protein. In some embodiments, the amide forms an intramolecular hydrogen bond with an acetate. In some embodiments, the amide forms an intermolecular hydrogen bond with the asparagine side chain and an intramolecular hydrogen bond with an acetate. In some embodiments, the ligand comprises a sulfur-containing thiophene. In some embodiments, the sulfur of thiophene is geometrically stabilized via steric-electronic interactions with the amino acid side chains of the DDB1 protein. In some embodiments, the sulfur of thiophene is geometrically stabilized via steric-electronic interactions with the side chains of asparagine (e.g., ASN1005). In some embodiments, the acetate contains methyl groups that form dispersion contact with the prepared water. In some embodiments, the acetate contains methyl groups that form dispersion contact with the amino acid side chains of the DDB1 protein. In some embodiments, the acetate contains methyl groups that form dispersion contact with the arginine (e.g., ARG722) side chains of the DDB1 protein. In some embodiments, the acetate contains methyl groups that form dispersion contact with the arginine side chains of the DDB1 protein and the prepared water. In some embodiments, the ligand contains a benzene ring. In some embodiments, the benzene ring forms dispersion contact with the amino acid side chains of the DDB1 protein.In some embodiments, the benzene ring forms dispersion contact with the alanine (e.g., ALA381) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the leucine (e.g., LEU328) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the proline (e.g., PRO358) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the valine (e.g., VAL1033) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the alanine, leucine, proline, and valine side chains of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the ALA381, LEU328, PRO358, and VAL1033 side chains of the DDB1 protein.

[0108] In some embodiments herein, in vivo modified proteins are disclosed. In some embodiments, the binding of the DDB1 protein to the ligand is such that the equilibrium dissociation constant (Kd) is less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, less than 60 μM, less than 50 μM, less than 45 μM, less than 40 μM, less than 35 μM, less than 30 μM, less than 25 μM, and less than 20 μM. The binding affinity includes Kd less than 15 μM, Kd less than 14 μM, Kd less than 13 μM, Kd less than 12 μM, Kd less than 11 μM, Kd less than 10 μM, Kd less than 9 μM, Kd less than 8 μM, Kd less than 7 μM, Kd less than 6 μM, Kd less than 5 μM, Kd less than 4 μM, Kd less than 3 μM, Kd less than 2 μM, or Kd less than 1 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes binding affinity of Kd less than 20 μM, Kd between 20 and 100 μM, or Kd less than 100 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes binding affinity as disclosed herein (e.g., the section titled “DDB1 Binding Molecules” or the binding affinity described in Table 6 or Table 7). In vivo manipulated DDB1 proteins may include DDB1 proteins that bind to ligands having one of the aforementioned binding affinities.

[0109] In some embodiments herein, in vivo modified proteins are disclosed. In some embodiments, the binding of the DDB1 binding moiety to the DDB1 protein is non-covalent. The binding may include non-covalent bonds. The binding may include one or more non-covalent bonds. Some non-limiting examples of non-covalent bonds include salt bridges, Coulomb interactions, hydrogen bonds, stereoelectronic interactions, or dispersion contacts. The binding may include combinations of non-covalent bonds. In some embodiments, the binding of the DDB1 binding moiety to the DDB1 protein is covalent.

[0110] Ligand-protein complex In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the ligand-protein complex comprises a ligand-DNA damage-binding protein 1 (DDB1) complex. In some embodiments, the ligand-DDB1 complex is formed by binding the DDB1 protein to the ligand. In some embodiments, the ligand is the DDB1 ligand. In some embodiments, binding occurs directly between the DDB1 protein and the ligand. In some embodiments, the DDB1 protein is directly bound to the ligand. In some embodiments, the binding is non-covalent. In some embodiments, the binding is covalent. In some embodiments, DDB1 is directly bound to the ligand. The ligand may be any ligand described herein. In some embodiments, the ligand comprises a DDB1 binding moiety, such as a DDB1 binding moiety described herein. In some embodiments, the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety that is covalently connected to a target protein binding moiety described herein via a linker.

[0111] In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the ligand-DDB1 complex is formed by directly binding the DDB1 protein to the ligand non-covalently, and the ligand includes a DDB1 binding portion. In some embodiments, the ligand-DDB1 complex is formed by directly binding the DDB1 protein to the ligand by covalent bond, and the ligand includes a DDB1 binding portion. In some embodiments, the ligand-DDB1 complex is formed by directly binding the DDB1 protein to a heterobifunctional compound non-covalently, and the heterobifunctional compound includes a DDB1 binding portion connected to a target protein binding portion by covalent bond via a linker. In some embodiments, the ligand-DDB1 complex is formed by directly binding the DDB1 protein to a heterobifunctional compound by covalent bond, and the heterobifunctional compound includes a DDB1 binding portion connected to a target protein binding portion by covalent bond via a linker.

[0112] In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the ligand includes a DDB1 binding moiety. In some embodiments, the ligand includes a linker. In some embodiments, the ligand includes a target protein binding moiety. In some embodiments, the DDB1 binding moiety is covalently connected to the linker. In some embodiments, the linker is further connected to the target protein binding moiety. In some embodiments, the DDB1 binding moiety is covalently connected to the target protein via the linker. In some embodiments, the DDB1 binding moiety is covalently connected to the target protein binding moiety without a linker. In some embodiments, the target protein binding moiety binds to a target protein, such as a target protein described herein. In some embodiments, the ligand includes a compound described herein. For example, the ligand may include a DDB1 binding moiety disclosed herein, a linker disclosed herein, or a target protein binding moiety disclosed herein. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand is a heterobifunctional compound including a DDB1 binding moiety covalently connected to a target protein binding moiety via a linker.

[0113] In some embodiments described herein, ligand-protein complexes are disclosed. In some embodiments, the DDB1 binding portion is bound to a binding region on the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes a β-propeller domain. In some embodiments, the β-propeller domain includes a β-propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein includes a BPC domain. In some embodiments, the binding region on the DDB1 protein includes the upper surface of the BPC domain.

[0114] In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the binding region on the DDB1 protein includes one or more of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033. In some embodiments, the following DDB1 residues are present: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA8 41, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033, one or more of these are involved in non-covalent binding between the DDB1 protein and the ligand. In some embodiments, the binding region on the DDB1 protein includes the amino acid residues described herein, such as in the section titled “Modified Proteins”.

[0115] In some embodiments, the binding of the DDB1 protein to the ligand includes one or more of the following: salt bridges, Coulomb interactions, hydrogen bonds, steric interactions, and dispersion contacts. In some embodiments, the binding of the DDB1 protein to the ligand includes salt bridges. In some embodiments, the binding of the DDB1 protein to the ligand includes Coulomb interactions. In some embodiments, the binding of the DDB1 protein to the ligand includes one or more hydrogen bonds. In some embodiments, the binding of the DDB1 protein to the ligand includes steric interactions. In some embodiments, the binding of the DDB1 protein to the ligand includes dispersion contacts.

[0116] In some embodiments, the DDB1 protein contains a BPC domain with a central lumen. In some embodiments, the ligand binds to the DDB1 protein in the central lumen of the BPC domain. In some embodiments, the DDB1 protein contains a WD40-motiff. In some embodiments, the WD40-motiff contains a center. In some embodiments, the ligand is anchored towards the center of the WD40-motiff. In some embodiments, the ligand is anchored towards the center of the WD40-motiff by a salt bridge. In some embodiments, the ligand contains a nitro group. In some embodiments, the salt bridge is between the primary amine of the amino acid in the DDB1 protein and the nitro group of the ligand. In some embodiments, the salt bridge is between the primary amine of the lysine (e.g., LYS723) in the DDB1 protein and the nitro group of the ligand.

[0117] In some embodiments, the ligand is anchored towards the center of the WD40-motiff by Coulomb interaction. In some embodiments, the ligand contains electron-deficient nitrogen. In some embodiments, the nitro group contains electron-deficient nitrogen. In some embodiments, the Coulomb interaction is between the electron-deficient nitrogen and the lone pair of water in the vicinity. In some embodiments, the water in the vicinity is aligned between the backbone carbonyl oxygen atoms of one or more amino acids in the DDB1 protein. In some embodiments, the water in the vicinity is aligned between the backbone carbonyl oxygen atoms of arginine (e.g., ARG722) in the DDB1 protein. In some embodiments, the water in the vicinity is aligned between the backbone carbonyl oxygen atoms of valine (e.g., VAL360) in the DDB1 protein. In some embodiments, the water in the vicinity is aligned between primary amines of lysine, such as LYS723. In some embodiments, the water in the vicinity is aligned between the backbone carbonyl oxygen atoms of arginine, the backbone carbonyl oxygen atoms of valine, and / or primary amines of lysine. In some embodiments, the surrounding water is aligned with the primary amine of LYS723 between the backbone carbonyl oxygen atoms of ARG722 and VAL360. In some embodiments, the ligand is anchored towards the center of the WD40-motiff by Coulomb interactions and salt bridges.

[0118] In some embodiments, the ligand comprises a thiazole. In some embodiments, the ligand comprises an amide. In some embodiments, the ligand comprises an acetate. In some embodiments, the ligand comprises one or more pi-faces. In some embodiments, the ligand comprises a pi-face of a thiazole. In some embodiments, the ligand comprises a pi-face of an amide. In some embodiments, the pi-faces of the thiazole and amide rest on an amino acid side chain. In some embodiments, the pi-faces of the thiazole and amide rest on a valine (e.g., VAL360) side chain. In some embodiments, the amide forms an intermolecular hydrogen bond with the amino acid side chain of the DDB1 protein. In some embodiments, the amide forms a hydrogen bond with the asparagine (e.g., ASN1005) side chain of the DDB1 protein. In some embodiments, the amide forms an intramolecular hydrogen bond with an acetate. In some embodiments, the amide forms an intermolecular hydrogen bond with the asparagine side chain and an intramolecular hydrogen bond with an acetate. In some embodiments, the ligand comprises a sulfur-containing thiophene. In some embodiments, the sulfur of thiophene is geometrically stabilized via steric-electronic interactions with the amino acid side chains of the DDB1 protein. In some embodiments, the sulfur of thiophene is geometrically stabilized via steric-electronic interactions with the side chains of asparagine (e.g., ASN1005). In some embodiments, the acetate contains methyl groups that form dispersion contact with the prepared water. In some embodiments, the acetate contains methyl groups that form dispersion contact with the amino acid side chains of the DDB1 protein. In some embodiments, the acetate contains methyl groups that form dispersion contact with the arginine (e.g., ARG722) side chains of the DDB1 protein. In some embodiments, the acetate contains methyl groups that form dispersion contact with the arginine side chains of the DDB1 protein and the prepared water. In some embodiments, the ligand contains a benzene ring. In some embodiments, the benzene ring forms dispersion contact with the amino acid side chains of the DDB1 protein.In some embodiments, the benzene ring forms dispersion contact with the alanine (e.g., ALA381) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the leucine (e.g., LEU328) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the proline (e.g., PRO358) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the valine (e.g., VAL1033) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the alanine, leucine, proline, and valine side chains of the DDB1 protein. In some embodiments, the benzene ring forms dispersion contact with the ALA381, LEU328, PRO358, and VAL1033 side chains of the DDB1 protein.

[0119] In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the binding of the DDB1 protein to the ligand is such that the equilibrium dissociation constant (Kd) is less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, less than 60 μM, less than 50 μM, less than 45 μM, less than 40 μM, less than 35 μM, less than 30 μM, less than 25 μM, and less than 20 μM. The binding affinities include those with Kd less than 15 μM, Kd less than 14 μM, Kd less than 13 μM, Kd less than 12 μM, Kd less than 11 μM, Kd less than 10 μM, Kd less than 9 μM, Kd less than 8 μM, Kd less than 7 μM, Kd less than 6 μM, Kd less than 5 μM, Kd less than 4 μM, Kd less than 3 μM, Kd less than 2 μM, or Kd less than 1 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes binding affinities with Kd less than 20 μM, Kd between 20 and 100 μM, or Kd less than 100 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes binding affinities disclosed herein (e.g., the section titled “DDB1 Binding Molecules” or the binding affinities listed in Table 6 or Table 7).

[0120] In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the binding of the DDB1 binding moiety to the DDB1 protein is non-covalent. In some embodiments, the binding of the DDB1 binding moiety to the DDB1 protein is covalent.

[0121] In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the complexes are formed in vivo. In some embodiments, the complexes are formed in vitro.

[0122] compound In some embodiments herein, compounds are disclosed. A compound may be or contain a DDB1 ligand. A compound may contain a DDB1 binding portion. A compound may contain a linker. A compound may contain a target protein binding portion. The ligand may be a heterobifunctional compound. The heterobifunctional compound may contain a DDB1 binding portion covalently connected to the target protein binding portion via a linker. A compound may contain a ligand. The ligand may contain a DDB1 binding portion. The ligand may contain a linker. The ligand may contain a target protein binding portion. The DDB1 binding portion may be connected to the target protein binding portion via a linker. The ligand may be a heterobifunctional compound. The heterobifunctional compound may contain a DDB1 binding portion covalently connected to the target protein binding portion via a linker.

[0123] In some embodiments of this specification, DDB1 ligands are disclosed. Ligands may include small molecules. An example of a small molecule is an organic compound with a molecular weight of less than 900 daltons. The molecular weight of a ligand may be less than 2500 daltons, less than 2250 daltons, less than 2000 daltons, less than 1750 daltons, less than 1500 daltons, or less than 1250 daltons. The molecular weight of a ligand may be less than 1000 daltons, less than 900 daltons, less than 800 daltons, less than 700 daltons, less than 600 daltons, or less than 500 daltons. The molecular weight of a ligand may be greater than 2500 daltons, greater than 2250 daltons, greater than 2000 daltons, greater than 1750 daltons, greater than 1500 daltons, or greater than 1250 daltons. The molecular weight of the ligand may be greater than 1000 Daltons, greater than 900 Daltons, greater than 800 Daltons, greater than 700 Daltons, greater than 600 Daltons, or greater than 500 Daltons.

[0124] In some embodiments herein, compounds for use in methods such as treatment methods are disclosed. Some embodiments include compounds for use in methods of degrading, inhibiting, or modulating proteins or target proteins. The compounds are or may include the compounds described herein. Some embodiments include methods for producing the compounds disclosed herein.

[0125] DDB1 connection part This specification describes compounds containing a DDB1 binding moiety. Some such compounds may be useful as regulators of DDB1 protein level or function, as part of a molecular glue, or as part of a targeted proteolytic agent. In some embodiments, the DDB1 binding moiety is included as part of a heterobifunctional compound.

[0126] This specification describes compounds containing a DDB1 binding moiety. In some embodiments, the DDB1 binding moiety binds to the DDB1 protein. In some embodiments, the DDB1 binding moiety binds to the DDB1 protein. In some embodiments, the compound binds to the DDB1 protein via the DDB1 binding moiety. In some embodiments, the compound binds to the DDB1 protein via the DDB1 binding moiety. In some examples, the compound of formula (I) includes one of the structures of formula (II), formula (IIa), or formula (IIb). In some embodiments, the compound or the DDB1 binding moiety does not inhibit DDB1 function. For example, in some embodiments, the binding of DDB1 to the DDB1 binding moiety may not prevent or reduce the association of DDB1 with a culin protein such as culin 4A or culin 4B. In some embodiments, the DDB1 binding moiety is a small molecule.

[0127] In some embodiments, the DDB1 coupling portion described herein is formula (II):

[0128] [ka] It includes the structure, During the ceremony, F 1 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13 S(=O)-, -S(=O)2NR 13 -, -NR 13S(=O)2-, -O-, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are bonded independently to hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a , -OCO2R a -C(=O)NR c Rd -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R a Each of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R bEach of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, and the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 5, and s is between 1 and 5.

[0129] In some embodiments of the compound of formula (II), F 1 is an aryl compound. In some embodiments of the compound of formula (II), F 1 is a heteroaryl compound. In some embodiments of the compound of formula (II), F1 F is a 5-12 member heteroaryl compound. In some embodiments of the compound of formula (II), F 1 is phenyl. In some embodiments of the compound of formula (II), F 1 is phenyl, and q is 1. In some embodiments of the compound of formula (II), F 2 is an aryl compound. In some embodiments of the compound of formula (II), F 2 is C6-C 12 It is an aryl compound. In some embodiments of the compound of formula (II), F 2 is a heteroaryl compound. In some embodiments of the compound of formula (II), F 2 F is a 5-12 member heteroaryl compound. In some embodiments of the compound of formula (II), F 2 It is a 5-membered ring heteroaryl. In some embodiments of the compound of formula (II), F 2 It is a 6-membered ring heteroaryl. In some embodiments of the compound of formula (II), F 2 is an N-heterocyclyl ring. In some embodiments, F 2 These are triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl. In some embodiments, F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl, where q is 1. In some embodiments, F 2 is a 5-6 member heteroaryl. In some embodiments, F 2 is a heteroaryl group, and the heteroaryl group has at least one nitrogen atom in the ring. In some embodiments, F 2 is a heteroaryl group, and the heteroaryl group has at least two nitrogen atoms in the ring. In some embodiments, F 2 is pyridyl, pyrimidinil, or pyrazinil. In some embodiments, F 2is a heteroaryl group, and the heteroaryl group has at least one sulfur atom in the ring. In some embodiments, F 2 is a heteroaryl group, and the heteroaryl group has at least one oxygen atom in the ring. In some embodiments, F 2 is thiazolyl, oxazolyl, furanyl, or thiophenyl. In some embodiments, F 2 is thiazolyl. In some embodiments, R 12 R is -NO2, halogen, methyl, halomethyl, phenyl, cyclopropyl, SO2CH3, or -CN, respectively, upon appearance. In some embodiments, R 12 is -NO2. In some embodiments of the compound of formula (IIb), R 12 In each instance, it is chloro or bromo. In some embodiments, L 2 is -NHC(=O) or -C(=O)NH-. In some embodiments, L 2 is -C(=O)NH-. In some embodiments, L 2 The compound is -C(=O)N(C1-C5 alkyl)-. In some embodiments, the DDB1 binding moiety comprises a nitazoxanide or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the DDB1 coupling portion described herein is formula (IIa):

[0131] [ka] It includes the structure, During the ceremony, F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13S(=O)-, -S(=O)2NR 13 -, -NR 13 S(=O)2-, -O-, C1-C4 alkyl, or C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are bonded independently to hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2Ra , -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R a Each of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R bEach of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, and the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 5, and s is between 1 and 5.

[0132] In some embodiments of the compound of formula (IIa), F 2 is an aryl compound. In some embodiments of the compound of formula (IIa), F 2 is C6-C 12It is an aryl compound. In some embodiments of the compound of formula (IIa), F 2 is a heteroaryl compound. In some embodiments of the compound of formula (IIa), F 2 It is a 5-12 member heteroaryl compound. In some embodiments of the compound of formula (IIa), F 2 These are triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl. In some embodiments of the compound of formula (IIa), F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl, where p is 1. In some embodiments of the compound of formula (IIa), F 2 It is a 5-12 member heteroaryl compound. In some embodiments of the compound of formula (IIa), F 2 is a heteroaryl group, and the heteroaryl group has at least one nitrogen atom in the ring. In some embodiments of the compound of formula (IIa), F 2 is a heteroaryl group, and the heteroaryl group has at least two nitrogen atoms in the ring. In some embodiments of the compound of formula (IIa), F 2 is pyridyl, pyrimidinil, or pyrazinil. In some embodiments, F 2 is a heteroaryl group, and the heteroaryl group has at least one sulfur atom in the ring. In some embodiments, F 2 is a heteroaryl group, and the heteroaryl group has at least one oxygen atom in the ring. In some embodiments of the compound of formula (IIa), F 2 is thiazolyl, oxazollyl, furanyl, or thiophenyl. In some embodiments of the compound of formula (IIa), F 2 is thiazolyl. In some embodiments of the compound of formula (IIa), R 12R is -NO2, halogen, methyl, halomethyl, phenyl, cyclopropyl, SO2CH3, or -CN, respectively, in its appearance. In some embodiments of the compound of formula (IIa), R 12 is -NO2. In some embodiments of the compound of formula (IIb), R 12 In each instance, it is chloro or bromo. In some embodiments of the compound of formula (IIa), L 2 L is -NHC(=O) or -C(=O)NH-. In some embodiments of the compound of formula (IIa), L 2 L is -C(=O)NH-. In some embodiments of the compound of formula (IIa), L 2 is -C(=O)N(C1-C5 alkyl)-. In some embodiments of the compound of formula (IIa), q is 1. In some embodiments of the compound of formula (IIa), q is 2.

[0133] In some embodiments, the compounds described herein are of formula (IIb):

[0134] [ka] It includes the structure, During the ceremony, A 4 and A 5 These are, independently, S, N, or O, and A 4 Or A 5 At least one of them is N, L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13 S(=O)-, -S(=O)2NR 13 -, -NR 13S(=O)2-, -O-, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are bonded independently to hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a , -OCO2R a -C(=O)NR c Rd -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R a Each of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R bEach of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, and the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 5, and s is between 1 and 3.

[0135] In some embodiments of the compound of formula (IIb), R 12R is -NO2, halogen, methyl, halomethyl, phenyl, isopropyl, cyclopropyl, SO2CH3, or -CN, respectively, in its appearance. In some embodiments of the compound of formula (IIb), R 12 is -NO2. In some embodiments of the compound of formula (IIb), R 12 In each instance, it is chloro or bromo. In some embodiments of the compound of formula (IIb), L 2 is -NHC(=O) or -C(=O)NH-. In some embodiments of the compound of formula (IIb), L 2 L is -C(=O)NH-. In some embodiments of the compound of formula (IIb), L 2 is -C(=O)N(C1-C5 alkyl)-. In some embodiments of the compound of formula (IIb), q is 1. In some embodiments of the compound of formula (IIb), q is 2.

[0136] In some embodiments, the DDB1 binding moiety is incorporated into a ligand described herein. In some embodiments, the DDB1 binding moiety is part of a modified protein described herein. In some embodiments, the DDB1 binding moiety is part of a ligand-protein complex described herein. In some embodiments, the DDB1 binding moiety is bound to a linker, such as a linker described herein. In some embodiments, the DDB1 binding moiety is covalently attached to a target protein described herein via the linker.

[0137] This specification describes compounds containing a DDB1 binding moiety. In some embodiments, the DDB1 binding moiety includes the compounds listed in Table 1.

[0138] [Table 1-1]

[0139] [Table 1-2]

[0140] Table 1-3

[0141] Table 1-4

[0142] Table 1-5

[0143] Table 1-6

[0144] Table 1-7

[0145] Table 1-8

[0146] Table 1-9

[0147] Table 1-10

[0148] Table 1-11

[0149] Table 1-12

[0150] [Table 1-13]

[0151] [Table 1-14]

[0152] [Table 1-15]

[0153] [Table 1-16]

[0154] [Table 1-17]

[0155] [Table 1-18]

[0156] [Table 1-19]

[0157] In some embodiments, the compounds in Table 1 are capped with a capping group to simulate a linker. In some examples, the capping group includes a substituted amino group. In some examples, the capping group includes an N-alkyl or N-dialkyl group, an acetamide, an alkyl or haloalkyl group, a lactam, an aminofuran, or an aminopyran group. While not bound by theory, in some examples, the capping group is used to approximate the effect on activity from a similar linker. For example, the DDB1 bond is structured as follows:

[0158] [ka] In some embodiments,

[0159] [ka] It is incorporated into compounds containing, where the wavy line indicates the binding site to the target protein binding site and / or linker. In another example, the DDB1 binding site has the following structure:

[0160] [ka] In some embodiments,

[0161] [ka] It is incorporated into compounds containing the compound, where the wavy line indicates the binding site to the target protein and / or linker.

[0162] In some embodiments herein, ligands comprising a DDB1 binding moiety that binds to or is bound to the DDB1 protein are disclosed. In some embodiments, the binding of the DDB1 protein to the ligand is such that the equilibrium dissociation constant (Kd) is less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, less than 60 μM, less than 50 μM, less than 45 μM, less than 40 μM, less than 35 μM, less than 30 μM, less than 25 μM, and less than 20 μM. Includes binding affinity of less than 15 μM, less than 14 μM, less than 13 μM, less than 12 μM, less than 11 μM, less than 10 μM, less than 9 μM, less than 8 μM, less than 7 μM, less than 6 μM, less than 5 μM, less than 4 μM, less than 3 μM, less than 2 μM, or less than 1 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity such that the Kd value is 100 μM, approximately 90 μM, approximately 80 μM, approximately 70 μM, approximately 60 μM, approximately 50 μM, approximately 45 μM, approximately 40 μM, approximately 35 μM, approximately 30 μM, approximately 25 μM, approximately 20 μM, approximately 15 μM, approximately 14 μM, approximately 13 μM, approximately 12 μM, approximately 11 μM, approximately 10 μM, approximately 9 μM, approximately 8 μM, approximately 7 μM, approximately 6 μM, approximately 5 μM, approximately 4 μM, approximately 3 μM, approximately 2 μM, or approximately 1 μM, or the range of the Kd value is defined by any two of the aforementioned Kd values. In some embodiments, the binding affinity between the DDB1 protein and the ligand includes a Kd value of 100 μM, 90 μM, 80 μM, 70 μM, 60 μM, 50 μM, 45 μM, 40 μM, 35 μM, 30 μM, 25 μM, 20 μM, 15 μM, 14 μM, 13 μM, 12 μM, 11 μM, 10 μM, 9 μM, 8 μM, 7 μM, 6 μM, 5 μM, 4 μM, 3 μM, 2 μM, or 1 μM, or a range of Kd values ​​defined by any two of the aforementioned Kd values.

[0163] In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 100 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 90 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 80 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 70 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 60 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 50 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 45 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 40 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 35 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 30 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 25 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 20 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 15 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 14 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 13 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 12 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 11 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 10 μM.In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 9 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 8 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 7 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 6 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 5 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 4 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 3 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 2 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value of less than 1 μM.

[0164] In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 100 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 90 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 80 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 70 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 60 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 50 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 45 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 40 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 35 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 30 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 25 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 20 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 15 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 14 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 13 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 12 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 11 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 10 μM.In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 9 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 8 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 7 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 6 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 5 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 4 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 3 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 2 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes a binding affinity with a Kd value greater than 1 μM.

[0165] In some embodiments, the binding of the DDB1 protein to the ligand includes binding affinities with a Kd of less than 20 μM, a Kd of 20 to 100 μM, or a Kd of less than 100 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes binding affinities with a Kd value of less than 20 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes binding affinities with a Kd value of 20 to 100 μM. In some embodiments, the binding of the DDB1 protein to the ligand includes binding affinities with a Kd value greater than 100 μM.

[0166] In some embodiments, the ligand comprises a compound from Table 6, or a derivative or salt thereof. The compound may include a peptide compound or a non-peptide compound. In some embodiments, the ligand from Table 6 has a Category A bond as defined in the table. In some embodiments, the ligand from Table 6 has a Category B bond as defined in the table. In some embodiments, the ligand from Table 6 has a Category C bond as defined in the table. In some embodiments, the ligand comprises a compound from Table 7, or a derivative or salt thereof. In some embodiments, the ligand from Table 7 has a Category A bond as defined in the table. In some embodiments, the ligand from Table 7 has a Category B bond as defined in the table.

[0167] In some embodiments, the connection between the DDB1 connection portion and DDB1 is a non-covalent bond. In some embodiments, the connection between the DDB1 connection portion and DDB1 is a covalent bond.

[0168] This specification describes the compounds in Table 2, which include a DDB1 binding moiety and a linker. The linker may include any of the linkers described herein. In some embodiments, the compound is bound to DDB1 via a DDB1 binding moiety. In some embodiments, the linker is a bond. In some embodiments, the linker is not a bond (e.g., not just a bond).

[0169] [Table 2-1]

[0170] [Table 2-2]

[0171] [Table 2-3]

[0172] Table 2-4

[0173] Table 2-5

[0174] Table 2-6

[0175] Table 2-7

[0176] Table 2-8

[0177] Table 2-9

[0178] Table 2-10

[0179] Table 2-11

[0180] In some embodiments, the DDB1 binding portion contains a peptide. In some embodiments, the DDB1 binding portion contains 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 or fewer, or 8 or fewer amino acids. In some embodiments, the DDB1 binding portion contains at least 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 or at least 8 amino acids. In some embodiments, the DDB1 binding portion contains about 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 or about 8 amino acids. In some embodiments, the DDB1 binding moiety includes 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, or 8 amino acids, or a range defined by any two of the aforementioned amino acid counts. In some embodiments, the DDB1 binding moiety includes a virus-derived peptide. In some embodiments, the DDB1 binding moiety includes the peptides listed in Table 3. In some embodiments, the DDB1 binding moiety includes the amino acid sequence of any one of SEQ ID NOs: 1-7 (e.g., SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7). In some embodiments, the DDB1 binding moiety includes the amino acid sequence of SEQ ID NO: 1 or a variant thereof. In some embodiments, the DDB1 binding moiety includes the amino acid sequence of SEQ ID NO: 2 or a variant thereof. In some embodiments, the DDB1 binding moiety includes the amino acid sequence of SEQ ID NO: 3 or a variant thereof. In some embodiments, the DDB1 binding moiety includes the amino acid sequence of SEQ ID NO: 4 or a variant thereof. In some embodiments, the DDB1 binding moiety includes the amino acid sequence of SEQ ID NO: 5 or a variant thereof. In some embodiments, the DDB1 binding moiety includes the amino acid sequence of SEQ ID NO: 6 or a variant thereof. In some embodiments, the DDB1 binding moiety includes the amino acid sequence of SEQ ID NO: 7 or a variant thereof. In some embodiments, the DDB1 binding moiety has at least 99% sequence identity with any one of SEQ ID NOs: 1 to 7. In some embodiments, the DDB1 binding moiety has at least 98% sequence identity with any one of SEQ ID NOs: 1 to 7.In some embodiments, the DDB1 binding portion has at least 97% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 96% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 95% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 94% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 93% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 92% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 91% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 90% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 89% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 88% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 87% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 86% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 85% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 80% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 75% sequence identity with any one of sequence numbers 1 to 7. In some embodiments, the DDB1 binding portion has at least 70% sequence identity with any one of sequence numbers 1 to 7.In some embodiments, the DDB1 binding moiety has at least 65% sequence identity with any one of SEQ ID NOs: 1-7. In some embodiments, the DDB1 binding moiety contains a variant of any one of SEQ ID NOs: 1-7, in which at least one residue is modified. In some embodiments, the modification includes insertion, deletion, or substitution. In some embodiments, the DDB1 binding moiety contains a variant of any one of SEQ ID NOs: 1-7, in which the peptide contains at least one non-standard amino acid.

[0181] [Table 3]

[0182] The peptide (e.g., the DDB1 binding moiety) may contain non-standard amino acids (e.g., amino acids other than the 20 amino acids typically encoded by triple codons). In some embodiments, the α-position of the non-standard amino acid has an (S) configuration. In some embodiments, the α-position of the non-standard amino acid has an (R) configuration. In some embodiments, the non-standard amino acid is an α-amino acid. In some embodiments, the non-standard amino acid is a β-amino acid or a γ-amino acid. In some embodiments, the non-standard amino acid is selected from the group consisting of aromatic side-chain amino acids, non-aromatic side-chain amino acids, aliphatic side-chain amino acids, side-chain amide amino acids, side-chain ester amino acids, heteroaromatic side-chain amino acids, side-chain thiol amino acids, β-amino acids, and skeletal-modified amino acids. In some embodiments, the non-standard amino acid is a derivative of tyrosine, histidine, tryptophan, or phenylalanine. In some embodiments, the amino acid derivatives include esters, amides, disulfides, carbamates, urea, phosphates, and ethers of amino acids. In some embodiments, the non-aromatic side-chain amino acid is serine, threonine, cysteine, methionine, arginine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, proline, glycine, alanine, valine, isoleucine, or a derivative of leucine. In some embodiments, the non-standard amino acid is selected from the group consisting of 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, β-aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, piperidine acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-diaminobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminoproprionic acid, N-ethylglycine, N-ethylasparagine, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylglycine, sarcosine, n-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, and ornithine.In some embodiments, the non-standard amino acid is a proline derivative. In some embodiments, the proline derivative is 3-fluoroproline, 4-fluoroproline, 3-hydroxyproline, 4-hydroxyproline, 3-aminoproline, 4-aminoproline, 3,4-dehydroproline, aziridine-2-carboxylic acid, azetidine-2-carboxylic acid, pipecolic acid, 4-oxa-proline, 3-thiaproline, or 4-thiaproline. In some embodiments, the non-standard amino acid includes lipids.

[0183] The peptide (e.g., the DDB1 binding moiety) may include modifications to an N-terminal amino group (N-terminal modification), a C-terminal acid group (C-terminal modification), or both. In some embodiments, the unmodified N-terminus contains hydrogen. In some embodiments, the unmodified C-terminus contains -OH. In some embodiments, the N-terminal modification is C1-C6 acyl, C1-C8 alkyl, C6-C 12 Aralkil, C5C 10 The modifier includes aryl, C4-C8 heteroaryl, formyl, or lipids. In some embodiments, the N-terminal modification is C6-C 12 Contains aralkyl. In some embodiments, the N-terminal modification contains C1-C6 acyl. In some embodiments, the N-terminal modification contains acetyl. In some embodiments, the N-terminal modification contains methyl, ethyl, propyl, or tert-butyl. In some embodiments, the N-terminal modification contains benzyl. In some embodiments, the N-terminal modification contains formyl. In some embodiments, the N-terminal modification contains lipids. In some embodiments, the C-terminal modification contains an amino group, which is optionally substituted. In some embodiments, the C-terminal modification contains an amino group, which is not substituted (-NH2). In some embodiments, the C-terminal modification contains an amino group, which is substituted. In some embodiments, the C-terminal modification is -NH2, -amino-acyl, -amino-C1-C8 alkyl, -amino-C6-C 12 Aralkyl, -amino-C5-C 10The C-terminal modification includes aryl, or -amino-C4-C8 heteroaryl, -amino-C4-C8 heteroaryl, or -O-(C1-C8 alkyl). In some embodiments, the C-terminal modification is -amino-C6-C 12 -Contains aralkyl. In some embodiments, the C-terminal modification contains -O-(C1-C8 alkyl). In some embodiments, the C-terminal modification is -amino-C6-C 12 -Includes aralkyl. In some embodiments, the C-terminal modification includes -NH-CH2Ph. In some embodiments, the C-terminal modification includes -OEt. In some embodiments, the C-terminal modification includes -OMe.

[0184] Peptides (e.g., the DDB1 binding portion) may contain lipids. Such lipids are covalently bonded to amino acids in the peptide. In some embodiments, the lipid is bonded to the N-terminus. In some embodiments, the lipid is bonded to cysteine, serine, lysine, threonine, or tyrosine. In some embodiments, the lipid is bonded to cysteine ​​and lysine. In some embodiments, the lipid is bonded to non-standard amino acids. In some embodiments, the lipid contains a hydrophobic group. In some embodiments, the lipid contains a fatty acid group. In some embodiments, the lipid is C6-C 20 Contains fatty acid groups. In some embodiments, the lipid contains steroids. In some embodiments, the lipid contains waxes. In some embodiments, the lipid contains alkyl groups. In some embodiments, the lipid is C6-C 20 Contains alkyl groups. In some embodiments, the lipids are C6-C 20 It contains an alkenyl group. In some embodiments, the lipid is C6-C 20 Alkyl alkyl group, C6-C 20 Alkenyl group, C6-C 20 Alkynyl group, or C6-C 20The lipid contains an acyl group. In some embodiments, the lipid contains a geranyl group, a farnesyl group, or a geranylgeranyl group. In some embodiments, the lipid contains an undecylloyl group, a lauroyl group, a tridecylloyl group, a myristoyl group, a palmitoyl group, or a stearoyl group. In some embodiments, the lipid is bonded to cysteine ​​by palmitoylation or prenylation. In some embodiments, the peptides described herein contain fatty acid esters, amides, or thioesters.

[0185] In some embodiments herein, a DDB1 binding moiety is disclosed. In some embodiments, the DDB1 binding moiety binds to the DDB1 protein. In some embodiments, the DDB1 binding moiety binds to a binding region on the DDB1 protein. In some embodiments, the DDB1 binding moiety binds to the DDB1 protein. In some embodiments, the DDB1 binding moiety binds to a binding region on the DDB1 protein. In some embodiments, the binding region on the DDB1 protein includes a β-propeller domain. In some embodiments, the binding region on the DDB1 protein includes a β-propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein includes the upper surface of the BPC domain. In some embodiments, the binding region on the DDB1 protein is the following DDB1 protein residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER8 15, including one or more of ALA834, VAL836, ALA841, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, and / or VAL1033.In some embodiments, the following DDB1 protein residues are used: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA8 41, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, and / or VAL1033 are involved in non-covalent binding between the DDB1 protein and the ligand. In some embodiments, the binding region on the DDB1 protein includes the amino acid residues described herein, such as in the section titled “Modified Proteins”.

[0186] Linker This specification describes compounds containing linkers. In some embodiments, the linker is connected to a DDB1 binding site as described herein. In some embodiments, the linker is connected to a target protein binding site as described herein. In some embodiments, the linker is connected to both the DDB1 binding site and the target protein binding site. In some embodiments, the connection is covalent. In some embodiments, the linker is incorporated into a ligand as described herein. In some embodiments, the compound of formula (I) described herein includes linkers of formulas (III), (IIIa), and (IIIb).

[0187] This specification describes compounds comprising a DDB1 bond and a linker. In some embodiments, the linker comprises optionally substituted polyethylene glycol (PEG). In some embodiments, the linker comprises optionally substituted alkyl chains. In some embodiments, the linker is a linear alkane. In some embodiments, the linker comprises optionally substituted C2-C 30 , C2-C25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20 It contains alkyl units. In some embodiments, the linker contains optionally substituted carbon rings. In some embodiments, the linker contains optionally substituted heterocycles. In some embodiments, the linker contains optionally substituted aryl rings. In some embodiments, the linker contains optionally substituted heteroaryl rings. In some embodiments, the linker contains ethers. In some embodiments, the linker is C2-C 30 , C2-C 25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20 It contains alkyl ether units. In some embodiments, the length of PEG is optionally substituted with -(O-CH2CH2)- units of 1-5, 2-7, 2-10, 2-20, 5-25, or 4-30. In some embodiments, the linker contains an amine. In some embodiments, the linker is C2-C 30 , C2-C 25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20 It contains alkylamino units. In some embodiments, the linker is optionally substituted with 1-5, 2-7, 2-10, 2-20, 5-25, or 4-30 -(NH-CH2CH2)- units. In some embodiments, the linker contains an amide. In some embodiments, the linker contains a sulfonamide. In some embodiments, the linker contains a carbamide. In some embodiments, the linker contains a carbamate. In some embodiments, the linker contains a carbonate. In some embodiments, the compound comprises a DDB1 binding moiety, a linker, and / or a target protein binding moiety. In some embodiments, the linker is of formula (III):

[0188] [ka] It is, During the ceremony, A, W, and B are independently selected from either null or divalent parts at each occurrence, and the divalent parts are R'-R'', R'COR'', R'CO2R'', and R'C(O)N(R 1 )R'', R'C(S)N(R 1 )R'', R'OR'', R'OC(O)R'', R'OC(O)OR'', R'OCON(R 1 )R'', R'SR'', R'SOR'', R'SO2R'', R'SO2N(R 1 )R'', R'N(R 1 )R'', R'N(R 1 )COR'', R'N(R 1 )C(O)OR'', R'N(R 1 )CON(R 2 )R'', R'N(R 1 )C(S)R'', R'N(R 1 )S(O)R'', R'N(R 1 )S(O)2R'', R'N(R 1 )S(O)2N(R 2 )R'', optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkylylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkylene, optionally substituted C2-C8 heteroalkylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13Spirocarbocykrill, optionally replaced with C5-C 13 Selected from spiroheterocyclyls, optionally substituted 3- to 10-membered carbocyclyls, optionally substituted 4- to 10-membered heterocyclyls, optionally substituted aryls, and optionally substituted heteroaryls. R' and R'' are independently replaced by null or optionally substituted with (C1-C8 alkylene)-R when they appear. r (Preferably CH2-R r ), R replaced by arbitrary selection r -(C1-C8 alkylene), optionally replaced with (C1-C8 alkylene)-R r -(C1-C8 alkyl), or selected from the divalent moiety, the divalent moiety being optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkylylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkylylene, optionally substituted C2-C8 heteroalkylylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13 Spirocarbocykrill, optionally replaced with C5-C 13 It consists of a spiroheterocyril, an optionally substituted aryl, and an optionally substituted heteroaryl. R rEach instance is replaced by an arbitrarily substituted 3-10 member carbocyclyl, an arbitrarily substituted 4-10 member heterocyclyl, or an arbitrarily substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13 Spirocarbocykrill, optionally replaced with C5-C 13 Selected from spiroheterocyrils, optionally substituted aryls, and optionally substituted heteroaryls, R 1 and R 2 Each instance is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R' and R'', R 1 and R 2 , R' and R 1 , R' and R 2 , R'' and R 1 , or R'' and R 2 They, together with the atoms to which they are connected, optionally form a 3-20 membered carbocykyl ring or a 4-20 membered heterocycline ring, and m is between 0 and 15.

[0189] In some embodiments of the linker of formula (III), A is (CH2)0-12 N(R 1 ) where B is null and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 OC(O), B is null, and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 N(R 1 )C(O), B is null, and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 C(O)O, where B is null and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 C(O)N(R 1 ) where B is null and W is alkylene. In some embodiments of the linker of formula (III), m is 2 to 10. In some embodiments of the linker of formula (III), m is 2 to 7. In some embodiments of the linker of formula (III), m is 5 to 10.

[0190] In some embodiments of the linker of formula (III), A is (CH2) 0-12 N(R 1 ) where B is O and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 OC(O), B is O, and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 N(R 1 )C(O), B is O, and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 C(O)O, where B is O and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 C(O)N(R 1) where B is O and W is alkylene. In some embodiments of the linker of formula (III), m is 2 to 12. In some embodiments of the linker of formula (III), m is 2 to 7. In some embodiments of the linker of formula (III), m is 5 to 12.

[0191] In some embodiments of the linker of formula (III), A is (CH2) 0-12 N(R 1 ) and B is N(R 2 ) and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 OC(O) and B is N(R 2 ) and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 N(R 1 )C(O) and B is N(R 2 ) and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 C(O)O and B is N(R 2 ) and W is alkylene. In some embodiments of the linker of formula (III), A is (CH2) 0-12 C(O)N(R 1 ) and B is N(R 2 ) and W is alkylene. In some embodiments of the linker of formula (III), m is 2 to 12. In some embodiments of the linker of formula (III), m is 2 to 7. In some embodiments of the linker of formula (III), m is 5 to 12.

[0192] In some embodiments, the linker is given by formula (IIIa):

[0193] [ka] It is, During the ceremony, R 1 , R 2 , R 3 , and R 4Each of these independently appears as hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, or optionally substituted C Selected from 1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylamino, C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R 1 and R 2 , R 3 and R 4 These, together with the atom to which they are connected, optionally form a 3-20 membered carbocykyl ring or a 4-20 membered heterocycline ring. A, W, and B are independently selected from either null or divalent parts at each occurrence, and the divalent parts are R'-R'', R'COR'', R'CO2R'', and R'C(O)N(R 5 )R'', R'C(S)N(R 5 )R'', R'OR'', R'OC(O)R'', R'OC(O)OR'', R'OCON(R 5 )R'', R'SR'', R'SOR'', R'SO2R'', R'SO2N(R 5 )R'', R'N(R 5 )R'', R'N(R 5 )COR'', R'N(R 5 )C(O)OR'', R'N(R 5 )CON(R 6 )R'', R'N(R 5 )C(S)R'', R'N(R5 )S(O)R'', R'N(R 5 )S(O)2R'', R'N(R 5 )S(O)2N(R 6 )R'', optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkylylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13 Spirocarbocykrill, optionally replaced with C5-C 13 Selected from spiroheterocyclyls, optionally substituted 3- to 10-membered carbocyclyls, optionally substituted 4- to 10-membered heterocyclyls, optionally substituted aryls, and optionally substituted heteroaryls. R' and R'' are independently replaced by null or optionally substituted with (C1-C8 alkylene)-R when they appear. r (Preferably CH2-R r ), R replaced by arbitrary selection r -(C1-C8 alkylene), optionally replaced with (C1-C8 alkylene)-R r-(C1-C8 alkylene), or selected from the divalent moiety, the divalent moiety is optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkylylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkylylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13 Spirocarbocykrill, optionally replaced with C5-C 13 It consists of a spiroheterocyril, an optionally substituted aryl, and an optionally substituted heteroaryl. R r Each instance is replaced by an arbitrarily substituted 3-10 member carbocyclyl, an arbitrarily substituted 4-10 member heterocyclyl, or an arbitrarily substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13 Spirocarbocykrill, optionally replaced with C5-C 13 Selected from spiroheterocyrils, optionally substituted aryls, and optionally substituted heteroaryls, R 5 and R 6At each occurrence, it is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3- to 10-membered carbocyclic, optionally substituted 4- to 10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, or R’ and R’’, R 5 and R 6 , R’ and R 5 , R’ and R 6 , R’’ and R 5 , R’’ and R 6 together with the atoms to which they are attached form a 3- to 20-membered cycloalkyl ring or a 4- to 20-membered heterocyclic ring, m is 0 to 15, n is 0 to 15 at each occurrence, and o is 0 to 15. [[ID=2"]]

[0194] In some embodiments, the linker is of formula (IIIb):

[0195]

Chemical formula

[0196] In some embodiments, the linker is given by formula (IIIc):

[0197] [ka] It is, During the ceremony, X is O, NH, and NR in each instance. 7 Selected from, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6at each occurrence, independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 10-membered carbocyclic, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 4- to 10-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, A and B are independently selected from null or a divalent moiety, and the divalent moiety is R’-R’’, R’COR’’, R’CO2R’’, R’C(O)N(R 8 )R’’, R’C(S)N(R 8 )R’’, R’OR’’, R’OC(O)R’’, R’OC(O)OR’’, R’OCON(R 8 )R’’, R’SR’’, R’SOR’’, R’SO2R’’, R’SO2N(R 8 )R’’, R’N(R 8 )R’’, R’N(R 8 )COR’’, R’N(R 8 )C(O)OR’’, R’N(R 8 )CON(R 9 )R’’, R’N(R 8 )C(S)R’’, R’N(R 8 )S(O)R’’, R’N(R 8 )S(O)2R’’, R’N(R 8 )S(O)2N(R 9)R'', optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkylylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13 Spirocarbocykrill, optionally replaced with C5-C 13 Selected from spiroheterocyclyls, optionally substituted 3- to 10-membered carbocyclyls, optionally substituted 4- to 10-membered heterocyclyls, optionally substituted aryls, and optionally substituted heteroaryls. R' and R'' are independently replaced by null or optionally substituted with (C1-C8 alkylene)-R when they appear. r (Preferably CH2-R r ), R replaced by arbitrary selection r-(C1-C8 alkylene), or selected from the divalent moiety, the divalent moiety is optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkylylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkylylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 alkylaminoC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13 Spirocarbocykrill, optionally replaced with C5-C 13 It consists of a spiroheterocyril, an optionally substituted aryl, and an optionally substituted heteroaryl. R r Each instance is replaced by an arbitrarily substituted 3-10 member carbocyclyl, an arbitrarily substituted 4-10 member heterocyclyl, or an arbitrarily substituted C4-C 13 Condensed carbocyclyl, optionally substituted with C5-C 13 Condensed heterocyclyl, optionally substituted C5-C 13 Cross-linked carbocyclyl, optionally substituted with C5-C 13 Cross-linked heterocyclyl, optionally substituted with C5-C 13 Spirocarbocykrill, optionally replaced with C5-C 13 Selected from spiroheterocyrils, optionally substituted aryls, and optionally substituted heteroaryls, R 7 , R 8 , and R9 Each instance is independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or R' and R'', R 8 and R 9 , R' and R 8 , R' and R 9 , R'' and R 8 , R'' and R 9 These, together with the atom to which they are connected, optionally form a 3-20 membered carbocykyl ring or a 4-20 membered heterocycline ring. m is between 0 and 15 in each instance. n is between 0 and 15 at each occurrence. o is 0 to 15, and p is between 0 and 15.

[0198] In some embodiments, the linker is given by formula (IIId):

[0199] [ka] It is, During the ceremony, A, W 1 , W 2 , and B are divalent parts in their respective appearances, and the divalent parts are independently null, R'-R'', R'COR'', R'C(O)OR'', R'C(O)N(R 1 )R'', R'C(S)N(R 1)R'', R'OR'', R'SR'', R'SOR'', R'SO2R'', R'SO2N(R 1 )R'', R'N(R 1 )R'', R'N(R 1 )COR'', R'N(R 1 )CON(R 2 )R'', R'N(R 1 )C(S)R'', optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkylylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 Selected from the group consisting of cycloalkyls, optionally substituted 3- to 13-membered heterocyclines, optionally substituted aryls, and optionally substituted heteroaryls, R' and R'' are independently substituted with null, Rr, or (C1-C8 alkylene)-R at their respective occurrences. r (Preferably CH2-R r ), R replaced by arbitrary selection r -(C1-C8 alkylene), optionally replaced with (C1-C8 alkylene)-R r -(C1-C8 alkylene), or selected from the divalent moiety, the divalent moiety being optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkylynylene, optionally substituted C1-C8 heteroalkylene, optionally substituted C2-C8 heteroalkenylene, optionally substituted C2-C8 heteroalkylynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8 alkoxy C1-C8 alkylene, optionally substituted C1-C8 alkylamino C1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C3-C 13Selected from cycloalkyls, optionally substituted 3- to 13-membered groups, optionally substituted aryls, and optionally substituted heteroaryls, R r Each instance of C3-C is replaced by an optional substitution. 10 Selected from carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, R 1 and R 2 Each of these independently appears as hydrogen, an optionally substituted C1-C8 alkyl, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C1-C8 heteroalkyl, an optionally substituted C2-C8 heteroalkenyl, an optionally substituted C2-C8 heteroalkynyl, an optionally substituted C1-C8 alkoxyalkyl, an optionally substituted C1-C8 haloalkyl, an optionally substituted C1-C8 hydroxyalkyl, an optionally substituted C1-C8 alkylamino C1-C8 alkyl, or an optionally substituted C3-C 10 Selected from the group consisting of carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, R' and R'', R 1 and R 2 , R' and R 1 , R' and R 2 , R'' and R 1 , or R'' and R 2 They become one with the atom to which they are connected, and optionally form C3-C 20 They form a carbocyclyl ring or a 3-20 membered heterocyclyl ring, and m is between 0 and 15.

[0200] In some embodiments, A and B are independently selected from null, CO, NH, NH-CO, CO-NH, CH2-NH-CO, CH2-CO-NH, NH-CO-CH2, CO-NH-CH2, CH2-NH-CH2-CO-NH, CH2-NH-CH2-NH-CO, -CO-NH, CO-NH-CH2-NH-CH2, CH2-NH-CH2. In some embodiments, o is 0 to 5. In some embodiments, the linker includes a ring selected from the group consisting of 3- to 13-membered rings, 3- to 13-membered condensed rings, 3- to 13-membered bridging rings, and 3- to 13-membered spiro rings. In some embodiments, the linker is a ring of formula (IIIC1a), formula (IIIC2a), formula (IIIC3a), formula (IIIC4a), and formula (IIIC5a).

[0201] [ka] It includes one or more rings selected from the group consisting of, During the ceremony, X' and Y' are independent of N and CR. b Selected from, A 1 B 1 , C 1 , and D 1 Each of these independently represents null, O, CO, SO, SO2, and NR upon their respective appearances. b , and CR b R c Selected from, A 2 B 2 , C 2 , and D 2 Each occurrence independently determines N and CR b Selected from, A 3 B 3 , C 3 , D 3 , and E 3 Each instance independently produces N, O, S, NRb, and CR. b Selected from, R b and R cEach of these independently appears as hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, or optionally substituted C Selected from 1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylamino, C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-8 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, and m 1 , n 1 , o 1 , and p 1 This is independently selected from 0, 1, 2, 3, 4, and 5.

[0202] In some embodiments, the linker includes one or more rings selected from the group consisting of formulas (IIIC1), (IIIC2), (IIIC3), (IIIC4), and (IIIC5).

[0203] [ka]

[0204] In some embodiments, the linker is

[0205] [ka] Includes one or more rings selected from.

[0206] In some embodiments, the linker is structure-(CH2) 0-12 NH(CH2) 2-12 It has NH-. In the 10 10 NH-, -NH(CH2) 11 NH-, or -NH(CH2) 12 It has NH-. In some embodiments, the linker has structure-(CH2) 0-12 NHC(=O)(CH2) 2-12 It has NH-. In several embodiments, the linker has the structures -NHC(=O)(CH2)2NH-, -NHC(=O)(CH2)3NH-, -NHC(=O)(CH2)4NH-, -NHC(=O)(CH2)5NH-, -NHC(=O)(CH2)6NH-, -NHC(=O)(CH2)7NH-, -NHC(=O)(CH2)8NH-, -NHC(=O)(CH2)9NH-, -NHC(=O)(CH2) 10 NH-, -NHC(=O)(CH2) 11 NH-, or -NHC(=O)(CH2) 12 It has NH-. In some embodiments, the linker has structure-(CH2) 0-12 NH(CH2) 2-12 The linker has the structure -NH(CH2)2C(=O)NH-, -NH(CH2)3C(=O)NH-, -NH(CH2)4C(=O)NH-, -NH(CH2)5C(=O)NH-, -NH(CH2)6C(=O)NH-, -NH(CH2)7C(=O)NH-, -NH(CH2)8C(=O)NH-, -NH(CH2)9C(=O)NH-, -NH(CH2) 10 C(=O)NH-, -NH(CH2) 11 C(=O)NH-, or -NH(CH2) 12 It has (=O)NH-. In some embodiments, the linker has the structure-(CH2) 0-12 C(=O)NH(CH2) 2-12The linker has the structure -C(=O)NH-. In some embodiments, the linker has the structure -C(=O)NH(CH2)2C(=O)NH-, -C(=O)NH(CH2)3C(=O)NH-, -C(=O)NH(CH2)4C(=O)NH-, -C(=O)NH(CH2)5C(=O)NH-, -C(=O)NH(CH2)6C(=O)NH-, -C(=O)NH(CH2)7C(=O)NH-, -C(=O)NH(CH2)8C(=O)NH-, -C(=O)NH(CH2)9C(=O)NH-, -C(=O)NH(CH2) 10 C(=O)NH-, -C(=O)NH(CH2) 11 C(=O)NH-, or -C(=O)NH(CH2) 12 The linker has the structure -(CH2)C(=O)NH(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2)3C(=O)NH-, -(CH2)C(=O)NH(CH2)4C(=O)NH-, -(CH2)C(=O)NH(CH2)5C(=O)NH-, -(CH2)C(=O)NH(CH2)6C(=O)NH-, -(CH2)C(=O)NH(CH2)7C(=O)NH-, -(CH2)C(=O)NH(CH2)8C(=O)NH-, -(CH2)C(=O)NH(CH2)9C(=O)NH-, -(CH2)C(=O)NH(CH2) 10 C(=O)NH-, -(CH2)C(=O)NH(CH2) 11 C(=O)NH-, or -(CH2)C(=O)NH(CH2) 12 The linker has the structure -(CH2)2C(=O)NH(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2)3C(=O)NH-, -(CH2)2C(=O)NH(CH2)4C(=O)NH-, -(CH2)2C(=O)NH(CH2)5C(=O)NH-, -(CH2)2C(=O)NH(CH2)6C(=O)NH-, -(CH2)2C(=O)NH(CH2)7C(=O)NH-, -(CH2)2C(=O)NH(CH2)8C(=O)NH-, -(CH2)2C(=O)NH(CH2)9C(=O)NH-, -(CH2)2C(=O)NH(CH2) 10C(=O)NH-, -(CH2)2C(=O)NH(CH2) 11 C(=O)NH-, or -(CH2)2C(=O)NH(CH2) 12 The linker has the structure -(CH2)3C(=O)NH(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2)3C(=O)NH-, -(CH2)3C(=O)NH(CH2)4C(=O)NH-, -(CH2)3C(=O)NH(CH2)5C(=O)NH-, -(CH2)3C(=O)NH(CH2)6C(=O)NH-, -(CH2)3C(=O)NH(CH2)7C(=O)NH-, -(CH2)3C(=O)NH(CH2)8C(=O)NH-, -(CH2)3C(=O)NH(CH2)9C(=O)NH-, -(CH2)3C(=O)NH(CH2) 10 C(=O)NH-, -(CH2)3C(=O)NH(CH2) 11 C(=O)NH-, or -(CH2)3C(=O)NH(CH2) 12 It contains (=O)NH-

[0207] In some embodiments, the linker is structure-(CH2) 0-12 NH(CH2CH2O) 1-12 The linker has the structure -NH(CH2CH2O)(CH2)2NH-, -NH(CH2CH2O)2(CH2)2NH-, -NH(CH2CH2O)3(CH2)2NH-, -NH(CH2CH2O)4(CH2)2NH-, -NH(CH2CH2O)5(CH2)2NH-, -NH(CH2CH2O)6(CH2)2NH-, -NH(CH2CH2O)7(CH2)2NH-, -NH(CH2CH2O)8(CH2)2NH-, -NH(CH2CH2O)9(CH2)2NH-, -NH(CH2CH2O) 10 (CH2)2NH-, -NH(CH2CH2O) 11 (CH2)2NH-, or -NH(CH2CH2O) 12 It has (CH2)2NH-. In some embodiments, the linker has the structure-(CH2) 0-12 NHC(=O)(CH2CH2O) 1-12It has (CH2)2NH-. In some embodiments, the linker has the structure-(CH2) 0-12 NH(CH2CH2O) 1-12 The linker has the structure -NH(CH2CH2O)(CH2)2C(=O)NH-, -NH(CH2CH2O)2(CH2)2C(=O)NH-, -NH(CH2CH2O)3(CH2)2C(=O)NH-, -NH(CH2CH2O)4(CH2)2C(=O)NH-, -NH(CH2CH2O)5(CH2)2C(=O)NH-, -NH(CH2CH2O)6(CH2)2C(=O)NH-, -NH(CH2CH2O)7(CH2)2C(=O)NH-, -NH(CH2CH2O)8(CH2)2C(=O)NH-, -NH(CH2CH2O)9(CH2)2C(=O)NH-, -NH(CH2CH2O) 10 (CH2)2C(=O)NH-, -NH(CH2CH2O) 11 (CH2)2C(=O)NH-, or -NH(CH2CH2O) 12 It has (CH2)2C(=O)NH-. In some embodiments, the linker has the structure-(CH2) 0-12 C(=O)NH(CH2CH2O) 1-12 The linker has the structure -C(=O)NH(CH2CH2O)(CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O)2(CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O)3(CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O)4(CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O)4(CH2)2C(=O)NH-, and -C(=O)NH(CH2CH2 O)5(CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O)6(CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O)7(CH2)2C(=O)NH- , -C(=O)NH(CH2CH2O)8(CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O)9(CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O) 10 (CH2)2C(=O)NH-, -C(=O)NH(CH2CH2O) 11(CH2)2C(=O)NH-, or -C(=O)NH(CH2CH2O) 12 The linker has the structure -(CH2)C(=O)NH-. In some embodiments, the linker has the structure -(CH2)C(=O)NH(CH2CH2O)(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2O)2(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2O)3(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2O)4(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2 O)5(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2O)6(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2O)7(CH2)2C(=O)NH-, -( CH2)C(=O)NH(CH2CH2O)8(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2O)9(CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2O) 10 (CH2)2C(=O)NH-, -(CH2)C(=O)NH(CH2CH2O) 11 (CH2)2C(=O)NH-, or -(CH2)C(=O)NH(CH2CH2O) 12 The linker has the structure -(CH2)2C(=O)NH-. In some embodiments, the linker has the structure -(CH2)2C(=O)NH(CH2CH2O)(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2O)2(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2O)3(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2O)4(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2 O)5(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2O)6(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2O)7(CH2)2C(=O)NH-, -( CH2)2C(=O)NH(CH2CH2O)8(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2O)9(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2O) 10(CH2)2C(=O)NH-, -(CH2)2C(=O)NH(CH2CH2O) 11 (CH2)2C(=O)NH-, or -(CH2)2C(=O)NH(CH2CH2O) 12 The linker has the structure -(CH2)3C(=O)NH-. In some embodiments, the linker has the structure -(CH2)3C(=O)NH(CH2CH2O)(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CH2O)2(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CH2O)3(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CH2O)4(CH2)2C(=O)NH-, -(CH2)3C(=O)N H(CH2CH2O)5(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CH2O)6(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CH2O)7(CH2) 2C(=O)NH-, -(CH2)3C(=O)NH(CH2CH2O)8(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CH2O)9(CH2)2C(=O)NH-, -(CH2) 3C(=O)NH(CH2CH2O) 10 (CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CH2O) 11 (CH2)2C(=O)NH-, or -(CH2)3C(=O)NH(CH2CH2O) 12 It contains (CH2)2C(=O)NH-

[0208] Target protein and target protein binding site In some embodiments herein, target proteins are disclosed. In some embodiments, the target protein comprises a transcription factor. In some embodiments, the target protein comprises an epigenetic modulator. In some embodiments, the target protein comprises p300 or CBP (CREB-binding protein). In some embodiments, the target protein is p300. In some embodiments, the target protein is CBP. In some embodiments, the target protein comprises a bromodomain-containing protein. In some embodiments, the target protein comprises bromodomain-containing protein 4 (BRD4). In some embodiments, the target protein comprises a kinase. In some embodiments, the target protein comprises a cyclin-dependent kinase. In some embodiments, the target protein comprises a cyclin-dependent kinase (CDK). In some embodiments, the target protein comprises cyclin-dependent kinase 4 (CDK4) or cyclin-dependent kinase 6 (CDK6). In some embodiments, the target protein is CDK4. In some embodiments, the target protein is CDK6. In some embodiments, the target protein is CDK9. In some embodiments, the target protein includes CDK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13. In some embodiments, the target protein includes tyrosine receptor kinase (Trk). In some embodiments, the target protein includes TrkA. In some embodiments, the target protein includes TrkB. In some embodiments, the target protein includes TrkC. In some embodiments, the target protein includes mitogenic factor-activated protein kinase (MKK or MEK). In some embodiments, the target protein includes MEK1. In some embodiments, the target protein includes MEK2. In some embodiments, a heterobifunctional compound degrades the target protein.

[0209] Some non-limiting examples of target proteins include B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, apoptotic pathway partners, BclIBax, C5a receptor, HMG-CoA reductase, PDE type V phosphodiesterase, PDE type IV phosphodiesterase, PDE I, PDE II, PDE III, squalene cyclase inhibitors, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclooxygenase 1, cyclooxygenase 2, receptors, 5HT receptor, dopamine receptor, G protein (e.g., Gq), histamine receptor, 5-lipoxygenase, tryptase, serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH, trypanosoma protein, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAK, STAT, RXR, RAR, HIV 1 protease, HIV 1 Integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance (MDR), protein P-glycoprotein, MRP, tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Ca+ channel, VCAM, integrin, VLA-4 integrin, selectin, CD40, CD40L, neurokinin, neurokinin receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras, Raf, Mek, Erk, interleukin-1 convertase, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus 1 (HSV-1) protease, cytomegalovirus (CMV) protease, poly(ADP-ribose) polymerase, cyclin-dependent kinase, vascular endothelial growth factor, oxytocin receptor, microsomal transport protein inhibitor, bile acid transport inhibitor, 5-α-reductase inhibitor, angiotensin II, glycine receptor, norepinephrine reuptake receptor Body, endothelin receptor, neuropeptide Y, neuropeptide Y receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase, AMP deaminase, purine receptor (e.g., P2Y1, P2Y2, P2Y4, P2Y6, or P2X1-7), farnesyltransferase, geranylgeranyltransferase, TrkA, receptor for NGF, β-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her2 The target protein may be one of the following: neu, telomerase inhibitor, cytosolic phospholipase A2, EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABAergic chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synethase, protoporphyrinogen oxidase, or enoylpyruvinyl sichimate-phosphate synthase. The target protein may include p25 or p35.

[0210] The target protein may contain a cyclin. In some embodiments, the cyclin is cyclin D. Cyclin D may contain cyclin D1. Cyclin D may contain cyclin D2. Cyclin D may contain cyclin D3. In some embodiments, the heterobifunctional compound degrades the cyclin. Some examples of cyclins include cyclin A, cyclin B, cyclin C, cyclin D, cyclin D1, cyclin D2, cyclin D3, cyclin E, cyclin H, cyclin K, cyclin T, or cyclin T1.

[0211] In some embodiments, the target protein includes a protein associated with a disease state. For example, the target protein may be present in or upregulated in a disease state. In some embodiments, the target protein includes a pathogen protein. In some embodiments, the target protein includes a viral protein. In some embodiments, the target protein includes a bacterial protein.

[0212] Target proteins are diverse and selected from proteins whose sequence, at least a portion of which is found in cells, is expressed in cells in such a way that it can bind to the target protein binding site. The term “protein” may include oligopeptides and polypeptide sequences of sufficient length to bind to the target protein binding site. Any other protein in eukaryotic or microbial systems, including viruses, bacteria, or fungi, described herein may be a target protein for ubiquitination mediated by the compounds disclosed herein. The target protein may be a eukaryotic protein.

[0213] Any protein that binds to a target site and acts on or can be degraded by a ubiquitin ligase may be considered a target protein. Generally, target proteins include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins involved in cellular integration functions including catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulatory activity, signal transducer activity, structural molecular activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell movement, membrane fusion, cell transmission, regulation of biological processes, development, cell differentiation, response to stimuli, and behavioral proteins. Proteins may include proteins with protein transporter activity, nuclear transport activity, ion transporter activity, channel transporter activity, carrier activity, permease activity, secretory activity, electron transporter activity, pathogenesis, chaperone regulatory activity, nucleic acid binding activity, transcription regulatory activity, extracellular tissue and revitalization activity, and translation regulatory activity. The target proteins may include eukaryotes and prokaryotes, including humans, livestock, microorganisms, plants, and other animals, including viruses, for targeting for drug therapy, and for determining targets for antibiotics and other antimicrobial agents.

[0214] In some embodiments, the target protein comprises one of Hsp90, kinase, MDM2, human BET bromodomain-containing protein, HDAC, lysine methyltransferase, angiogenic protein, immunomodulator protein, or aryl hydrocarbon receptor (AHR). In some embodiments, the target protein comprises a heat shock protein (HSP) such as HSP90. In some embodiments, the target protein comprises a kinase or phosphatase. In some embodiments, the target protein comprises a kinase. In some embodiments, the kinase is a tyrosine kinase. In some embodiments, the kinase is VEGFR3. In some embodiments, the kinase is an aurora kinase. In some embodiments, the kinase is ALK. In some embodiments, the kinase is JAK2. In some embodiments, the kinase is Alk. In some embodiments, the kinase is Met. In some embodiments, the kinase is Abl. In some embodiments, the kinase is B-Raf or Mek. In some embodiments, the target protein comprises a phosphatase. In some embodiments, the phosphatase is a protein tyrosine phosphatase. In some embodiments, the phosphatase comprises an SHP-2 domain. In some embodiments, the target protein includes MDM. In some embodiments, MDM is MDM2. In some embodiments, the target protein includes HDAC. In some embodiments, the target protein includes a methyltransferase such as lysine methyltransferase. In some embodiments, the target protein includes angiogenesis. In some embodiments, the target protein includes an immunomodulator or immunosuppressive protein. In some embodiments, the target protein includes an aryl hydrocarbon receptor (AHR). In some embodiments, the target protein includes a RAF receptor. In some embodiments, the target protein includes FKBP. In some embodiments, the target protein includes an estrogen receptor or an androgen receptor. In some embodiments, the target protein includes an androgen receptor. In some embodiments, the target protein includes an estrogen receptor.In some embodiments, the target protein includes a thyroid hormone receptor. In some embodiments, the target protein includes an HIV protein such as an HIV protease or HIV integrase. In some embodiments, the target protein includes an HCV protein such as an HCV protease. In some embodiments, the target protein includes acyl-protein thioesterase-1 or -2.

[0215] In some embodiments of this specification, target protein-binding moieties are disclosed. For example, ligands described herein may include a target protein-binding moiety. In some embodiments, the target protein binds to or is bound by the target protein-binding moiety. In some embodiments, the target protein-binding moiety binds to the target protein. In some embodiments, the binding of the ligand to the target protein in a cell results in the degradation of the target protein. For example, the ligand may increase ubiquitination-mediated degradation of the target protein or proteasomal degradation of the target protein. The target protein-binding moiety can be any molecule that binds to the target protein. For example, the target protein-binding moiety can be any small molecule known to bind to the target protein.

[0216] In some embodiments of this specification, compounds comprising a DDB1 binding moiety are disclosed. In some embodiments, the DDB1 binding moiety binds to the DDB1 protein. In some embodiments, the DDB1 binding moiety is bound to the DDB1 protein. In some embodiments, the compound binds to the DDB1 protein via the DDB1 binding moiety. In some embodiments, the compound is bound to the DDB1 protein via the DDB1 binding moiety. In some embodiments, the DDB1 binding moiety is incorporated into a ligand described herein. In some embodiments, the DDB1 binding moiety is part of a modified protein described herein. In some embodiments, the DDB1 binding moiety is part of a ligand-protein complex described herein. In some embodiments, the DDB1 binding moiety binds to a linker, such as a linker described herein. In some embodiments, the DDB1 binding moiety is covalently attached to a target protein described herein via a linker. In some embodiments, the target protein binding moiety is incorporated into a molecular structure or formula disclosed herein.

[0217] Non-limiting examples of small molecule target protein binding sites include, in particular, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHRs). By ligating the DDB1 binding site to the target protein binding site, the target protein can be ubiquitinated and / or degraded by proteases.

[0218] In one embodiment, the protein-binding portion is a C1-C compound substituted with a haloalkane (preferably at least one halo group, preferably a halo group located at the distal end of the alkyl group (i.e., away from the linker or DDB1 binding portion)). 10 It is an alkyl group and may covalently bind to dehalogenase enzymes in patients or subjects, or in diagnostic assays.

[0219] The target protein binding moieties of this disclosure include any moiety that specifically binds to a protein (e.g., a target protein), and the following are non-limiting examples of small molecule target protein moieties: in particular, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHRs). The compositions described herein illustrate some of the members of such small molecule target protein binding moieties. Such small molecule target protein binding moieties further include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the protein of interest. These binding moieties may be linked to a DDB1 binding moiety via a linker to present the target protein (to which the protein target moiety is bound) in close proximity to a ubiquitin ligase for ubiquitination and degradation.

[0220] In some embodiments, the target protein-binding moiety includes a haloalkyl group, which generally has a length of about 1 or 2 carbons to about 12 carbons, frequently about 2 to 10 carbons, frequently about 3 to about 8 carbons, and more frequently about 4 to about 6 carbons. The haloalkyl group is generally a linear alkyl group (although branched alkyl groups may also be used) and is capped at the ends with at least one halogen group, preferably one halogen group, and frequently one chloride group. The haloalkyl target protein-binding moiety for use in this disclosure may be represented by the chemical structure -(CH2)v-halo, where v is an integer of any of 2 to about 12, frequently about 3 to about 8, and more frequently 4 to about 6. The halo may be any halogen, preferably Cl or Br, and more frequently Cl.

[0221] In some embodiments, the target protein binding site has a w of 0 to 3, preferably 1 or 2.

[0222] [ka] This group selectively binds to target proteins, including estrogen receptors, and may be useful in treating diseases regulated via estrogen receptors, specifically cancers such as breast cancer, endometrial cancer, ovarian cancer, and uterine cancer.

[0223] Examples of target protein-binding moieties according to this disclosure include haloalkanehalogenase inhibitors, Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting human BET bromodomain-containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting aryl hydrocarbon receptors (AHRs). Several compositions described later illustrate some of the members of this type of small molecule target protein-binding moiety. Such small molecule target protein-binding moieties further include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target the protein of interest.

[0224] In some embodiments, the target protein binding moiety comprises a heat shock protein (HSP; e.g., HSP90) binder or inhibitor. Examples of HSP90 inhibitors used herein include N-[4-(3H-imidazo[4,5-C]pyridine-2-yl)-9H-fluoren-9-yl]-succinamide, 8-[(2,4-dimethylphenyl)sulfanyl]-3-penta-4-in-1-yl-3H-purine-6-amine, and 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(morpholine-4-ylmethyl)phenyl] Examples include, but are not limited to, isoxazole-3-carboxamide, PU3, or (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] or its derivatives (e.g., 17-alkylamino-17-desmethoxygeldanamycin).

[0225] In some embodiments, N-[4-(3H-imidazo[4,5-C]pyridine-2-yl)-9H-fluoren-9-yl]succinamide is bonded to the linker described herein via its terminal amide group. In some embodiments, 8-[(2,4-dimethylphenyl)sulfanyl]-3-penta-4-in-1-yl-3H-purine-6-amine is bonded to the linker described herein via its terminal acetylene group. In some embodiments, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(morpholine-4-ylmethyl)phenyl]isoxazole-3-carboxamide is bonded to the linker described herein via its amide group (for example, in the amine or in the alkyl group on the amine). In some embodiments, PU3 is bonded to the linker described herein via its butyl group. In some embodiments, (4E,6Z,8S,9S,10E,12S,13R,14S,16R)-13-hydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-azabicyclo[16.3.1] or a derivative thereof is bonded to the linker described herein by an amide group.

[0226] In some embodiments, the target protein binding moiety includes a kinase inhibitor or a phosphatase inhibitor. In some embodiments, the target protein binding moiety includes a kinase inhibitor. In some embodiments, the kinase inhibitor is a tyrosine kinase inhibitor. In some embodiments, the kinase inhibitor is a VEGFR3 inhibitor. In some embodiments, the kinase inhibitor is an Aurora kinase inhibitor. In some embodiments, the kinase inhibitor is an ALK inhibitor. In some embodiments, the kinase inhibitor is a JAK2 inhibitor. In some embodiments, the kinase inhibitor is an Alk inhibitor. In some embodiments,

[0227] Kinase inhibitors are Met inhibitors. In some embodiments, kinase inhibitors are Abl inhibitors. In some embodiments, kinase inhibitors are B-Raf / Mek inhibitors. Non-limiting examples of kinase inhibitors include erlotinib, sunitinib, sorafenib, desatinib, lapatinib, U09-CX-5279, Y1W, Y1X, 1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea, 2,6-naphthyridine, 07U, YCF, XK9, NXP, N- One of the following is an example: {4-[(1E)-N-(N-hydroxycarbamimidoyl)ethanehydrazonoyl]phenyl}-7-nitro-1H-indole-2-carboxamide, afatinib, fostamatinib, gefitinib, lenvatinib, vandetanib, vemurafenib, gleevec, pazopanib, AT-9283, TAE684, nilotinib, NVP-BSK805, crizotinib, JNJ FMX, or forretinib.

[0228] In some embodiments, erlotinib is bonded to the linker described herein via its ether group. In some embodiments, sunitinib is bonded to the linker described herein via its pyrrole moiety. In some embodiments, sorafenib is bonded to the linker described herein via its phenyl moiety. In some embodiments, desatinib is bonded to the linker described herein via its pyrimidine. In some embodiments, lapatinib is bonded to the linker described herein via the terminal methyl of its sulfonylmethyl group. In some embodiments, U09-CX-5279 is bonded to the linker described herein via its amine (aniline), carboxylic acid, or amine α, or via the cyclopropyl group. In some embodiments, 1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridine-6-yl]sulfanyl}benzyl)urea is bonded to the linker described herein via its propyl group. In some embodiments, Y1W is bonded to the linker described herein via its propyl or butyl group. In some embodiments, 6TP is bonded to the linker described herein via a terminal methyl group attached to the amide moiety. In some embodiments, 07U is bonded to the linker described herein via its secondary amine or terminal amino group. In some embodiments, YCF is bonded to the linker described herein via one of its terminal hydroxyl groups. In some embodiments, XK9 is bonded to the linker described herein via its terminal hydroxyl group. In some embodiments, NXP is bonded to the linker described herein via its terminal hydrazone group (NXP). In some embodiments, afatinib is bonded to the linker described herein via its aliphatic amine group. In some embodiments, fostamatinib is bonded to the linker described herein via its methoxy group. In some embodiments, gefitinib is bonded to the linker described herein via its methoxy or ether group.In some embodiments, lenvatinib is bonded to the linker described herein via its cyclopropyl group. In some embodiments, vandetanib is bonded to the linker described herein via its methoxy or hydroxyl group. In some embodiments, vemurafenib is bonded to the linker described herein via its sulfonylpropyl group. In some embodiments, gleevec is bonded to the linker described herein via its amide or anilineamine group. In some embodiments, pazopanib is bonded to the linker described herein via its phenyl moiety or anilineamine group. In some embodiments, AT-9283 is bonded to the linker described herein via its phenyl moiety. In some embodiments, TAE684 is bonded to the linker described herein via its phenyl moiety. In some embodiments, nilotinib is bonded to the linker described herein via its phenyl moiety or anilineamine group. In some embodiments, crizotinib is bonded to the linker described herein via its phenyl moiety or diazole group. In some embodiments, crizotinib is bonded to the linker described herein via its phenyl moiety or diazole group. In some embodiments, JNJFMX is bonded to the linker described herein via its phenyl moiety.

[0229] In some embodiments, the target protein binding moiety includes a phosphatase inhibitor. In some embodiments, the phosphatase inhibitor is a protein tyrosine phosphatase inhibitor. In some embodiments, the phosphatase inhibitor is an inhibitor of the SHP-2 domain of tyrosine phosphatase. A non-limiting example of the phosphatase inhibitor includes PTP1B. Non-limiting examples of phosphatase inhibitors are shown in Table 4.

[0230] In some embodiments, the target protein binding moiety comprises an MDM inhibitor. In some embodiments, the MDM inhibitor is an MDM2 inhibitor. Non-limiting examples of MDM2 inhibitors include any one of nutrin-3, nutrin-2, nutrin-1, or trans-4-iodo-4'-boranyl chalcone. In some embodiments, nutrin-3, nutrin-2, or nutrin-1 is bound to the linker described herein via a methoxy group or a hydroxyl group. In some embodiments, trans-4-iodo-4'-boranyl chalcone is bound to the linker described herein via its hydroxyl group. Non-limiting examples of MDM2 inhibitors are shown in Table 4.

[0231] In some embodiments, the target protein binding moiety includes a compound that targets a human BET bromodomain-containing protein. In some embodiments, the compound that targets the human BET bromodomain-containing protein is 3,5-dimethylisoxazole. Non-limiting examples of compounds that target the human BET bromodomain-containing protein are shown in Table 4.

[0232] In some embodiments, the target protein-binding moiety includes a compound that inhibits HDAC. Non-limiting examples of HDAC-inhibiting compounds are shown in Table 4.

[0233] In some embodiments, the target protein binding moiety comprises a compound that inhibits a methyltransferase, such as lysine methyltransferase. In some embodiments, the methyltransferase is human lysine methyltransferase. In some embodiments, the lysine methyltransferase inhibitor is azacitidine. In some embodiments, azacitidine is bound to the linker described herein via a hydroxyl group or an amino group. In some embodiments, the lysine methyltransferase inhibitor is decitabine. In some embodiments, decitabine is bound to the linker described herein via a hydroxyl group or an amino group. Non-limiting examples of lysine methyltransferase inhibitors are included in Table 4.

[0234] In some embodiments, the target protein binding moiety includes an angiogenesis inhibitor. Non-limiting examples of angiogenesis inhibitors include GA-1, estradiol, testosterone, DHT, ovalycin, or fumagiline.

[0235] In some embodiments, the target protein binding moiety includes an immunosuppressive compound. Non-limiting examples of immunosuppressive compounds include AP21998, glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, or methylprednisolone), beclomethasone dipropionate, methotrexate, cyclosporine, tacrolimus, rapamycin, or actinomycin. In some embodiments, glucocorticoids are bound to the linker described herein via a hydroxyl group. In some embodiments, beclomethasone dipropionate is bound to the linker described herein via a propionate group. In some embodiments, methotrexate is bound to the linker described herein via one of its terminal hydroxyls. In some embodiments, cyclosporine is bound to the linker described herein via a butyl group. In some embodiments, tacrolimus is bound to the linker described herein via a methoxy group. In some embodiments, rapamycin is bound to the linker described herein via a methoxy group. In some embodiments, actinomycin is bonded to the linker described herein via an isopropyl group.

[0236] In some embodiments, the target protein binding moiety includes compounds that target aryl hydrocarbon acceptors (AHRs). Non-limiting examples of AHR-targeting compounds include apigenin, SR1, or LGC006.

[0237] In some embodiments, the target protein binding moiety includes a compound that targets the RAF receptor. Non-limiting examples of compounds that target the RAF receptor are shown in Table 4.

[0238] In some embodiments, the target protein binding moiety includes a compound that targets FKBP. Non-limiting examples of compounds that target FKBP are shown in Table 4.

[0239] In some embodiments, the target protein binding moiety includes a compound that targets the androgen receptor. Non-limiting examples of compounds that target the androgen receptor include any one of RU59063, SARM, DHT, MDV3100, ARN-509, hexahydrobenzisoxazole, or tetramethylcyclobutane. Non-limiting examples of compounds that target the androgen receptor are shown in Table 4.

[0240] In some embodiments, the target protein binding moiety includes a compound that targets the estrogen receptor. Non-limiting examples of compounds that target the estrogen receptor are shown in Table 4.

[0241] In some embodiments, the target protein binding moiety includes a compound that targets a thyroid hormone receptor. Non-limiting examples of compounds that target thyroid hormone receptors are shown in Table 4.

[0242] In some embodiments, the target protein binding moiety includes a compound that inhibits HIV protease. Non-limiting examples of compounds that inhibit HIV protease are shown in Table 4.

[0243] In some embodiments, the target protein binding moiety includes a compound that inhibits HIV integrase. Non-limiting examples of compounds that inhibit HIV integrase are shown in Table 4.

[0244] In some embodiments, the target protein binding moiety includes compounds that target HCV proteases. Non-limiting examples of compounds that target HCV proteases are shown in Table 4.

[0245] In some embodiments, the target protein binding moiety includes a compound that targets acyl-protein thioesterase-1 and / or -2. Compounds that target acyl-protein thioesterase-1 and / or -2 are listed in Table 4.

[0246] In some embodiments, compounds containing the target protein binding moiety are shown in Table 4. In the table, "R" or a wavy line indicates an optional binding site to a linker or other molecule, such as a DDB1 binding moiety.

[0247] [Table 4-1]

[0248] [Table 4-2]

[0249] [Table 4-3]

[0250] [Table 4-4]

[0251] [Table 4-5]

[0252] [Table 4-6]

[0253] [Table 4-7]

[0254] [Table 4-8]

[0255] [Table 4-9]

[0256] [Table 4-10]

[0257] [Table 4-11]

[0258] Heterobifunctional compounds This specification describes heterobifunctional compounds. Such compounds may be useful for a variety of purposes, including use as molecular glues or targeted proteolytic agents. Heterobifunctional compounds may be small molecules. Heterobifunctional compounds may be included in the methods described herein. For example, heterobifunctional compounds may be included in a pharmaceutical composition and administered to a subject.

[0259] In some embodiments herein, heterobifunctional compounds and pharmaceutical compositions comprising such compounds are provided. In some embodiments, the heterobifunctional compounds described herein include a DNA damage-binding protein 1 (DDB1) binding moiety, a linker, and / or a target protein binding moiety. In some embodiments, the heterobifunctional compounds described herein include a DDB1 binding moiety and a target protein binding moiety. In some embodiments, the heterobifunctional compound includes a DDB1 binding moiety covalently connected to the target protein binding moiety via a linker. In some embodiments, the DDB1 binding moiety is a natural product. In some embodiments, the DDB1 binding moiety is a synthetic product. In some embodiments, the target protein binding moiety is configured to bind to a target protein. In some embodiments, the compounds described herein are of formula (I): Z 1 -L 1 -Z 2 Equation (I) It includes the structure, During the ceremony, Z 1 This is the target protein binding site, L 1 It is a linker, Z 2 This is the DDB1 connection portion.

[0260] In some embodiments, the compounds described herein are of formula (IIc):

[0261] [ka] It includes the structure, During the ceremony, F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13 S(=O)-, -S(=O)2NR 13 -, -NR 13 S(=O)2-, -O-, C1-C4 alkyl, or C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R dThey are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are, independently, hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a , -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -Ra , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R a Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R b Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R dEach is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, and the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 4, s is 1 to 5, L 1 is a linker, and Z 1 This is the target protein binding site.

[0262] In some embodiments, the compounds described herein are of formula (IId):

[0263] [ka] It includes the structure, During the ceremony, F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13S(=O)-, -S(=O)2NR 13 -, -NR 13 S(=O)2-, -O-, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are, independently, hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a, -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R a Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R bEach is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, and the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 4, s is 1 to 5, L 1 is a linker, and Z 1 This is the target protein binding site.

[0264] In some embodiments, the compounds described herein are of formula (IIe):

[0265] [ka] It includes the structure, During the ceremony, F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13 S(=O)-, -S(=O)2NR 13 -, -NR 13 S(=O)2-, -O-, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are, independently, hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a , -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R aEach is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R b Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R dEach of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, where the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 4, s is 1 to 5, L 1 is a linker, and Z 1 This is the target protein binding site.

[0266] In some embodiments, R 11 and R 12 These are, independently, hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a , -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -ORa , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is optionally replaced by 1, 2, or 3 of the above, and optionally at least one R 11 This is a bond that is connected to a linker.

[0267] In some embodiments, the compound of formula (IIc-IIe) is F 2 is an aryl compound. In some embodiments of the compounds of formula (IIc-IIe), F 2 is C6-C 12 It is an aryl compound. In some embodiments of the compounds of formula (IIc-IIe), F 2 is a heteroaryl compound. In some embodiments of the compound of formula (IIc-IIe), F 2 It is a 5-12 member heteroaryl compound. In some embodiments of the compound of formula (IIa), F 2 These are triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl. In some embodiments of the compound of formula (IIa), F 2 is triazolyl, tetrazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl, where p is 1. In some embodiments of the compound of formula (IIa), F 2 It is a 5-12 member heteroaryl compound. In some embodiments of the compound of formula (IIa), F 2 is a heteroaryl group, and the heteroaryl group has at least one nitrogen atom in the ring. In some embodiments of the compound of formula (IIa), F 2is a heteroaryl group, and the heteroaryl group has at least two nitrogen atoms in the ring. In some embodiments of the compound of formula (IIa), F 2 is pyridyl, pyrimidinil, or pyrazinil. In some embodiments, F 2 is a heteroaryl group, and the heteroaryl group has at least one sulfur atom in the ring. In some embodiments, F 2 is a heteroaryl group, and the heteroaryl group has at least one oxygen atom in the ring. In some embodiments of the compound of formula (IIa), F 2 is thiazolyl, oxazollyl, furanyl, or thiophenyl. In some embodiments of the compound of formula (IIa), F 2 is thiazolyl. In some embodiments of the compound of formula (IIa), R 12 R is -NO2, halogen, methyl, halomethyl, phenyl, cyclopropyl, SO2CH3, or -CN, respectively, upon appearance. In some embodiments of the compound of formula (IIa), R 12 is -NO2. In some embodiments of the compound of formula (IIb), R 12 In each instance, it is chloro or bromo. In some embodiments of the compound of formula (IIa), L 2 is -NHC(=O) or -C(=O)NH-. In some embodiments of the compounds of formula (IIc-IIe), L 2 L is -C(=O)NH-. In some embodiments of the compound of formula (IIc-IIe), L 2 is -C(=O)N(C1-C5 alkyl)-. In some embodiments of the compound of formula (IIc-IIe), q is 1. In some embodiments of the compound of formula (IIc-IIe), q is 2. In some embodiments of the compound of formula (IIc-IIe), the linker is a bond. In some embodiments of the compound of formula (IIc-IIe), the linker is not a bond.

[0268] This specification describes compounds such as ligands comprising a DDB1 binding moiety, a linker, and a target protein binding moiety. In some embodiments, the compound binds to DDB1 via the DDB1 binding moiety. In some embodiments, the compound is bound to DDB1 via the DDB1 binding moiety. In some examples, the target protein binding moiety recruits a target protein to be ubiquitinated by a complex containing DDB1. In some examples, the target protein is subsequently degraded. In some examples, the target protein may be any protein desirable for binding or degradation. For example, the target protein may include any protein that may undergo proteasomal degradation, or any protein useful for binding by the ligands described herein. In some embodiments, the target protein includes the target proteins described herein. In some embodiments, the target protein binding moiety includes a CBP binding moiety. In some embodiments, the target protein binding moiety includes a p300 binding moiety. In some embodiments, the target protein binding moiety is a TrkA binding moiety. In some embodiments, the target protein binding moiety is a TrkB binding moiety. In some embodiments, the target protein binding moiety is a TrkC binding moiety. In some embodiments, the target protein binding site is a CDK4 binding site. In some embodiments, the target protein binding site is a CDK6 binding site. In some embodiments, the target protein binding site is a MEK1 binding site. In some embodiments, the target protein binding site is a MEK2 binding site. In some embodiments, the target protein binding site is a transcriptional co-factor. In some embodiments, the target protein binding site is a BRD4 binding site.

[0269] The compounds may include any embodiment of the compounds shown in Table 5, such as the DDB1 binding moiety, linker, or target protein binding moiety of the compounds shown in Table 5. In some embodiments, compounds including the DDB1 binding moiety, linker, and target protein binding moiety are shown in Table 5.

[0270] Table 5-1

[0271] Table 5-2

[0272] Table 5-3

[0273] Table 5-4

[0274] Table 5-5

[0275] Table 5-6

[0276] Table 5-7

[0277] Table 5-8

[0278] Table 5-9

[0279] Table 5-10

[0280] Table 5-11

[0281] Table 5-12

[0282] Table 5-13

[0283] Table 5-14

[0284] Table 5-15

[0285] Table 5-16

[0286] Table 5-17

[0287] Table 5-18

[0288] Table 5-19

[0289] Table 5-20

[0290] Table 5-21

[0291] Table 5-22

[0292] Table 5-23

[0293] Table 5-24

[0294] Table 5-25

[0295] Table 5-26

[0296] Table 5-27

[0297] Table 5-28

[0298] Table 5-29

[0299] Table 5-30

[0300] Table 5-31

[0301] Table 5-32

[0302] Table 5-33

[0303] Table 5-34

[0304] Table 5-35

[0305] Table 5-36

[0306] Table 5-37

[0307] Table 5-38

[0308] Table 5-39

[0309] Table 5-40

[0310] Table 5-41

[0311] Table 5-42

[0312] Table 5-43

[0313] Table 5-44

[0314] Table 5-45

[0315] Table 5-46

[0316] Table 5-47

[0317] Table 5-48

[0318] Table 5-49

[0319] Table 5-50

[0320] Table 5-51

[0321] Table 5-52

[0322] Table 5-53

[0323] Table 5-54

[0324] Table 5-55

[0325] Table 5-56

[0326] Table 5-57

[0327] Table 5-58

[0328] Table 5-59

[0329] Table 5-60

[0330] Table 5-61

[0331] Table 5-62

[0332] Table 5-63

[0333] Table 5-64

[0334] Table 5-65

[0335] Table 5-66

[0336] Table 5-67

[0337] Table 5-68

[0338] Table 5-69

[0339] Table 5-70

[0340] Table 5-71

[0341] [Table 5-72]

[0342] The compounds described herein may be useful for binding to DNA damage-binding protein 1 (DDB1), binding to and / or degrading target proteins, inducing subsequent cellular activity, and / or inhibiting microorganisms such as viruses and bacteria. In some embodiments, the compounds are used as antiviral agents. For example, compounds such as those containing ligands described herein may compete with one or more viral proteins. In some embodiments, the compounds are used as antiparasitic agents. In some embodiments, the compounds are used as molecular glue to hold two molecules, for example, the DDB1 protein and / or a target protein. In some embodiments, the compounds are used as degrading agents. For example, the heterobifunctional compounds described herein may be used as targeted proteolytic agents.

[0343] Preparation of compounds The compounds used in the chemical reactions described herein are prepared starting from commercially available chemicals and / or compounds described in the chemical literature, in accordance with organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" include Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U..), Lancaster Synthesis (Windham, NH), Maybridge Chemical It is obtained from standard commercial sources, including Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0344] Suitable reference books and papers that detail the synthesis of reactants useful for the preparation of the compounds described herein, or provide references to papers describing such preparations, include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; "Organic Functional Group Preparations" by SRSandler et al., 2nd Ed., Academic Press, New York, 1983; "Modern Synthetic Reactions" by HO House, 2nd Ed., WABenjamin, Inc., Menlo Park, Calif., 1972; "Heterocyclic Chemistry" by TLGilchrist, 2nd Ed., John Wiley & Sons, New York, 1992; and "Advanced Organic Chemistry: Reactions, Mechanisms and Structure" by J. March, 4th Ed., Wiley-Interscience, New York, 1992. Further appropriate references and papers that detail the synthesis of reactants useful for the preparation of the compounds described herein, or provide references to papers describing such preparations, include, for example, Fuhrhop, J. and Penzlin G., “Organic Synthesis: Concepts, Methods, Starting Materials,” Second, Revised and Enlarged Edition (1994), John Wiley & Sons, ISBN: 3 527-29074-5; Hoffman, RV, “Organic Chemistry, An Intermediate Text” (1996), Oxford University Press, ISBN 0-19-509618-5; Larock, RC, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations,” 2nd Edition (1999), Wiley-VCH, ISBN: 0-471-19031-4; March, J."Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; "Modern Carbonyl Chemistry" (2000) by Otera, J. (editor) Wiley-VCH, ISBN: 3-527-29871-1; "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) by Patai, S. Interscience, ISBN: 0-471-93022-9; "Organic Chemistry" 7th Edition (2000) by Solomons, TWG John Wiley & Sons, ISBN: 0-471-19095-0; "Intermediate Organic Chemistry" 2nd Edition by Stowell, JC Examples include *Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2*, *Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia* (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes, *Organic Reactions* (1942-2000) John Wiley & Sons, in over 55 volumes, and *Chemistry of Functional Groups* John Wiley & Sons, in 73 volumes.

[0345] Alternatively, specific and similar reactants are identified by known chemical product and reactant indexes prepared by the American Chemical Society's Chemical Abstract Service, which is available through most public and university libraries, as well as online data services (for details, contact the American Chemical Society in Washington, D.C.). Chemicals that are known but not commercially available in catalogs are prepared at the discretion of specialized chemical synthesis facilities, where many standard chemical supply facilities (e.g., those listed above) offer specialized chemical synthesis services. For the preparation and selection of pharmaceutical salts of the compounds described herein, see "Handbook of Pharmaceutical Salts" by PHStahl & C.G. Wermuth, Verlag Helvetica Chimica Acta, Zurich, 2002.

[0346] As described in the Examples section, the compounds described herein are prepared using methods common in the art of organic synthesis. Alternative synthetic methods are also used to produce the compounds described herein. Some embodiments include methods for producing the heterobifunctional compounds disclosed herein.

[0347] Treatment methods and pharmaceutical compositions In some embodiments, the compounds described herein are used to treat a subject. In some embodiments, the compounds described herein are used to degrade a target protein. Some embodiments involve administering the compounds described herein to a subject. The compounds may be any ligand described herein. Some embodiments involve administering a pharmaceutical composition containing the compounds described herein to a subject. Some embodiments involve providing the compounds or pharmaceutical compositions described herein for administration to a subject.

[0348] In some embodiments, the modified proteins disclosed herein are formed in vivo upon administration of a compound or pharmaceutical composition to a subject. In some embodiments, the ligand-protein complexes disclosed herein are formed by administration of a compound or pharmaceutical composition to a subject.

[0349] In some embodiments, the compounds described herein are administered as pure chemical substances. In other embodiments, the compounds described herein are combined with a pharmaceutically appropriate or acceptable carrier (hereinafter also referred to herein as a pharmaceutically appropriate (or acceptable) excipient, a physiologically appropriate (or acceptable) excipient, or a physiologically appropriate (or acceptable) carrier) selected based on a chosen route of administration and, for example, the standard pharmacopoeia described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). One embodiment provides a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0350] This specification provides pharmaceutical compositions comprising at least one compound described herein, or a stereoisomer thereof, a pharmaceutically acceptable salt, or an N-oxide thereof, together with one or more pharmaceutically acceptable carriers. Acceptable or suitable carriers (or excipients) are those compatible with the other components of the composition and not harmful to the recipient of the composition (i.e., the subject or patient). In some embodiments, the excipients include buffers or solutions.

[0351] In some embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, less than about 1%, or less than 0.1% of other small organic molecules, such as unreacted intermediates or synthetic byproducts produced in one or more steps of the synthesis method.

[0352] Some embodiments involve the use of compounds such as ligands described herein, ligand-DDB1 complexes, or in vivo modified DDB1 proteins. Use may include use as an antiviral agent. Use may include use as a molecular glue. Use may include use as a targeted proteolytic agent. In some embodiments, use involves administration of the compound to a subject. In some embodiments, use involves contact between a sample and the compound.

[0353] In some embodiments herein, methods are provided for degrading a target protein in a subject. Some embodiments include administering a ligand described herein to a subject. Some embodiments include administering a ligand to a subject that includes a DNA damage-binding protein 1 (DDB1) binding moiety covalently linked to a target protein binding moiety via a linker. In some embodiments, the subject is a subject requiring ligand administration or treatment with a ligand. Some embodiments include a method for modulating a target protein, comprising the step of administering a therapeutically effective dose of a compound described herein (e.g., a heterobifunctional compound) to a subject requiring administration. In some embodiments, the target protein is reduced in the subject compared to a baseline measurement. After administration of a heterobifunctional compound described herein to a subject, the target protein measurement may be reduced in a tissue sample or fluid sample of the subject compared to a baseline target protein measurement in a first tissue sample or fluid sample of the subject. Some embodiments include measuring the reduction in CDK after administration.

[0354] Some embodiments involve obtaining baseline measurements of the target protein. Baseline measurements may be obtained in a first sample obtained before administering the compound described herein to the subject. The first sample may include a fluid sample. The first sample may include a tissue sample. Baseline measurements may be obtained directly from the subject. Baseline measurements may include concentrations. Baseline measurements may be normalized to, for example, the weight of the sample, the volume of the sample, the sum of sample protein measurements, or housekeeping protein measurements.

[0355] Some embodiments involve obtaining measurements of a target protein. Measurements may be obtained in a second sample obtained after administering the compound described herein to a subject. Measurements may also be obtained in a second sample obtained during administration of the compound described herein to a subject. The second sample may include a fluid sample. The second sample may include a tissue sample. Measurements may be obtained directly from the subject. Measurements may be normalized to, for example, the weight of the sample, the volume of the sample, the sum of sample protein measurements, or housekeeping protein measurements.

[0356] Measurement or baseline measurement of the target protein may involve any method known in the art. For example, the measurement or baseline measurement may be obtained using an assay such as an immunoassay, colorimetric assay, lateral flow assay, fluorescence assay, proteomics assay, or cell-based assay. Immunoassays may include immunoblotting such as Western blot or dot blot, enzyme-linked immunosorbent assay, or immunostaining. Proteomics assays may include mass spectrometry. The measured or baseline measurement may be obtained using flow cytometry. The measured or baseline measurement may be obtained using chromatography, such as high-performance liquid chromatography.

[0357] The target protein may be any target protein included herein, as well as other target proteins not specified, or may include them. Some embodiments include methods for degrading cyclin-dependent kinases (CDKs). Some embodiments include methods for degrading target proteins containing CDKs. Some examples of such cyclin-dependent kinases include, but are not limited to, CDK4 or CDK6. Some embodiments include methods for modulating CDKs, which include administering a therapeutically effective dose of a compound described herein (e.g., a heterobifunctional compound) to a subject in need of administration. In some embodiments, the CDK is reduced in the subject compared to a baseline measurement. Some embodiments include measuring the decrease in CDK after administration.

[0358] Some embodiments include methods for degrading cyclins. Some embodiments include methods for degrading target proteins containing cyclins. Some examples of such cyclins include cyclin D, such as cyclin D1, cyclin D2, and cyclin D3, or cyclin E. Some embodiments include methods for modulating cyclins, comprising the step of administering a therapeutically effective dose of a compound described herein (e.g., a heterobifunctional compound) to a subject requiring administration. Some embodiments include methods for modulating cyclin D, comprising the step of administering a therapeutically effective dose of a compound described herein (e.g., a heterobifunctional compound) to a subject requiring administration. In some embodiments, the cyclin decreases in the subject compared to a baseline measurement. Some embodiments include measuring the decrease in cyclins after administration.

[0359] Some embodiments include methods for degrading transcription factors. Non-limiting examples of transcription factors include CBP and P300. Some embodiments include methods for degrading target proteins containing CBP or P300. Some embodiments include methods for degrading target proteins containing CBP. Some embodiments include methods for degrading target proteins containing P300. Some embodiments include methods for modulating transcription factors, comprising the step of administering a therapeutically effective dose of a compound described herein (e.g., a heterobifunctional compound) to a subject requiring administration. In some embodiments, the transcription factor is reduced in the subject compared to a baseline measurement. Some embodiments include measuring the decrease in the transcription factor after administration. Further examples of target proteins are included herein.

[0360] Examples of subjects include vertebrates, animals, mammals, dogs, cats, cattle, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subjects are mammals. In some embodiments, the subjects are humans.

[0361] In some embodiments, the administration of a ligand to a subject involves administering an effective amount of ligand sufficient to degrade the target protein. In some embodiments, after the administration of the ligand to the subject, the target protein is ubiquitinated to form a ubiquitinated target protein. In some embodiments, the administration is intravenous. In some embodiments, the administration includes injection. In some embodiments, the administration includes cutaneous administration. In some embodiments, the administration includes subcutaneous administration. In some embodiments, the administration includes intraperitoneal administration. In some embodiments, the administration includes oral administration. In some embodiments, the route of administration is intravenous, oral, subcutaneous, intraperitoneal, ocular, intraocular, intramuscular, interstitial, intraarterial, intracranial, intraventricular, intrasynovial, transepithelial, transdermal, inhalation, ocular (opthalmic), sublingual, buccal, topical, cutaneous, rectal, nasal, inhalation, or spray. In some embodiments, the administration is intramuscular. In some embodiments, the administration is intrasacral. In some embodiments, the administration is subcutaneous. In some embodiments, the administration is oral. In some embodiments, the administration is sublingual. In some embodiments, administration is buccal. In some embodiments, administration is rectal. In some embodiments, administration is vaginal. In some embodiments, administration is intraocular. In some embodiments, administration is intraaural. In some embodiments, administration is intranasal. In some embodiments, administration is by inhalation. In some embodiments, administration is by spraying. In some embodiments, administration is by skin. In some embodiments, administration is local. In some embodiments, administration is transdermal. In some embodiments, administration is systemic.

[0362] In some embodiments herein, methods for degrading a target protein in a sample are provided. Some embodiments involve contacting the target protein with a ligand described herein. Some embodiments involve contacting the target protein with a ligand containing a DNA damage-binding protein 1 (DDB1) binding moiety that is covalently linked to the target protein-binding moiety via a linker.

[0363] In some embodiments, the sample is a biological sample. In some embodiments, the biological sample includes tissue, cells, or body fluids. In some embodiments, contact is performed in vitro. In some embodiments, contact is performed in vivo. In some embodiments, after contact with the ligand, the target protein is ubiquitinated to form a ubiquitinated target protein.

[0364] In some embodiments, the ubiquitinated target protein is degraded after administration or contact. In some embodiments, the ubiquitinated target protein is degraded. In some embodiments, the degradation of the target protein is specific to the target protein. In some embodiments, the target protein is degraded by proteasomes. In some embodiments, the target protein is degraded by proteasomes.

[0365] In some embodiments, after administration or contact, the ligand binds to the DDB1 protein to form a ligand-DDB1 complex. In some embodiments, the ligand binds directly to the DDB1 protein via the DDB1 binding moiety of the ligand. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is non-covalent. In some embodiments, the binding between the DDB1 binding moiety and the DDB1 protein is covalent. In some embodiments, the target protein is ubiquitinated by a ubiquitin E3 ligase complex containing the DDB1 protein. In some embodiments, the ligand (e.g., a DDB1 ligand) recruits the ubiquitin E3 ligase complex to the target protein via the DDB1 binding moiety. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand comprises a targeted proteolytic inducer. In some embodiments, the ligand is synthetic. In some embodiments, the ligand comprises the ligands described herein.

[0366] The target proteins degraded using the methods described herein may be any of the target proteins described herein, or may include them. In some embodiments, the target proteins are transcription factors, CBP, p300, kinases, receptors, TRK, TrkA, TrkB, TrkC, cyclin-dependent kinases, CDK4, CDK6, B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, apoptotic pathway partners, BclIBax, C5a receptor, HMG-CoA reductase, PDE type V phosphodiesterase, PDE type IV phosphodiesterase type 4, PDE I, PDE II, PDE III, squalene cyclase inhibitor, CXCR1, CXCR2, nitric oxide synthase, cyclooxygenase 1, cyclooxygenase 2, receptor, 5HT receptor, dopamine receptor, G protein, Gq, histamine receptor, 5-lipoxygenase, tryptase, serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH, trypanosoma protein, glycogen phosphorylase, carbonic anhydrase, chemokine receptor, JAK, STAT, RXR, RAR, HIV 1 protease, HIV 1 integrase, influenza, neuraminidase, hepatitis B reverse transcriptase, sodium channel, multidrug resistance, protein P-glycoprotein, MRP, tyrosine kinase, CD23, CD124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-αR, ICAM1, Ca+ channel, VCAM, integrin, VLA-4 integrin, selectin, CD40, CD40L, neurokinin, neurokinin receptor, inosine monophosphate dehydrogenase, p38 MAP kinase, Ras, Raf, Mek, Erk, interleukin-1 convertase, caspase, HCV, NS3 protease, HCV NS3RNA helicase, glycinamide ribonucleotide formyltransferase, rhinovirus 3C protease, herpes simplex virus 1 protease, cytomegalovirus protease, poly-ADP ribose polymerase, vascular endothelial growth factor, oxytocin receptor, microsomal transport protein inhibitor, bile acid transport inhibitor, 5-α reductase inhibitor, angiotensin II, glycine receptor, noradrenaline reuptake receptor, endothelin receptor, neuropeptide Y, neuropeptide Y receptor, estrogen receptor, androgen receptor, adenosine receptor, adenosine kinase, AMP deaminase, purine receptor, P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7, farnesyltransferase, geranylgeranyltransferase, NGF receptor, beta-amyloid, tyrosine kinase, Flk-IIKDR, vitronectin receptor, integrin receptor, Her2 The present invention comprises one of the following: neu, telomerase inhibitor, cytosolic phospholipase A2, EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABAergic chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium-releasing channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synethase, protoporphyrinogen oxidase, or enoylpyruvinyl sichimate-phosphate synthase. Some embodiments include multiple target proteins, such as combinations of any two or more of the target proteins disclosed herein.

[0367] The compounds described herein (including compounds containing a DDB1 binding moiety) may be useful as: 1) antiviral agents; 2) DDB1 protein level regulators (e.g., those that increase or decrease DDB1 protein levels); 3) DDB1 function regulators (e.g., those that activate or inhibit DDB1); 4) molecular glues (e.g., those that increase protein-protein interactions between DDB1 and another protein); 5) affecting the activity or protein level of a second protein via molecular glue function; 6) decreasing the protein level of a second protein via molecular glue function; 7) increasing the protein level of a second protein via molecular glue function; 8) decreasing the activity of a second protein via molecular glue function; or 9) increasing the activity of a second protein via molecular glue function.

[0368] The compounds described herein may be useful in treating diseases or disorders. For example, the compounds may be administered to subjects suffering from a disease or disorder. Administration may reduce the severity of the disease or disorder in the subject compared to baseline measurements. The compounds may bind to target proteins involved in the disease or disorder, resulting in inhibition or degradation of the target proteins. The compounds are heterobifunctional compounds and contain both a DDB1 binding site and a target protein binding site, where the target protein is involved in the disease or disorder. The target protein may exacerbate the disease or disorder. The target protein may prevent or reduce inhibition of the disease or disorder.

[0369] In some embodiments, the compounds described herein are used as antimicrobial agents. For example, the compounds may be administered to subjects suffering from microbial infections. Administration may reduce the severity of the microbial infection in the subject compared to baseline measurements. The compounds may bind to target proteins involved in microbial infections, resulting in inhibition or degradation of the target proteins. Examples of microbial infections include viral infections. Examples of microbial infections include bacterial infections. The compounds are heterobifunctional compounds and contain a DDB1 binding site and a target protein binding site, where the target protein is a microbial protein. Examples of microbial proteins include viral proteins. Examples of microbial proteins include bacterial proteins. The target protein may be a non-microbial protein that exacerbates the microbial infection. The target protein may be a non-microbial protein that prevents or reduces inhibition of the microbial infection. In some embodiments, the compounds enter target cells, bind to microbial proteins within the cells via the target protein binding site, and bind to DDB1 via the DDB1 binding site, inducing ubiquitin-mediated degradation of the microbial protein. Such actions may be useful against microorganisms such as bacteria and viruses that infect or reside within cells.

[0370] The compounds described herein may be useful for regulating DDB1 protein levels. For example, the compounds may be used to increase or decrease DDB1 protein levels. In some embodiments, compounds containing the DDB1 binding moiety described herein are used to increase DDB1 protein levels. For example, the compounds may bind to DDB1 and prevent its degradation. In some embodiments, compounds containing the DDB1 binding moiety described herein are used to decrease DDB1 protein levels. For example, the compounds may bind to DDB1 and increase its degradation. The compounds may be heterobifunctional compounds and may contain a DDB1 binding moiety that is linked (directly or via a linker) to a second moiety that increases or decreases the degradation of the DDB1 protein. This may be achieved by the second moiety binding to a target protein. In some such embodiments, the target protein may include an E3 ubiquitin ligase protein that enhances the degradation of the DDB1 protein. In some embodiments, the compounds are not heterobifunctional compounds. In some embodiments, the compounds contain or consist of a DDB1 binding moiety. In some embodiments, the compound comprises or consists of the structure of formula (II), the compounds provided in Table 1, or derivatives or salts thereof. In some embodiments, the compound is administered to a subject to increase DDB1 protein levels in the subject. Administration may increase DDB1 activity in the subject compared to baseline measurements. In some embodiments, the compound is administered to a subject to decrease DDB1 protein levels in the subject. Administration may decrease DDB1 activity in the subject compared to baseline measurements.

[0371] The compounds described herein may be useful for modulating DDB1 function. For example, the compounds may be used to activate or inhibit DDB1. In some embodiments, compounds containing the DDB1 binding moieties described herein are used to increase DDB1 activity. For example, the compounds may activate DDB1 by binding to DDB1. The compounds may activate DDB1 allosterically. The compounds may activate DDB1 by binding to a protein binding site on DDB1. In some embodiments, compounds containing the DDB1 binding moieties described herein are used to decrease DDB1 activity. For example, the compounds may inhibit DDB1 by binding to DDB1. The compounds may inhibit DDB1 allosterically. The compounds may inhibit DDB1 by binding to the active site of DDB1. The compounds may inhibit DDB1 by binding to a protein binding site on DDB1. The compounds are heterobifunctional compounds and may contain a DDB1 binding moiety that is linked (directly or via a linker) to a second portion that increases or decreases the activity of the DDB1 protein. This may be achieved by the second portion binding to the target protein. In some embodiments, the compound is administered to a subject to increase DDB1 activity in the subject. Upon administration, DDB1 activity in the subject may increase compared to baseline measurements. In some embodiments, the compound is administered to a subject to decrease DDB1 activity in the subject. Upon administration, DDB1 activity in the subject may decrease compared to baseline measurements.

[0372] The compounds described herein may be useful as molecular glues. For example, a compound may bind to and hold multiple molecules. In some embodiments, the molecular glue binds to DDB1 and a target protein. The compound may achieve this as a heterobifunctional compound containing a DDB1 binding portion and a target protein binding portion. The compound may increase the protein-protein interaction between DDB1 and the target protein. The compound may act as a molecular glue to regulate the activity or amount of a target protein. As a molecular glue, the compound may decrease the amount of the target protein. As a molecular glue, the compound may reduce the amount of the target protein. As a molecular glue, the compound may decrease the activity of the target protein. As a molecular glue, the compound may increase the activity of the target protein.

[0373] In some embodiments herein, methods for degrading a target protein in cells are disclosed. These methods include degrading the target protein via direct binding to an intermediate protein (e.g., a first protein) that interacts with the target protein. This may be referred to as cross-linking degradation. Some embodiments include administering a binding molecule to cells. The binding molecule may include ligands or compounds disclosed herein. The ligand may be a heterobifunctional compound. The binding molecule may bind to a first protein that interacts with the target protein. The target protein may be degraded before the first protein. In some embodiments, the first protein is not degraded. Some embodiments include degrading the target protein by administering a first protein that interacts with the target protein to cells, where the target protein is degraded before the first protein, or the first protein is not degraded. Some embodiments include measuring the target protein in cells. Some embodiments include measuring the first protein in cells. In some embodiments, the interaction between the target protein and the first protein is binding. In some embodiments, the interaction between the target protein and the first protein is dimerization. The target protein may include the target proteins described herein. The first protein may include other target proteins described herein. In some embodiments, the target protein includes a cyclin. In some embodiments, the target protein includes cyclin D. In some embodiments, cyclin D includes cyclin D1, cyclin D2, or cyclin D3. Cyclin D may include cyclin D1. Cyclin D may include cyclin D2. Cyclin D may include cyclin D3. In some embodiments, the first protein includes a cyclin-dependent kinase (CDK). The CDK may include CDK4. The CDK may include CDK6. In some embodiments, the first protein includes CDK4 or CDK6. In some embodiments, the binding molecule reduces cell viability. In some embodiments, the cells are eukaryotic cells.In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, the cells are cancer cells. In some embodiments, administering the binding molecule to cells includes administering the binding molecule to a subject containing cells. In some embodiments, the binding molecule recruits a ubiquitin E3 ligase that ubiquitinates a target protein. In some embodiments, the E3 ubiquitin ligase comprises DNA damage-binding protein 1 (DDB1) or von Hippel-Lindau tumor suppressor (VHL). The E3 ubiquitin ligase may contain DDB1. The E3 ubiquitin ligase may contain VHL. In some embodiments, the binding molecule comprises a heterobifunctional compound comprising an E3 ubiquitin ligase binding moiety covalently connected to a first protein-binding moiety via a linker. The first protein-binding moiety may comprise a target protein-binding moiety disclosed herein. In some embodiments, the binding molecule comprises a structure disclosed herein.

[0374] In some embodiments herein, a method is disclosed that includes the step of degrading a cyclin that interacts with a cyclin-dependent kinase (CDK) by administering a binding molecule that binds to the CDK to cells (e.g., a cross-linking degradation method). In some embodiments, the cyclin is degraded before the CDK, or the CDK is not degraded. In some embodiments, the cyclin is degraded before the CDK. In some embodiments, the CDK is not degraded. In some embodiments, the method includes measuring the cyclin in cells. In some embodiments, the method includes measuring the CDK in cells. In some embodiments, the interaction between the cyclin and the CDK includes binding or dimerization. The interaction may include binding. The interaction may include dimerization. In some embodiments, the cyclin includes cyclin D. In some embodiments, cyclin D includes cyclin D1, cyclin D2, or cyclin D3. In some embodiments, the CDK comprises CDK4 or CDK6. The CDK may contain CDK4. The CDK may contain CDK6. In some embodiments, the binding molecule reduces cell viability. In some embodiments, the cells are eukaryotic cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells. In some embodiments, the cells are cancer cells. In some embodiments, administering the binding molecule to cells comprises administering the binding molecule to a subject containing cells. In some embodiments, the binding molecule recruits a ubiquitin E3 ligase that ubiquitinates cyclins. In some embodiments, the E3 ubiquitin ligase comprises DNA damage-binding protein 1 (DDB1) or von Hippel-Lindau tumor suppressor (VHL). The E3 ubiquitin ligase may contain DDB1. The E3 ubiquitin ligase may contain VHL. In some embodiments, the binding molecule comprises a heterobifunctional compound including an E3 ubiquitin ligase binding moiety that is covalently connected to the CDK binding moiety via a linker.In some embodiments, the E3 ubiquitin ligase binding moiety comprises the chemical structure disclosed herein. In some embodiments, the CDK binding moiety comprises the target protein binding moiety disclosed herein. In some embodiments, the binding molecule comprises the ligand disclosed herein.

[0375] Numbered Embodiments Some embodiments include one of the following: 1. A ligand-DNA damage-binding protein 1 (DDB1) complex, the ligand-DDB1 complex being formed by directly binding a DDB1 protein to a DDB1 ligand containing a DDB1 binding site. 2. The ligand-DDB1 complex according to Embodiment 1, wherein the DDB1 binding portion is bound to a binding region on the DDB1 protein. 3. The ligand-DDB1 complex according to Embodiment 2, wherein the binding region on the DDB1 protein includes a β-propeller domain. 4. The ligand-DDB1 complex according to Embodiment 3, wherein the β-propeller domain includes a β-propeller C (BPC) domain. 5. The ligand-DDB1 complex according to Embodiment 4, wherein the binding region on the DDB1 protein includes the upper surface of the BPC domain. 6. The binding region on the DDB1 protein is the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA8 A ligand-DDB1 complex according to any one of Embodiments 2 to 5, comprising one or more of 41, ALA869, TYR871, SER872, MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033. 7. The following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, ALA869, TYR871, SER87 2, a ligand-DDB1 complex according to any one of Embodiments 1 to 6, wherein one or more of MET910, LEU912, TYR913, LEU926, TRP953, SER955, ALA956, ASN970, ALA971, PHE972, PHE1003, ASN1005, VAL1006, or VAL1033 are involved in the binding of the DDB1 protein to the DDB1 ligand. 8. A ligand-DDB1 complex according to any one of embodiments 1 to 7, wherein the binding between the DDB1 binding site and the DDB1 protein is non-covalent. 9. Binding of DDB1 protein to DDB1 ligand is such that the equilibrium dissociation constant (Kd) is less than 100 μM, less than 90 μM, less than 80 μM, less than 70 μM, less than 60 μM, less than 50 μM, less than 45 μM, less than 40 μM, less than 35 μM, less than 30 μM, less than 25 μM, less than 20 μM, less than 15 μM, and less than 14 μM. A ligand-DDB1 complex according to any one of Embodiments 1 to 8, comprising binding affinity of less than μM, Kd less than 13 μM, Kd less than 12 μM, Kd less than 11 μM, Kd less than 10 μM, Kd less than 9 μM, Kd less than 8 μM, Kd less than 7 μM, Kd less than 6 μM, Kd less than 5 μM, Kd less than 4 μM, Kd less than 3 μM, Kd less than 2 μM, or Kd less than 1 μM. 10. A ligand-DDB1 complex according to any one of Embodiments 1 to 9, wherein the binding of the DDB1 protein to the DDB1 ligand includes binding affinities such as Kd less than 20 μM, Kd between 20 and 100 μM, or Kd greater than 100 μM. 11. A ligand-DDB1 complex according to any one of Embodiments 1 to 7, wherein the binding between the DDB1 binding site and the DDB1 protein is covalent. 12. A ligand-DDB1 complex according to any one of Embodiments 1 to 11, wherein the DDB1 ligand is a small molecule. 13. The ligand-DDB1 complex according to any one of Embodiments 1 to 12, wherein the DDB1 ligand is a heterobifunctional compound comprising a DDB1 binding moiety that is covalently connected to a target protein binding moiety via a linker. 14. A ligand-DDB1 complex according to any one of Embodiments 1 to 13, wherein the DDB1 ligand is synthetic. 15. The DDB1 connection part is given by equation (II):

[0376] [ka] The structure of, or a pharmaceutically acceptable salt thereof, During the ceremony, F 1 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13 S(=O)-, -S(=O)2NR 13 -, -NR 13 S(=O)2-, -O-, C1-C4 alkyl, or C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NRc R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are bonded independently to hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a , -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR aC1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , or -OR a , or NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is optionally replaced by 1, 2, or 3 of the above, and optionally at least one R 11 This is a bond attached to a linker, R a Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R bEach is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, and the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 5, and A ligand-DDB1 complex according to any one of embodiments 1 to 14, wherein s is 0 to 20. 16. The DDB1 connection part is given by equation (IIa):

[0377] [ka] A ligand-DDB1 complex according to any one of embodiments 1 to 15, comprising the structure of [the specified structure]. 17.F 2 A ligand-DDB1 complex according to embodiment 15 or 16, wherein is a heteroaryl ligand. 18.F 2 A ligand-DDB1 complex according to any one of embodiments 15 to 17, wherein is a 5-membered or 6-membered ring heteroaryl. 19.F 2 The ligand-DDB1 complex according to any one of Embodiments 15 to 18, wherein the ligand is triazolyl, tetrazolyl, furanil, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl. 20. The DDB1 connection part is given by equation (IIb):

[0378] [ka] It includes the structure, In the formula, A 4 and A 5 Each of them is independently CR 12 , S, N, or O, A 4 Or A 5 A ligand-DDB1 complex according to any one of embodiments 1 to 19, wherein at least one of the members is N, S, or O. 21.A 4 N is A 5 The ligand-DDB1 complex according to Embodiment 20, wherein S is present. 22. The DDB1 connection part,

[0379] [ka] It includes the structure, A ligand-DDB1 complex according to any one of embodiments 1 to 21, wherein a wavy line indicates an optional binding site to a linker or ligand. 23.R 12The ligand-DDB1 complex according to any one of embodiments 15 to 22, wherein the ligand is -NO2, Cl, or Br. 24.L 2 However, -NR c C(=O)- or -C(=O)NR c - The ligand-DDB1 complex according to any one of embodiments 15 to 23. 25.R c A ligand-DDB1 complex according to any one of embodiments 15 to 24, wherein is H or CH3. 26. A ligand-DDB1 complex according to any one of embodiments 15 to 25, wherein q is 1 or 2. A ligand-DDB1 complex according to any one of embodiments 15 to 26, wherein 27.s is 1 or 2. 28. The DDB1 connection part,

[0380] [ka]

[0381] [ka]

[0382] [ka]

[0383] [ka]

[0384] [ka]

[0385] [ka] A ligand-DDB1 complex according to any one of embodiments 1 to 27, including the ligand-DDB1 complex described above. 29. The DDB1 connection part,

[0386] [ka] A ligand-DDB1 complex according to any one of embodiments 1 to 28, including the ligand-DDB1 complex described above. 30. The DDB1 connection part,

[0387] [ka]

[0388] [ka] A ligand-DDB1 complex according to any one of embodiments 1 to 29, including the ligand-DDB1 complex described above. 31. The DDB1 connection part,

[0389] [ka] A ligand-DDB1 complex according to any one of embodiments 1 to 30, including the ligand-DDB1 complex described above. 32. A ligand-DDB1 complex according to any one of embodiments 1 to 31, wherein the DDB1 binding portion is connected to the linker by covalent bond. 33. The ligand-DDB1 complex according to Embodiment 32, wherein the linker is not bound. 34. The ligand-DDB1 complex according to embodiment 32 or 33, wherein a linker is further connected to the target protein binding site. 35. The ligand-DDB1 complex according to embodiment 34, wherein the target protein binding portion binds to the target protein. 36. The DDB1 ligand is given by formula (I) Z 1 -L 1 -Z 2 Equation (I) It is a heterobifunctional ligand that includes, During the ceremony, Z 1This is the target protein binding site, L 1 It is a linker, Z 2 The ligand-DDB1 complex according to embodiment 35, wherein is the DDB1 binding portion. 37. The DDB1 ligand is given by formula (IIc):

[0390] [ka] A heterobifunctional ligand comprising the structure, During the ceremony, F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13 S(=O)-, -S(=O)2NR 13 -, -NR 13 S(=O)²⁻, -O-, C1-C4 alkyl, or C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NRc R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are, independently, hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a , -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R dThey are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R a Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R b Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R dEach is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, and the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 4, s is 1 to 5, L 1 is a linker, and Z 1 The ligand-DDB1 complex according to embodiment 36, wherein the target protein binding portion is the target protein binding portion. 38. The DDB1 ligand is given by formula (IId):

[0391] [ka] A heterobifunctional ligand comprising the structure, During the ceremony, F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13S(=O)-, -S(=O)2NR 13 -, -NR 13 S(=O)2-, -O-, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are, independently, hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a, -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R a Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R bEach is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each of these, together with the nitrogen atom to which they are bonded, forms a heterocyclyl or heteroaryl, and the heterocyclyl and heteroaryl are optionally substituted with one, two, or three of the following: halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. q is 1 to 4, s is 1 to 5, L 1 is a linker, and Z 1 The ligand-DDB1 complex according to embodiment 36, wherein the target protein binding portion is the target protein binding portion. 39. The DDB1 ligand is given by formula (IIe):

[0392] [ka] A heterobifunctional ligand comprising the structure, During the ceremony, F 2 These are aryl, heteroaryl, carbocykryl, or heterocycloalkyl compounds. L 2 This is a bond, -C(=O)NR 13 -, -NR 13 C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O)2-, -S(=O)NR 13 -, -NR 13 S(=O)-, -S(=O)2NR 13 -, -NR 13 S(=O)2-, -O-, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 alkenyl, or C1-C4 alkynyl, where R 13 These are hydrogen and -S(=O)R, respectively, independently. b -S(=O)2R d -S(=O)2NR c R d -C(=O)R b , -CO2R a -C(=O)NR c R d C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OR a , or -NR c R d It is replaced by one, two, or three of the following, R 11 and R 12 These are, independently, hydrogen, halogen, -CN, and -R. a , -OR a , -SR a -S(=O)R b -NO2, -NR c R d -S(=O)2R d , -NR a S(=O)2R d -S(=O)2NR c R d -C(=O)R b -OC(=O)R b , -CO2R a , -OCO2R a -C(=O)NR c R d -OC(=O)NR c R d , -NR a C(=O)NR c R d , -NR a C(=O)R b , -NR a C(=O)OR a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -R a , -OR a , or -NR c R d They are optionally substituted with 1, 2, or 3 of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R a , -OR a , or -NR c R d It is replaced by one, two, or three of the following, R aEach is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R b Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 carbocyrill, C2-C8 heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH2, and carbocyrill, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OMe, or -NH2. R c and R d Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl...

Claims

1. Formulas (IIc), (IId), or (IIe): 【Chemistry 1】 A compound that binds to DDB1 containing the structure of or a pharmaceutically acceptable salt thereof, During the ceremony, F ２ It is a five-membered ring heteroaryl, L ２ is a bond, -C(=O)NR １３ -, -NR １３ C(=O)-, -C(=O)-, -C(=S)-, -S-, -S(=O), -S(=O) ２ -, -S(=O)NR １３ -, -NR １３ S(=O)-, -S(=O) ２ NR １３ -, -NR １３ S(=O) ２ -, -O-, C １ -C ４ alkylene, or C １ -C ４ haloalkylene, C １ -C ４ heteroalkylene, C １ -C ４ alkoxylene, C １ -C ４ [[ID=۴۰]]alkylaminylene, C ２ -C ４ alkenylene, or C ２ -C ４ alkynylene, where R １３ is independently hydrogen, -S(=O)R ｂ -, -S(=O) ２ R ｄ -, -S(=O) ２ NR ｃ R ｄ -, -C(=O)R ｂ -, -CO ２ ]R ａ ｃ -, -C(=O)NR ｄ R １ C ６ -C ２ alkyl, C ６ -C ２ alkenyl, C ６ -C １ alkynyl, C ６ -C ３ heteroalkyl, C ８ -C ２ carbocyclic, C ８ -C ａ Heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OR ａ , or -NR ｃ R ｄ They are optionally substituted with one, two, or three of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ａ , or -NR ｃ R ｄ It is replaced by one, two, or three of the following, R １１ and R １２ are each independently hydrogen, halogen, -CN, -R ａ -OR ａ -SR ａ -S(=O)R ｂ -NO ２ -NR ｃ R ｄ -S(=O) ２ R ｄ -NR ａ S(=O) ２ R ｄ -S(=O) ２ NR ｃ R ｄ -C(=O)R ｂ -OC(=O)R ｂ -CO ２ R ａ -OCO ２ R ａ -C(=O)NR ｃ R ｄ -OC(=O)NR ｃ R ｄ -NR ａ C(=O)NR ｃ [[ID=�8]]R ｄ -NR ａ C(=O)R ｂ -NR ａ C(=O)OR ａ C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ heteroalkyl, C ３ -C ８ carbocyclic, C id=89 ２ -C ８ heterocyclic, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogen, -R ａ -OR ａ or -NR ｃ R ｄ They are optionally substituted with one, two, or three of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -R ａ , -OR ａ , or -NR ｃ R ｄ It is replaced by one, two, or three of the following, R ａ These are hydrogen and C, respectively, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Heteroalkyl, C ３ -C ８ Carbocyclyl, C ２ -C ８ A heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OH, -OMe, or -NH ２ They are optionally substituted with one, two, or three of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, -OMe, or -NH ２ It is replaced by one, two, or three of the following, R ｂ These are hydrogen and C, respectively, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Heteroalkyl, C ３ -C ８ Carbocyclyl, C ２ -C ８ A heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OH, -OMe, or -NH ２ They are optionally substituted with one, two, or three of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, -OMe, or -NH ２ It is replaced by one, two, or three of the following, R ｃ and R ｄ These are hydrogen and C, respectively, independently. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Heteroalkyl, C ３ -C ８ Carbocyclyl, C ２ -C ８ A heterocyclyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, and heteroalkyl are halogens, -OH, -OMe, or -NH ２ They are optionally substituted with one, two, or three of the following, and carbocyclyl, heterocyclyl, aryl, and heteroaryl are halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, -OMe, or -NH ２ It is replaced by one, two, or three of the following, or R ｃ and R ｄ Each of these atoms, together with the nitrogen atom to which they are bonded, forms a heterocycline or heteroaryl, and heterocyclines and heteroaryls are halogens, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OH, -OMe, or -NH ２ It is replaced by one, two, or three of the following, q is 1 to 4, s is 1 to 5, L １ is a linker, and Z １ This is the target protein binding site, The aforementioned compound, 2-(6-aminohexanamide)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide (BL-1), 2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanamide)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide (BL-2), 2-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanamide)-N-(5-nitrothiazole-2-yl)benzamide (BL-3), 2-Acetamido-N4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-N1-(4-methyl-5-nitrothiazole-2-yl)terephthalamide (BL-5), 2-Acetamido-N4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-N1-(5-nitrothiazole-2-yl)terephthalamide (BL-6), 2-Acetamide-4-((7-aminoheptyl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide (BL-7), 2-Acetamido-4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide (BL-8), 2-Acetamido-4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-N-(5-nitrothiazole-2-yl)benzamide (BL-9), 2-Acetamido-4-((4-aminobutyl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide (BL-11), and Compounds that bind to DDB1 or pharmaceutically acceptable salts thereof, comprising a substructure selected from the group consisting of 2-acetamido-4-((4-aminobutyl)amino)-N-(5-nitrothiophen-2-yl)benzamide (BL-20).

2. Z １ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is a target protein binding moiety that binds to BRD4.

3. 2-Acetamide-4-((4-(2-(4-(5-Acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)-3,4-dihydroquinoline-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-yl)piperidine-1-yl)acetamide)butyl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide (D-2), and Compounds that bind to DDB1, selected from the group consisting of 2-acetamido-4-((4-(2-(4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)-3,4-dihydroquinoline-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-yl)piperidine-1-yl)acetamido)butyl)amino)-N-(5-nitrothiophen-2-yl)benzamide (D-13), or pharmaceutically acceptable salts thereof.

4. (S)-2-acetamido-4-((2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamido)ethyl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide(D-26), (S)-2-acetamide-4-((7-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)heptyl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide(D-29), (S)-2-acetamide-4-((10-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)decyl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide(D-31), (S)-2-acetamide-4-((2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)acetamide)ethoxy)ethyl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide(D-32), (S)-2-acetamido-4-((1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecane-17-yl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide (D-35), and Compounds that bind to DDB1 or pharmaceutically acceptable salts thereof, selected from the group consisting of (S)-2-acetamido-4-((1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-yl)-2-oxo-6,9,12,15,18,21-hexaoxa-3-azatrichosane-23-yl)amino)-N-(4-methyl-5-nitrothiazole-2-yl)benzamide (D-37).

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