Modified Proteins and Protein Degraders

Abstract

Provided herein are compounds, pharmaceutical compositions, and methods for binding or degrading target proteins. Further provided herein are bifunctional compounds having a DNA damage binding protein 1 (DDB1) binding moiety, a linker, and a target binding moiety.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of PCT Application No. PCT / CN2021 / 123848, filed October 14, 2021, and PCT Application No. PCT / CN2021 / 133363, filed November 26, 2021, which applications are incorporated herein by reference in their entireties.

[0002] Sequence Listing This application has been submitted electronically in XML file format, accompanied by a Sequence Listing which is incorporated herein by reference in its entirety. A copy of this XML is titled 54922_715_603_SL.xml, created on October 5, 2022, and is 1727 bytes in size. [Background technology]

[0003] Progression through the cell cycle is part of the development of a single-celled fertilized egg into a mature organism. Such progression involves a series of cellular events, including DNA replication and cell division into daughter cells. Cell proliferation is controlled during the G1 phase of the cell cycle, which is further regulated in mammalian cells primarily by CDK4 and its closely related paralog, CDK6. CDK4 / 6 itself is catalytically inactive and is activated by binding of cyclin D proteins. Human cells express three cyclin D proteins, D1, D2, and D3, which are expressed at low levels in non-dividing cells. Various mitogenic signals can transactivate cyclin D proteins, leading to CDK4 / 6 activation. Activated CDK4 / 6 catalyzes the phosphorylation of the retinoblastoma (RB) proteins RB1, p107 (RBL1), and p130 (RBL2). In their hypophosphorylated state, RB proteins bind to and inhibit the function of transcription factors in the E2F family. Phosphorylation of RB protein by CDK4 / 6 separates it from E2F, allowing E2F to activate the expression of multiple genes involved in DNA replication. CDK4 / 6 inhibitors, such as INK4, negatively regulate CDK4 / 6 and cell proliferation in an RB-dependent manner. INK4, cyclin D, CDK4 / 6, and RB are part of a pathway that controls the G1 to S transition.

[0004] The cell cycle is central to many cancers. Dysregulation of the INK4-cyclin D-CDK4 / 6-RB pathway is paramount in cellular transformation and the initiation of most cancers. Cancer genomic studies have further validated the importance of the INK4-cyclin D-CDK4 / 6-RB pathway in cancer progression. All genes in this pathway are frequently mutated in various cancer types, including breast cancer, glioblastoma (GBM), ovarian cancer, lung cancer, esophageal squamous cell carcinoma (ESCC), liver cancer, bladder cancer, head and neck squamous cell carcinoma (HNSCC), and cutaneous melanoma (SKCM).

[0005] Among the genes in the INK4-cyclin D-CDK4 / 6-RB pathway, cyclin D represents a highly valued cancer target. As the first identified cell cycle oncogene, cyclin D is frequently amplified in a wide range of human cancers by genomic amplification or overexpression mechanisms, including 23-57% of ESCC, 26-39% of HNSCC, 5-30% of NSCLC, 25% of pancreatic cancer, 15-20% of breast cancer, and 26% of endometrial cancer. In addition to its function as a CDK4 / 6 activator, cyclin D possesses CDK4 / 6- and RB-independent functions. For example, cyclin D interacts with transcription factors and regulates their activity. Furthermore, analysis of cyclin D interactors by proteomic screens revealed its function in DNA repair. Another study demonstrated a kinase-independent role for cyclin D in chromosomal instability. Recently, cyclin D was identified as a top cancer therapeutic target by the Functional Cancer Dependency Map (DepMap) project. However, due to the lack of a functional active site, cyclin D was previously considered undruggable.

[0006] Three CDK4 / 6 inhibitors, palbociclib, ribociclib, and abemaciclib, have been approved for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy (ET), such as estrogen receptor (ER) inhibitors and aromatase inhibitors (AIs). Abemaciclib is also approved as monotherapy for men and women whose disease has progressed after ET and before chemotherapy in the metastatic setting. Each agent has been shown to significantly improve progression-free survival (PFS) when combined with endocrine therapy. However, between 33% and 70% of patients develop acquired resistance after 2 to 3 years of treatment with CDK4 / 6 inhibitors.

[0007] Much of the resistance to CDK4 / 6 inhibitors is not related to active site mutations, which are seen with other kinase inhibitors and can be overcome by the development of next-generation inhibitors. Instead, mutations in genes upstream of cyclin D, such as RTK, RAS, AKT, and YAP, appear to be a common theme and are associated with upregulated cyclin D expression. Therefore, inhibition of cyclin D can likely achieve higher potency than CDK4 / 6 inhibitors alone, overcome resistance to CDK4 / 6 inhibitors, and target the oncogenic functions of cyclin D that are independent of CDK4 / 6.

[0008] There is a medical need for compounds and methods for the selective degradation of target proteins, including cyclin D. Summary of the Invention

[0009] Disclosed herein are heterobifunctional compounds and compositions comprising a DDB1 (damaged DNA binding protein 1) E3 ligase binding moiety linked to a target protein binding moiety by a bivalent linker, and methods of making and using such compounds and compositions.

[0010] In one aspect herein, a compound of formula (I)

[0011] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, A is a target protein binding moiety; L 1 is the linker, B is a compound of formula (II):

[0012] [ka] is a DDB1 binding moiety having the structure During the ceremony, Ring Q is phenyl or a 5- or 6-membered monocyclic heteroaryl; L 2 is a bond, -O-, -NR 4A -, -NR 4B -C(=O)-, -NR 4B -C(=O)-(C1-C3 alkylene)-NR 4A -, -NR 4B -C(=O)-(C1-C3 alkylene)-O-, -(C1-C3 alkylene)-NR 4B -C(=O)-, -C(=O)NR 4A -, -C1-C3 alkylene-, -C2-C3 alkenylene-, -C2-C3 alkynylene-, C3-C8 cycloalkylene, or C2-C8 heterocyclene; R 1 are independently hydrogen, halogen, -CN, NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 1 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, OH, or O-C1-C4 alkyl; R 3 are independently hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , -OC(=O)R4A , -N(R 4A )C(=O)R 4B , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 3 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 4A and R 4B are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B together with the atoms to which they are connected, and optionally C2-C 12 forming a heterocyclyl, p is 1, 2, or 3; Heterobifunctional compounds are disclosed wherein q is 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof.

[0013] In some embodiments, ring Q is a 5-membered monocyclic heteroaryl. In some embodiments, the 5-membered monocyclic heteroaryl is pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

[0014] In some embodiments, the DDB1 binding moiety of formula (II) is represented by formula (III-1) or (III-2):

[0015] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 1 is O, S, or NR 5 and X 2 and X 5 are independently N or CH; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl; R 1A and R 1B are independently hydrogen, halogen, CN, -NO2, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R 1A and R 1B together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0016] In some embodiments, X 1 is O or S, and X 2 is N. In some embodiments, R 2 is H. In some embodiments, X 5 is CH.

[0017] In some embodiments, R 1Ais selected from hydrogen, halogen, NO, —OCH, —C(═O)CH, —C(═O)OCH, —C(═O)NH, —C(═O)NHCH, —C(═O)N(CH), —CH, —CF, —CHCH, —CH(CH), —C(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. 1A is selected from hydrogen, halogen, —OCH, —C(═O)CH, —C(═O)OCH, —CH, —CF, —CHCH, —CH(CH), —C(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. 1B is selected from hydrogen, halogen, NO, —OCH, —C(═O)CH, —C(═O)OCH, —C(═O)NH, —C(═O)NHCH, —C(═O)N(CH), —CF, or phenyl. 1B is selected from hydrogen, halogen, —OCH, —C(═O)CH, —C(═O)OCH, —CF, or phenyl. 1B is selected from -CH3, -CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0018] In some embodiments, ring Q is phenyl or a 6-membered monocyclic heteroaryl. In some embodiments, the 6-membered monocyclic heteroaryl is pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl.

[0019] In some embodiments, the DDB1 binding moiety of formula (II) has formula (V-1):

[0020] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 3 is N or CH, X 4 But, CR 1E or N, R 1C , R 1D , and R 1E are independently hydrogen, halogen, CN, -NO2, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R 1C and R 1D , or R 1D and R 1E together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0021] In some embodiments, R 2 is hydrogen. 3 is N. In some embodiments, X 3 is CH. In some embodiments, R 1C and R 1E are hydrogen, and R 1D is hydrogen, halogen, -NO2, -CN, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl. 1C and R 1E are hydrogen, and R 1Dis hydrogen, halogen, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or heteroaryl.

[0022] In some embodiments, X 3 and X 4 is N and R 1C is hydrogen and R 1D is hydrogen, halogen, -NO2, -CN, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl. 3 and X 4 is N and R 1C is hydrogen and R 1D is hydrogen, halogen, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or heteroaryl. 3 and X 4 is N and R 1C is hydrogen and R 1D -OR 4A , -NR 4B R 4A, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl. 3 and X 4 is N and R 1C is hydrogen and R 1D is -NR 4B R 4A In some embodiments, X 3 and X 4 is N and R 1C is hydrogen and R 1D is -N(CH3)2.

[0023] In some embodiments, X 3 is N and X 4 is CR 1E and R 1C is hydrogen and R 1D and R 1E are each independently hydrogen, halogen, or -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4-7 membered heterocycloalkyl, aryl, or heteroaryl. 3 is N and X 4 is CR 1E and R 1C is hydrogen and R 1D and R 1E are each independently hydrogen, halogen, or -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or heteroaryl. 3 is N and X 4 is CR 1E and R 1C is hydrogen and R 1D and R 1E are each independently hydrogen, halogen, or -OR 4A , -NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocycloalkyl.

[0024] In some embodiments, X 3 is N and X 4 is CR 1E and R 1C is hydrogen and R 1D and R 1E together with the atoms to which they are connected, C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0025] In some embodiments, R 3 are each independently halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C cycloalkoxy, C-C cycloalkylamino, C-C cycloalkyl, or C-C heterocyclyl. 3 are each independently halogen, CN, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C alkylamido, C-C cycloalkoxy, C-C cycloalkylamino, C-C cycloalkylamido, C-C cycloalkyl, or C-C heterocyclyl.3 is a halogen. In some embodiments, R 3 is F or Cl. In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is CHF or CF. In some embodiments, R 3 is CN. In some embodiments, R 3 is C1-C6 alkylamino. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is CH3. In some embodiments, R 3 is CH3, CH2CH3, CH(CH3)2, C(CH3)3, or cyclopropyl.

[0026] In some embodiments, two R 3 together with the atoms to which they are connected, C3-C 13 Cycloalkyl, C2-C 12 In some embodiments, two R 3 together with the atom to which they are attached form a C-C cycloalkyl, a 5- to 6-membered heterocyclyl, a phenyl, or a 5- to 6-membered heteroaryl. 3 together with the atom to which they are attached form a cyclopentyl, cyclohexyl, pyrrole, pyrazole, or imidazole.

[0027] In some embodiments, p is 1 or 2. In some embodiments, L 2 is a bond. In some embodiments, L 2 is -C(=O)NR 4B -, -NR 4A -(C1-C3 alkylene)-C(=O)NR 4B -, or -O-(C1-C3 alkylene)-C(=O)NR 4B In some embodiments, L 2is —C(═O)NH—, —NH—(CH)—C(═O)NH—, or —O—(CH)—C(═O)NH—. In some embodiments, L 2 is -NR 4A - or -O-. In some such embodiments, L 2 In some such embodiments, L 2 is -O-.

[0028] In some embodiments, the linker L1 has the formula (L):

[0029] [ka] or a pharmaceutically acceptable salt or solvate thereof; During the ceremony, A L , W L 1 , W L 2 , and B L Each occurrence of R represents a bond (i.e., no group is present), L a -R L b , R L a COR L b , R L a C(O)OR L b , R L a C(O)N(R L 1 )R L b , R L a C(S)N(R L 1 )R L b , R L a OR L b , R L a SR L b , R La SOR L b , R L a SO2R L b , R L a SO2N(R L 1 )R L b , R L a N(R L 1 )R L b , R L a N(R L 1 )COR L b , R L a N(R L 1 )CON(R L 2 )R L b , R L a N(R L 1 )C(S)R L b , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 1-8 membered heteroalkylene, optionally substituted 2-8 membered heteroalkenylene, optionally substituted 2-8 membered heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 a divalent radical independently selected from the group consisting of cycloalkylene, optionally substituted 3- to 13-membered heterocyclene, optionally substituted arylene, and optionally substituted heteroarylene, wherein: R L a and R L b are each independently a bond (i.e., no group), RL r , optionally substituted (C-C alkylene)-R L r , optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), or optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 1-8 membered heteroalkylene, optionally substituted 2-8 membered heteroalkenylene, optionally substituted 2-8 membered heteroalkynylene, 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 C3-C 13 a divalent moiety consisting of cycloalkylene, optionally substituted 3- to 13-membered heterocyclene, optionally substituted arylene, or optionally substituted heteroarylene; R L r each independently represents an optionally substituted C-C 10 selected from cycloalkylene, optionally substituted 3- to 10-membered heterocyclene, optionally substituted arylene, and optionally substituted heteroarylene; R L 1 and R.L. 2 are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10selected from cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R L a and R L b , R L 1 and R L 2 , R L a and R L 1 , R L a and R L 2 , R L b and R L 1 , or R L b and R.L. 2 together with the atoms to which they are attached, and optionally C3-C 20 forming a carbocyclyl or 3- to 20-membered heterocyclyl ring, m L is an integer from 1 to 15.

[0030] In some embodiments, A L is a bond, —C(═O)—, —C(═O)NH—, —NH—, —NH—C(═O)—, —O—, —(C-C alkylene)-C(═O)NH—, —(C-C alkylene)-C(═O)—, —(C-C alkylene)NH—, —(C-C alkylene)-NH—C(═O)—, —(C-C alkylene)-O—, —C-C alkylene-, or —C-C alkynylene. L is a bond, -C(=O)-, -C(=O)NH-, -NH-, -NH-C(=O)-, -O-, -(C-C alkylene)-, -NH-(C-C alkylene)-, -O-(C-C alkylene)-, -C(=O)-(C-C alkylene), -C(=O)NH-(C-C alkylene), -NH-C(=O)-(C-C alkylene)-, or -C-C alkynylene-. In some embodiments, W L1 are each independently R L r or C1-C3 alkylene, W L 2 are each independently a bond, O, or NH. L 1 are each independently a bond, O, or NH, and W L 2 are each independently R L r or C1-C3 alkylene. In some embodiments, W L 1 are each independently C1-C3 alkylene; W L 2 are each independently a bond or O. In some embodiments, W L 1 are each independently a bond or O, and W L 2 are each independently C1-C3 alkylene. L 1 -W L 2 Each - is independently -CH2CH2O- or -CH2-. In some embodiments, m L is selected from 1 to 10.

[0031] In some embodiments, the linker L 1 is -(CH2) p1 C(=O)NH(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 C(=O)NH(CH2) p2 -, -(CH2) p1 NHC(=O)-(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 NHC(=O)-(CH2) p2 -, -(CH2) p1 C(=O)-(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1C(=O)-(CH2) p2 -, -(CH2) p1 NH(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 NH(CH2) p2 -, -(CH2CH2O) p2 -(CH2) p3 - or -(CH2) p2 -, where p1 is an integer from 0 to 8, p2 is an integer from 1 to 15, and p3 is an integer from 0 to 8.

[0032] In some embodiments, A is a target protein binding moiety that comprises a cyclin-dependent kinase 4 (CDK4) binding moiety or a cyclin-dependent kinase 6 (CDK6) binding moiety.

[0033] In some embodiments, the target protein binding moiety has formula (A):

[0034] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X A 1 , X A 2 , Y A 1 , and Y A 2 However, each is independently CR A 4 or N, R A 1 But NR A 5 R A 6 , N(R A 5 )C(O)R A 6 , aryl, or heteroaryl; R A 2is hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C heteroalkyl, C-C cycloalkyl, or C-C heterocyclyl; or R A 1 and R A 2 optionally, taken together with the atom to which they are attached, form an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl; L 3 But -R A 3A_ R A 3B -, and R A 3A and R A 3B each independently represents a bond (i.e., no group), —O—, —S—, or —NR A 7 -, -C(=O)-, -C(=O)NR A 7 -, -S(=O)-, -S(=O)NR A 7 -, -S(=O)2-, -S(=O)2NR A 7 -, C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, C2-C 12 heterocyclene, arylene, or heteroarylene; R A 4 are independently hydrogen, halogen, CN, NO2, NR A 8 R A 9 , -C(=O)R A 10 , -C(=O)OR A 10 , -C(=O)NR A 8 R A 9 , -NRA 8 C(=O)R A 10 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R A 5 and R A 6 is independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R A 5 and R A 6 optionally, together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; R A 7 , R A 8 , R A 9 , and R A 10 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R A 8 and R A 9 taken together with the atom to which they are attached optionally form a 3- to 20-membered heterocyclyl ring.

[0035] In some embodiments, the target protein binding moiety of Formula (A) is represented by Formula (A1), (A2), or (A3):

[0036] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Y A 3 But, CR A 19 or N, R A 11 , R A 14 , and R A 18 are each independently selected from hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxyalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or C-C heterocyclyl, aryl, or heteroaryl; R A 12 and R A 15 However, each independently, R A 20 , C.O.R. A 20 , CO2R A 20 , or CONR A 20 R A 21 and R A 20 and R A 21 are each independently selected from hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxyalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or C-C heterocyclyl; or R A 20 and R A 21 optionally, together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; R A 13is hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 heteroalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl; R A 16 and R A 17 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl, aryl, or heteroaryl; or R A 16 and R A 17 taken together with the atom to which they are attached optionally form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclyl; R A 19 is independently selected from hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxyalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or C-C heterocyclyl; m A is 0, 1, or 2.

[0037] In some embodiments, the target protein binding moiety of Formula (A) has Formula (A4):

[0038] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X A 3 But, CR A 25 or N, R A 22 is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R A 23 , R A 24 , and R A 25 are each independently selected from hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxyalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or C-C heterocyclyl.

[0039] In some embodiments, X A 1 , X A 2 , and X A 3 are each N. In some embodiments, Y A 1 , Y A 2 , and Y A 3 are CH, respectively.

[0040] In some embodiments, m A is 1. In some embodiments, R A 1 is selected from aryl or heteroaryl. A 2 , R A 4 , R A 13 , R A 19 , R A 23 , and R A24 are each independently selected from hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl.

[0041] In some embodiments, R A 2 , R A 4 , R A 13 , R A 19 , R A 23 , and R A 24 are each independently selected from hydrogen, F, Cl, CH, CHCH, CH(CH), CF, CHF, CHF, cyclopropyl, or cyclobutyl. A 11 and R A 14 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl. A 11 and R A 14 are each independently selected from C1-C8 alkyl or C3-C8 cycloalkyl. A 12 and R A 15 are each independently R A 20 , C.O.R. A 20 , or CONR A 20 R A 21 Selected from R A 20 and R A 21 are each independently selected from C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl. A 12 and R A 15 are independently COR A20 or CONR A 20 R A 21 Selected from R A 20 and R A 21 are each independently selected from C1-C8 alkyl. In some embodiments, R A 16 and R A 17 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl. A 16 and R A 17 are taken together with the atoms to which they are attached to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl ring. A 18 and R A 22 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl. A 18 and R A 22 are each independently selected from H, CH3, CH2CH3, CH(CH3)2, CF3, CHF2, cyclopropyl, or cyclobutyl.

[0042] In some embodiments, L 3 is a bond, C1-C3 alkylene, C3-C8 cycloalkylene, C2-C8 heteroalkylene, C2-C8 heterocyclyl, -(C1-C3 alkylene)-(C3-C8 cycloalkylene)-, -(C1-C3 alkylene)-(C2-C8 heterocyclylene)-, or -(C1-C3 alkylene)-(C2-C8 heteroalkylene)-.

[0043] In some embodiments, L 3 is a bond,

[0044] [ka] is.

[0045] In some embodiments, the target protein binding moiety of formula (A) is

[0046] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0047] In some embodiments, A is a target protein binding moiety that comprises a CBP and / or a p300 binding moiety.

[0048] In some embodiments, the target protein binding moiety has formula (B-1):

[0049] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Y B 1 But CHR B 4 or NR B4 and Y B 2 is CH or N, Y B 3 But, CR B 2 or N, R B 1 is an optionally substituted 5-6 membered heteroaryl; R B 2 are each independently hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C heteroalkyl, C-C cycloalkyl, or C-C heterocyclyl; R B4 But -C(=O)R B 8 , -C(=O)OR B 8 , -C(=O)NR B 6 R B 7 , or -NR B 6 C(=O)R B 8 and L 4 But -R B 3A_ R B 3B -, and R B 3A and R B 3B are each independently a bond, -O-, -S-, or -NR B 5 -, -C(=O)-, -C(=O)NR B 5 -, -S(=O)-, -S(=O)NR B 5 -, -S(=O)2-, -S(=O)2NR B 5 -, C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, C2-C 12 heterocyclene, arylene, or heteroarylene; R B 5 , R B 6 , R B 7 , and R B 8 are each independently selected from C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R B 6 and R B7 optionally, together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; x 3B is 0, 1, or 2.

[0050] In some embodiments, the target protein binding moiety of formula (B-1) has formula (B-2):

[0051] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0052] In some embodiments, R B 4 is -C(=O)R B 8 or -C(=O)NHR B 8 and R B 8 is C1-C8 alkyl. In some embodiments, R B 4 is -C(=O)R B 8 or -C(=O)NHR B 8 and R B 8 is CH3. In some embodiments, R B 2 is halogen, CN, NO, C-C alkyl, C-C haloalkyl, or C-C alkoxy. B 2 is CHCF. In some embodiments, R B 1 is an optionally substituted 5-membered monocyclic heteroaryl selected from pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. B 1is an optionally substituted pyrazolyl. In some embodiments, R B 1 is pyrazolyl substituted with methyl. 4 is a bond, C1-C3 alkylene, C3-C8 cycloalkylene, C2-C8 heteroalkylene, C2-C8 heterocyclene, -(C1-C3 alkylene)-(C3-C8 cycloalkylene)-, -(C1-C3 alkylene)-(C2-C8 heterocyclene)-, or -(C1-C3 alkylene)-(C2-C8 heteroalkylene)-.

[0053] In some embodiments, the target protein binding moiety of formula (B-1) is

[0054] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0055] In some embodiments, A is a target protein binding moiety that comprises a BET bromodomain-containing protein binding moiety.

[0056] In some embodiments, the target protein binding moiety has formula (C-1), (C-2), (C-3), (C-4), (C-5), or (C-6):

[0057] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0058] [ka] but,

[0059] [ka] and X C1 and X C 2 However, each is independently CR C 3 or N, Y C 1 is O, S, or -C(R C 2 )=C(R C 2 )- and Y C 2 But C(R C 7 )2 or NR C 7 and R C 1 is hydrogen or optionally substituted C6-C 10 aryl or 5- to 10-membered heteroaryl; R C 2 are independently hydrogen, halogen, CN, NO2, NR C 4 R C 5 , -C(=O)R C 6 , -C(=O)OR C 4 , -C(=O)NR C 4 R C 5 , -OC(=O)R C 6 , -N(R C 4 )C(=O)R C 6 , C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, or C1-C8 alkylaryl; R C 3 are independently hydrogen, halogen, CN, NO2, NR C 4 R C 5, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, aryl, or heteroaryl; R C 4 , R C 5 , and R C 6 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R C 4 and R C 5 optionally, together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; R C 7 are independently hydrogen, NR C 4 R C 5 , OR C 4 , -C(=O)R C 6 , -C(=O)OR C 6 , -C(=O)NR C 4 R C 5 , -(C1-C8 alkyl)-C(=O)NR C 4 R C , -OC(=O)R C 6 , -N(R C 8 )C(=O)R C 6 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, or R C 7 two of which, together with the atom to which they are attached, optionally form a C3-C8 cycloalkyl or a C2-C8 heterocyclyl; x 4C is 1, 2, or 3.

[0060] In some embodiments,

[0061] [ka] teeth,

[0062] [ka] In some embodiments,

[0063] [ka] teeth,

[0064] [ka] In some embodiments, X C 1 and X C 2 are each independently N. In some embodiments, Y C 1 is S. In some embodiments, Y C 1 is -C(R C 2 )=C(R C 2 )-. In some embodiments, Y C 2 is C(R C 7 )2. In some embodiments, Y C 2 is NR C 7 In some embodiments, R C 3 is hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl. C 2are each independently hydrogen, halogen, C-C alkyl, C-C alkynyl, C-C haloalkyl, C-C alkoxy, C-C alkoxyalkyl, aryl, or heteroaryl. C 1 is an optionally substituted C6-C 10 aryl, optionally 1 to 4 halogens, CN, NO2, NR C 4 R C 5 , -C(=O)R C 6 , -C(=O)OR C 6 , -C(=O)NR C 4 R C 5 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl. 4C is 2 and R C 2 are each independently C1-C8 alkyl. 4C is 2 and R C 2 are each independently C1-C8 alkoxy.

[0065] In some embodiments, the target protein binding moiety is

[0066] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0067] In some embodiments, the DDB1 binding moiety binds to a binding region on the DDB1 protein. In some embodiments, the DDB1 binding moiety binds non-covalently to the binding region. In some embodiments, the binding region comprises a beta-propeller domain. In some embodiments, the beta-propeller domain comprises a beta-propeller C (BPC) domain. In some embodiments, the binding region comprises the top surface of the BPC domain.

[0068] In some embodiments, the binding region comprises 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.

[0069] In some embodiments, the binding between the DDB1 binding moiety and the binding region comprises a binding affinity with an equilibrium dissociation constant (Kd) of less than 100 μM, a Kd of less than 90 μM, a Kd of less than 80 μM, a Kd of less than 70 μM, a Kd of less than 60 μM, a Kd of less than 50 μM, a Kd of less than 45 μM, a Kd of less than 40 μM, a Kd of less than 35 μM, a Kd of less than 30 μM, a Kd of less than 25 μM, a Kd of less than 20 μM, a Kd of less than 15 μM, a Kd of less than 14 μM, a Kd of less than 13 μM, a Kd of less than 12 μM, a Kd of less than 11 μM, a Kd of less than 10 μM, a Kd of less than 9 μM, a Kd of less than 8 μM, a Kd of less than 7 μM, a Kd of less than 6 μM, a Kd of less than 5 μM, a Kd of less than 4 μM, a Kd of less than 3 μM, a Kd of less than 2 μM, or a Kd of less than 1 μM. In some embodiments, the binding between the DDB1 binding moiety and the binding region comprises a binding affinity having a Kd of less than 20 μM, a Kd of 20-100 μM, or a Kd of greater than 100 μM.

[0070] In another aspect herein, there is provided an in vivo modified protein comprising a DNA damage binding protein 1 (DDB1) protein directly bound to a DDB1 ligand, wherein the DDB1 ligand comprises a heterobifunctional compound described herein.

[0071] In another aspect herein, there is provided a method for degrading a target protein, comprising contacting the target protein with a heterobifunctional compound described herein.

[0072] In some embodiments, contacting the target protein with the heterobifunctional compound comprises contacting a cell containing the target protein with a heterobifunctional compound described herein. In some embodiments, contacting the target protein with the heterobifunctional compound comprises administering the heterobifunctional compound to a subject containing the aforementioned cell. In some embodiments, the contacting results in degradation of the target protein. In some embodiments, the degradation is determined by immunoassay. In some embodiments, the degradation is ubiquitin-mediated. In some embodiments, the degradation is carried out by the proteasome.

[0073] Described herein are modified proteins and protein-ligand complexes. In some embodiments, the modified proteins and protein-ligand complexes are useful in biotechnology applications, such as the selective degradation of target proteins, molecular glues, or antimicrobial agents.

[0074] Incorporation by Reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference for the specific purposes identified herein. [Brief explanation of the drawings]

[0075] [Figure 1A] FIG. 1 shows an SPR sensorgram of heterobifunctional compound CPD-004 binding to DDB1. [Figure 1B]FIG. 1 shows an SPR sensorgram of heterobifunctional compound CPD-031 binding to DDB1. [Figure 2A] FIG. 1 shows immunoblots of cyclin D1, cyclin D2, cyclin D3, CDK4, CDK6, cleaved caspase-3, and p-Rb proteins expressed by Calu-1 cells after treatment with a dose range of the CDK4 / 6 inhibitor palbociclib or the heterobifunctional compounds CPD-002 or CPD-004 for 16 hours. [Figure 2B] FIG. 1 shows immunoblots of cyclin D1, cyclin D3, CDK4, and CDK6 proteins expressed by BT-549 cells after 16 hours of treatment with a dose range of the CDK4 / 6 inhibitor palbociclib or the heterobifunctional compounds CPD-002 or CPD-004. [Figure 3] FIG. 1 shows immunoblots of cyclin D1, cyclin D2, cyclin D3, CDK4, CDK6, and p-Rb proteins expressed by Calu-1 cells after treatment with a dose range of the heterobifunctional compound CPD-031 for 16 hours. [Figure 4A] FIG. 1 shows immunoblots of cyclin D1, cyclin D2, cyclin D3, CDK4, CDK6, and p-Rb proteins expressed by Calu-1 cells after treatment with the heterobifunctional compound CPD-002 at various time points. [Figure 4B] FIG. 1 shows immunoblots of cyclin D1, cyclin D2, cyclin D3, CDK4, CDK6, and p-Rb proteins expressed by Calu-1 cells after treatment with the heterobifunctional compound CPD-031 at various time points. [Figure 5A] Figure 1 shows immunoblots of cyclin D1, cyclin D2, and cyclin D3 proteins expressed by Calu-1 cells after treatment with heterobifunctional compounds CPD-002 and CPD-004 in the presence or absence of MLN4924 (MLN), MG-132 (MG), or TAK-243 (TAK). [Figure 5B] Figure 1 shows immunoblots of cyclin D1, cyclin D2, and cyclin D3 proteins expressed by Calu-1 cells after treatment with the heterobifunctional compound CPD-031 in the presence or absence of MLN4924 (MLN), MG-132 (MG), or TAK-243 (TAK). [Figure 5C] FIG. 1 shows immunoblots of cyclin D1 protein expressed in parental or DDB1 knockout Hs578T cells after 4 hours of treatment with the heterobifunctional compound CPD-031 at the indicated concentrations. [Figure 6A] FIG. 1 shows immunoblots of cyclin D1, cyclin D2, cyclin D3, and CDK4 proteins expressed by Calu-1 cells after treatment with a dose range of the control compound CPD-042 for 16 hours. [Figure 6B] FIG. 1 shows immunoblots of cyclin D1, cyclin D2, cyclin D3, and CDK4 proteins expressed by Calu-1 cells after treatment with a dose range of the control compound CPD-049 for 16 hours. [Figure 6C] FIG. 1 shows the anti-survival curves of Calu-1 cells in the presence of CPD-002 and CPD-042. [Figure 6D] FIG. 1 shows the anti-survival curves of Calu-1 cells in the presence of CPD-031 and CPD-049. [Figure 7] FIG. 1 shows the anti-survival curves of Calu-1, NCI-H522, BT-549, Hs578T, or MIA PaCa-2 cells in the presence of palbociclib, ribociclib, abemaciclib, CPD-002, or CPD-031. [Figure 8] FIG. 1 shows immunoblots of P300 and CBP proteins expressed by LNCaP, Calu-1, NCI-H1703, or MM.1R cells after 8 hours of treatment with a dose range of the heterobifunctional compound CPD-191. [Figure 9]FIG. 1 shows immunoblots of BRD4 protein expressed by Daudi, SU-DHL-4, or MDA-MB-231 cells after 8 hours of treatment with a dose range of the heterobifunctional compound CPD-253. [Figure 10A] FIG. 1 shows immunoblots of cyclin D1, cyclin D3, CDK4, p-Rb, FoxM1, and cyclin A2 proteins expressed by T47D cells after treatment with a dose range of the heterobifunctional compound CPD-343 or its control compound CPD-380 for 48 hours. [Figure 10B] FIG. 10B shows the anti-survival curve of T47D cells in the presence of CP-343 or CPD-380 for 6 days. [Figure 11A] Immunoblot: Immunoblot of cyclin D1, CDK4, and CDK6 proteins expressed by Calu-1 cells after treatment with the reference heterobifunctional compounds CP-10 or BSJ-03-123 for 8 hours. [Figure 11B] FIG. 1 shows the anti-survival curve of Calu-1 cells in the presence of CP-10 or GJ-03-123 for 3 days. [Figure 12] FIG. 1 shows flow cytometry analysis of Annexin V / 7-AAD stained T47D cells after treatment with the indicated concentrations of DMSO, palbociclib, the heterobifunctional compound CPD-343, or the control compound CPD-380 for 6 days. [Figure 13] FIG. 1 shows the anti-survival curves of T47D parental or palbociclib-resistant cells in the presence of palbociclib or the heterobifunctional compound CPD-343 for 6 days. DETAILED DESCRIPTION OF THE INVENTION

[0076] DDB1 (Damaged DNA-binding protein 1) was first identified as a subunit of a heterodimeric complex involved in DNA repair. It was subsequently discovered that DDB1 functions as a linker protein, connecting substrate receptor proteins to CUL4 to assemble multiple CUL4-RING E3 ligase complexes (CRL4s). The CRL family of E3 ligases is frequently hijacked by various viruses to degrade different host restriction factors, likely due to the intrinsic flexibility of CRL ligases. Notably, DDB1 is the E3 factor most frequently hijacked. Structural analysis of DDB1 in complexes containing HBx or SV5-VH-Box motifs has provided important insights into the binding site of DDB1.

[0077] Disclosed herein are heterobifunctional compounds that modulate cyclin D, P300 / CBP, or BRD4 protein levels. These inhibitors were developed by recruiting the DDB1 E3 ubiquitin ligase in an approach that allows for more flexible modulation of protein levels in vitro and in vivo compared to techniques such as gene knockout or small hairpin RNA-mediated (shRNA) knockdown. Unlike gene knockout or shRNA knockdown, the small molecule approach further provides the opportunity to test dose- and time-dependence in disease models by adjusting the administration route, concentration, and frequency of the corresponding heterobifunctional small molecule compound. These compounds were designed by incorporating three moieties: a DDB1 ligand, a linker, and a CDK4 / 6, P300 / CBP, or BRD4 binder.

[0078] The compounds described herein may be useful for several purposes, including, but not limited to, use as 1) antivirals, 2) DDB1 protein level modulators (e.g., increasing or decreasing DDB1 protein levels), 3) DDB1 function modulators (e.g., DDB1 activators or inhibitors), 4) molecular binding agents (e.g., increasing protein-protein interactions between DDB1 and another protein), or 5) targeted proteolytic agents. Molecular binding agents, or targeted proteolytic agents, may be useful for affecting the activity or protein levels of another protein.

[0079] definition As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, reference to "the cell" includes a reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth.

[0080] When ranges relating to physical properties, such as molecular weight, or chemical properties, such as chemical formula, are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be encompassed. The term "about," when referring to a number or numerical range, means that the referenced number or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus, in some instances, the number or numerical range may vary by between 1% and 15% of the stated number or numerical range.

[0081] The term "comprising" (and related terms such as "comprise," "comprises," "having," or "including") is not intended to exclude that in other particular embodiments, embodiments such as, for example, any composition of matter, composition of matter, method, or process described herein, "consist of" or "consist essentially of" the recited features.

[0082] As used in this specification and the appended claims, the following terms have the meanings indicated below, unless expressly stated to the contrary.

[0083] "Amino" refers to the -NH2 radical.

[0084] "Cyano" refers to the -CN radical.

[0085] "Nitro" refers to the -NO2 radical.

[0086] "Oxa" refers to the -O- radical.

[0087] "Oxo" refers to the =O radical.

[0088] "Thioxo" refers to the =S radical.

[0089] "Imino" refers to the =NH radical.

[0090] "Oximo" refers to the =N-OH radical.

[0091] "Hydrazino" refers to the =N-NH2 radical.

[0092] "Alkyl" refers to a group consisting solely of carbon and hydrogen atoms, without unsaturation, having from 1 to 15 carbon atoms (e.g., C1-C 15Alkyl) refers to a straight or branched hydrocarbon chain radical. In certain embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1-C 13 In some embodiments, an alkyl contains 1 to 8 carbon atoms (e.g., a C1-C8 alkyl). In other embodiments, an alkyl contains 1 to 5 carbon atoms (e.g., a C1-C5 alkyl). In other embodiments, an alkyl contains 1 to 4 carbon atoms (e.g., a C1-C4 alkyl). In other embodiments, an alkyl contains 1 to 3 carbon atoms (e.g., a C1-C3 alkyl). In other embodiments, an alkyl contains 1 to 2 carbon atoms (e.g., a C1-C2 alkyl). In other embodiments, an alkyl contains 1 carbon atom (e.g., a C1 alkyl). In other embodiments, an alkyl contains 5 to 15 carbon atoms (e.g., a C5-C 15 In other embodiments, an alkyl group contains 5 to 8 carbon atoms (e.g., a C5-C8 alkyl). In other embodiments, an alkyl group contains 2 to 5 carbon atoms (e.g., a C2-C5 alkyl). In other embodiments, an alkyl group contains 3 to 5 carbon atoms (e.g., a C3-C5 alkyl). In other embodiments, an 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). An alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, an alkyl group may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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 OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), optionally substituted with one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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).

[0093] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0094] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2 trifluoroethyl, 1,2 difluoroethyl, 3 bromo 2 fluoropropyl, and 1,2 dibromoethyl.

[0095] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to substituted or unsubstituted alkyl, alkenyl, and alkynyl groups, respectively, having one or more skeletal atoms selected from atoms other than carbon. Exemplary skeletal atoms selected from atoms other than carbon include, for example, O, N, P, Si, S, or combinations thereof, where the nitrogen, phosphorus, and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. When given, numerical ranges refer to the total chain length. For example, a 1-8-membered heteroalkyl has a chain length of 1-8 atoms, including both carbon and heteroatoms. Such a heteroalkyl chain is sometimes referred to herein as a "C1-C8 heteroalkyl." The same heteroalkyl chain may alternatively be referred to as a 1-8-membered heteroalkyl. Connection to the remainder of the molecule can be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless otherwise specified in the specification, a heteroalkyl, heteroalkenyl, or heteroalkynyl group is optionally substituted with one or more substituents, such as those described herein. Divalent heteroalkyl, heteroalkenyl, and heteroalkynyl moieties may also be referred to as heteroalkylene, heteroalkenylene, or heteroalkynylene moieties, respectively. It will be understood that the number and position of heteroatoms in a saturated or unsaturated heteroalkyl chain is limited to the extent that such a compound is chemically stable (i.e., excluding peroxide moieties, etc.).

[0096] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In some embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. A divalent alkenyl moiety is sometimes referred to as an alkenylene moiety. Unless otherwise specified in the specification, an alkenyl group may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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 OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), optionally replaced by one or more of R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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).

[0097] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 6 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. A divalent alkynyl moiety is sometimes referred to as an alkynylene moiety. Unless otherwise specified in the specification, an alkynyl group may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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 OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), optionally replaced by one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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).

[0098] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the rest of the molecule, consists solely of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through a carbon atom in the alkylene chain or any two carbon atoms within the chain. In certain embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified in the specification, an alkylene chain may contain any of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, 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 OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (t is 1 or 2), optionally replaced by one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (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).

[0099] "Aryl" refers to a radical derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. A divalent aryl moiety is sometimes referred to as an arylene moiety. The monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and carbon atoms from 5 to 18 carbon atoms, and at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include an aryl radical that is optionally substituted by one or more substituents, the substituents being independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, 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 OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and R a are each 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 are each independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0100] "Aralkyl" is a group of the formula -R c -aryl radicals, such as methylene and ethylene, where R c is an alkylene chain as defined above. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0101] "Carbocyclyl" or "cycloalkyl" refers to a stable monocyclic or polycyclic non-aromatic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having from 3 to 15 carbon atoms (i.e., "C3-C 15 Such cycloalkyl ring systems may alternatively be referred to as 3-15 membered cycloalkyls. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms (i.e., "C3-C 10 In other embodiments, a carbocyclyl contains 3 to 8 carbon atoms (i.e., a "C3-C8 cycloalkyl"), or 5 to 7 carbon atoms (i.e., a "C5-C7 cycloalkyl"). A carbocyclyl can be attached to the remainder of the molecule by a single bond or an exocyclic double bond. A carbocyclyl is fully saturated (i.e., contains only one C-C bond) or partially unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl." A partially unsaturated carbocyclyl ring is sometimes referred to as a cyclo-alkenyl or cycloalkynyl moiety. A divalent cycloalkyl moiety is sometimes referred to as a cycloalkylene moiety.

[0102] Examples of monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Examples of polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is intended to include carbocyclyl radicals optionally substituted by one or more substituents, the substituents being independently alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, 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 OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and R a are each 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 are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0103] A "carbocyclylalkyl" is a group of the formula -R c -carbocyclyl radical, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0104] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0105] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, e.g., 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 as defined above for an alkyl group.

[0106] "Heterocyclyl" or "heterocycloalkyl" refers to a heterocyclic group of 2 to 14 carbon atoms and 2 to 14 heterocyclic groups containing nitrogen, oxygen, and sulfur (i.e., N, O, and S(O)). z and z is 0, 1, or 2. Such ring systems are referred to herein as "C2-C 14A heterocyclyl may be referred to as a "heterocyclyl" or alternatively as a 3- to 20-membered heterocyclyl. Similarly, "C2-C8 heterocyclyl" refers to a ring system containing 2 to 8 carbon atoms and 1 to 6 heteroatoms, preferably 1 to 3 heteroatoms; this ring system may alternatively be referred to as a 3- to 14-membered heterocyclyl. In some embodiments herein, heterocyclyl ring systems include 5- to 6-membered heterocyclyls, 3- to 8-membered heterocyclyls, 3- to 10-membered heterocyclyls, or 3- to 13-membered heterocyclyls, each of which preferably contains 1 to 3 heteroatoms. A divalent heterocycloalkyl moiety may be referred to as a heterocyclene moiety. Unless otherwise specified specifically in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including fused or bridged ring systems. It will be understood that the number and position of heteroatoms in a heterocycle are limited to the extent that such compounds are chemically stable. The heteroatoms in a heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl radicals, as defined above, optionally substituted by one or more substituents, including alkyl, alkenyl, alkynyl, halo, fluoroalkyl, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, 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 OR a (t is 1 or 2), and -Rb -S(O) t N(R a )2 (t is 1 or 2), and R a are each 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 are each independently a direct bond or a linear or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0107] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is 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.

[0108] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one heteroatom, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is 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, 2- or 3-pyrrolidinyl, and the like.

[0109] "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. A divalent heteroaryl moiety may be referred to as a heteroarylene moiety. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which at least one ring is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel theory. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring.

[0110] Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzo Thieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 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-hexahydrocycloocta[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, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyl Naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 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[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, 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-cyclohexyl Examples of thieno[4,5]thieno[2,3-d]pyrimidinyl include, but are not limited to, buta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyridinyl, and thiophenyl (i.e., thienyl).

[0111] Unless stated otherwise specifically in the specification, the term "heteroaryl" is intended to include heteroaryl radicals, as defined above, optionally substituted by one or more substituents, including alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, 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)ORa , -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 OR a (t is 1 or 2), and -R b -S(O) t N(R a )2 (t is 1 or 2), and R a are each 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 bare each independently a direct bond or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain, and unless otherwise specified, each of the above substituents is unsubstituted.

[0112] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0113] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0114] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, thus giving rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R) or (S). Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When a compound described herein contains an alkene double bond, and unless otherwise specified, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as racemic and optically pure forms thereof, and all tautomers, are intended to be included. The term "geometric isomer" refers to E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0115] "Tautomer" refers to a molecule capable of proton transfer from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In situations 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. Some examples of tautomeric equilibrium include:

[0116] [ka] Examples include:

[0117] In some embodiments, the compounds disclosed herein are used in various enriched isotopic forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14 In one embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can increase the duration of action of a drug by improving metabolic stability or efficacy.

[0118] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0119] The compounds of the present disclosure may optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain unnatural proportions of atomic isotopes, such as deuterium ( 2 H), tritium ( 3H), iodine-125( 125 I), or carbon-14 ( 14 It may be labeled with an isotope 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 at I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0120] In certain embodiments, the compounds disclosed herein comprise: 2 exchanged with H atoms 1 Some or all of the H atoms are present. Methods for synthesizing deuterium-containing compounds are known in the art, and non-limiting examples include the following synthesis methods:

[0121] Deuterium-substituted compounds are synthesized using a variety of methods, including those described in: Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, p. 110; 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.

[0122] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to effect the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0123] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0124] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, including, for example, 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, salicylic acid, etc. Thus, 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, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Additionally, salts of amino acids such as arginate, gluconate, galacturonate, and the like are contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared 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.

[0125] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological effectiveness and properties of the free acid, which salt is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic 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, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0126] Heterobifunctional Compounds In some embodiments, heterobifunctional compounds and pharmaceutical compositions comprising the compounds are provided herein. In some embodiments, the heterobifunctional compounds described herein comprise 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 comprise a DDB1 binding moiety and a target protein binding moiety. In some embodiments, the heterobifunctional compound comprising the DDB1 binding moiety is covalently linked 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.

[0127] In one aspect herein, a compound of formula (I)

[0128] [ka] or a pharmaceutically acceptable salt or solvate thereof, wherein A is a target protein binding moiety and L 1 is a linker and B is a DDB1 binding moiety, or a pharmaceutically acceptable salt or solvate thereof.

[0129] In another aspect herein, compounds are described that comprise a DNA damage binding protein 1 (DDB1) binding moiety. In some embodiments, the compound comprises a DBB1 binding moiety but does not comprise a linker and / or a target protein binding moiety. Representative examples of such DDB1 binding compounds are shown in Table 1. In some embodiments, the compound comprises a DBB1 binding moiety and a linker but does not comprise a target protein. Representative examples of such compounds are shown in Table 2.

[0130] DDB1 connection part In some embodiments, compounds comprising a DDB1 binding moiety are disclosed herein. The compounds may consist of a DDB1 binding moiety or may comprise heterobifunctional molecules comprising a DDB1 binding moiety. In some embodiments, the compounds only comprise a DDB1 moiety. The compounds may be useful in any of the aspects disclosed herein.

[0131] In a preferred embodiment, the DDB1 binding moiety has formula (II):

[0132] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Ring Q is phenyl or a 5- or 6-membered monocyclic heteroaryl; L 2 is a bond, -O-, -NR 4A -, -NR 4B -C(=O)-, -NR 4B -C(=O)-(C1-C3 alkylene)-NR 4A -, -NR 4B -C(=O)-(C1-C3 alkylene)-O-, -(C1-C3 alkylene)-NR 4B -C(=O)-, -C(=O)NR 4A -, -C1-C3 alkylene-, -C2-C3 alkenylene-, -C2-C3 alkynylene-, C3-C8 cycloalkylene, or C2-C8 heterocyclene; R 1 are independently hydrogen, halogen, -CN, NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 1together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, OH, or O-C1-C4 alkyl; R 3 are independently hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , -OC(=O)R 4A , -N(R 4A )C(=O)R 4B , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 3 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 4A and R 4B are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B together with the atoms to which they are connected, and optionally C2-C 12 forming a heterocyclyl, p is 1, 2, or 3; q is 1, 2 or 3.

[0133] In some embodiments of Formula (II), L2 is para to the carboxamide moiety. In some embodiments of Formula (II), L 2 is meta to the carboxamide moiety. In some embodiments of Formula (II), L 2 is ortho to the carboxamide moiety.

[0134] In some embodiments, the DDB1 binding moiety has the structure of formula (II'):

[0135] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Ring Q is phenyl or a 5- or 6-membered monocyclic heteroaryl; L 2 However, it does not exist or -O-, -NR 4A -, -NR 4B -C(=O)-, -NR 4B -C(=O)-(C1-C3 alkylene)-NR 4A -, -NR 4B -C(=O)-(C1-C3 alkylene)-O-, -(C1-C3 alkylene)-NR 4B -C(=O)-, -C(=O)NR 4A -, -C1-C3 alkylene-, -C2-C3 alkenylene-, -C2-C3 alkynylene-, C3-C8 cycloalkyl, or C2-C8 heterocyclyl; R 1 However, hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's1 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, OH, or O-C1-C4; R 3 are independently hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 3 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 4A and R 4B are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B together with the atoms to which they are connected, and optionally C2-C 12 forming a heterocyclyl, p is 1, 2, or 3; q is 1, 2 or 3.

[0136] In some embodiments, the DDB1 binding moiety has formula (II")

[0137] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Ring Q is phenyl or a 5- or 6-membered monocyclic heteroaryl; L 2 However, it does not exist or -O-, -NR 4A -, -NR 4B -C(=O)-, -NR 4B -C(=O)-(C1-C3 alkylene)-NR 4A -, -NR 4B -C(=O)-(C1-C3 alkylene)-O-, -(C1-C3 alkylene)-NR 4B -C(=O)-, -C(=O)NR 4A -, -C1-C3 alkylene-, -C2-C3 alkenylene-, -C2-C3 alkynylene-, C3-C8 cycloalkyl, or 4- to 7-membered heterocyclyl; R 1 But hydrogen, halogen, -CN, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 3 But hydrogen, halogen, -CN, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; p is 1, 2, or 3; q is 1, 2 or 3.

[0138] Each of the embodiments described herein for Formula (II) is applicable to Formula (II') or Formula (II") to the extent that the embodiments are inconsistent with the definitions of Formula (II') or Formula (II"); a description of Formula (II) may be substituted for a description of Formula (II') or Formula (II").

[0139] In some embodiments of the DDB1-binding moiety of Formula (II), ring Q is a 5-membered monocyclic heteroaryl. In some embodiments, ring Q is a 5-membered monocyclic heteroaryl containing at least one N atom. In some embodiments, ring Q is selected from the group consisting of pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. In some embodiments, ring Q is selected from the group consisting of furan, thienyl, oxazole, or thiazole. In some embodiments, ring Q is selected from the group consisting of imidazolyl or pyrazolyl. In some embodiments, ring Q is selected from the group consisting of pyrazolyl or thiazolyl.

[0140] In some embodiments, the DDB1 binding moiety of formula (II) has formula (III-1):

[0141] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 1is O, S, or NR 5 and X 2 is N or CH, R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl; R 1A and R 1B are independently hydrogen, halogen, CN, -NO2, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R 1A and R 1B together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0142] In some embodiments, the DDB1 binding moiety of formula (II) has formula (III-2):

[0143] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 2 and X 5 are independently N or CH; R 1A and R 1B are independently hydrogen, halogen, CN, -NO2, -OR 4A , -NR 4B R 4A , -C(=O)R 4A, -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R 1A and R 1B together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0144] In some embodiments of formula (III-1) herein, X 1 is O or S, and X 2 is N. In some embodiments, X 1 is O or S, and X 2 is CH. In some embodiments, X 1 is O and X 2 is N. In some embodiments, X 1 is S and X 2 is N.

[0145] In some embodiments of formula (III-2) herein, X 5 In some embodiments of formula (III-2) herein, X 5 is CH and X 2 is N. In some embodiments of formula (III-2) herein, X 5 is CH and X 2 is CH. In some embodiments, X 5 is N. In some embodiments, X 5 is N and X 2 is N. In some embodiments, X 5 is N and X 2 is CH.

[0146] In some embodiments of formula (II), (III-1), or (III-2) herein, R2 is H. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. 2 may contain OH or O-C1-C4 alkyl.

[0147] In some embodiments, the DDB1 binding moiety of formula (II) is represented by formula (IV-1):

[0148] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0149] In some embodiments, the DDB1 binding moiety of formula (II) is represented by formula (IV-1) or (IV-3):

[0150] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0151] In some embodiments, the DDB1 binding moiety of formula (II) has formula (IVa), (IVb), (IVc), or (IVd):

[0152] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0153] In some embodiments, the DDB1 binding moiety of formula (II) is represented by formula (IV-4):

[0154] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R 3A and R 3B are independently hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , -OC(=O)R 4A , -N(R 4A )C(=O)R 4B , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B together with the atoms to which they are connected, and optionally C2-C 12 Forming a heterocyclyl. In some embodiments, the DDB1 binding moiety of formula (II) has formula (IVe), (IVf), or (IVg):

[0155] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0156] In some embodiments, the DDB1 binding moiety of formula (II) has formula (IV-5):

[0157] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R 3A and R 3B are independently hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , -OC(=O)R 4A , -N(R 4A )C(=O)R 4B , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B together with the atoms to which they are connected, and optionally C2-C 12 Forming a heterocyclyl.

[0158] In some embodiments, the DDB1 binding moiety of formula (II) is represented by formula (IVh), (IVi), (IVj), or (IVk):

[0159] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0160] In some embodiments of formulas (IV-1) to (IV-5) or (IVa) to (IVk), R 1Ais selected from hydrogen, halogen, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —CH3, —CHCF2, —CF3, —CH2CH3, —CH(CH3)2, —C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In some embodiments, R 1A is selected from hydrogen, halogen, —OCH, —C(═O)CH, —C(═O)OCH, —CH, —CF, —CHCH, —CH(CH), —C(CH), cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. 1A is selected from hydrogen, —C(═O)CH 3 , —C(═O)OCH 3 , —CH 3 , or phenyl.

[0161] In some embodiments, R 1B is selected from hydrogen, halogen, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —CHCF2, —CF3, or phenyl. 1B is selected from -CH, -CH(CH), -C(CH), cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1B is selected from hydrogen, halogen, —OCH, —C(═O)CH, —C(═O)OCH, —CF, or phenyl. 1B is selected from -CH3, -CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0162] In some embodiments, ring Q is phenyl or a 6-membered monocyclic heteroaryl. In some embodiments, ring Q is phenyl. In some embodiments, ring Q is a 6-membered monocyclic heteroaryl. In some embodiments, the 6-membered heteroaryl contains 1 to 2 N atoms. In some embodiments, ring Q is a 5-membered heteroaryl. In some embodiments, the 5-membered heteroaryl contains 1 to 2 N atoms. In some embodiments, ring Q is selected from pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl. In some embodiments, ring Q is pyridinyl, pyrazinyl, or triazinyl. In some embodiments, ring Q is pyridinyl. In some embodiments, ring Q is pyrazinyl.

[0163] In some embodiments, the DDB1 binding moiety of formula (II) has formula (V-1):

[0164] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 3 is N or CH, X 4 But N or CR 1E and R 1C , R 1D , and R 1E are independently hydrogen, halogen, CN, -NO2, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R 1C and R 1D , or R 1D and R1E together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0165] In some embodiments, the DDB1 binding moiety of formula (II) has formula (V-2):

[0166] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 3 , X 4 , R 1C , R 1D , and R 1E is defined as in formula (V-1), R 3A and R 3B are independently hydrogen, halogen, -NO2, -CN, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , -OC(=O)R 4A , -N(R 4A )C(=O)R 4B , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B together with the atoms to which they are connected, and optionally C2-C12 Forming a heterocyclyl.

[0167] In some embodiments, X 4 is N. In some embodiments, X 4 is CR 1E is.

[0168] In some embodiments, the DDB1 binding moiety of formula (II) has formula (V-3):

[0169] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 3 , R 1C , R 1D , and R 1E is defined as in formula (V-1).

[0170] In some embodiments, the DDB1 binding moiety of formula (II) is represented by formula (VIa), (IVi), (VIc), or (VId):

[0171] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 3 , X 4 , R 1C , R 1D , and R 1E is defined as in formula (V-1).

[0172] In some embodiments, the DDB1 binding moiety of formula (II) is represented by formula (VIe), (VIf), or (VIg):

[0173] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 3 , X 4 , R 1C , R 1D , and R 1E is defined as in formula (V-1), R 3A , R 3B , R 4A , and R 4B is defined as in formula (V-2).

[0174] In some embodiments of formula (V-1), (V-2), (V-3), or (VIa)-(VIg) herein, X 3 is N. In other such embodiments, X 3 is CH.

[0175] In some embodiments of formula (V-1), (V-2), (V-3), or (VIa)-(VIg) herein, R 1C and R 1E are hydrogen, and R 1D is hydrogen, halogen, CN, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl. In some such embodiments, R 1C and R 1E are hydrogen, and R 1D is halogen, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl.

[0176] In some embodiments, X 3 and X 4 is N and R 1C is hydrogen and R 1D is hydrogen, halogen, -NO2, -CN, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl. 3 and X 4 is N and R 1C is hydrogen and R 1D is hydrogen, halogen, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or heteroaryl. 3 and X 4 is N and R 1C is hydrogen and R 1D -OR 4A , -NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl. 3 and X 4 is N and R 1C is hydrogen and R 1D is -NR4B R 4A In some embodiments, X 3 and X 4 is N and R 1C is hydrogen and R 1D is -N(CH3)2.

[0177] In some embodiments, X 3 is N and X 4 is CR 1E and R 1C is hydrogen and R 1D and R 1E are each independently hydrogen, halogen, or -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or heteroaryl. 3 is N and X 4 is CR 1E and R 1C is hydrogen and R 1D and R 1E are each independently hydrogen, halogen, or -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, aryl, or heteroaryl. 3 is N and X 4 is CR 1E and R 1C is hydrogen and R 1D and R 1E are each independently hydrogen, halogen, or -OR4A , -NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, or 4- to 7-membered heterocycloalkyl.

[0178] In some embodiments, X 3 is N and X 4 is CR 1E and R 1C is hydrogen and R 1D and R 1E together with the atoms to which they are connected, C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0179] In some embodiments, R 1D is C-C alkyl, C-C heteroalkyl, C-C cycloalkyl, or C-C heterocyclyl. 1D is methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, cyclopropyl, or t-butyl. 1D is C1-C6 alkyl. In some embodiments, R 1D is methyl, ethyl, n-propyl, isopropyl, or t-butyl. 1D is methyl. In some embodiments, R 1D is hydrogen. In some embodiments, R 1D is -NR 4B R 4A In some embodiments, R 1D is -NH, NH(CH), -N(CH). In some embodiments, R 1D is —N(CH). In some embodiments, R 1D -OR 4A In some embodiments, R 1Dis —OH, —OCH, —OCHF, —OCF, —OCH(CH), —O-cyclopropyl. 1D is —OCH. In some embodiments, R 1D is H.

[0180] In some embodiments, R 3 are each independently hydrogen, halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C cycloalkoxy, C-C cycloalkylamino, C-C cycloalkyl, or C-C heterocyclyl. 3 is F, Cl, Br, CH, CHF, CF, CHCH, CH(CH), cyclopropyl, CN, —NH, NH(CH), NH(i-Pr), NH(n-Bu), NH(t-Bu), or N(CH). In some embodiments, R 3 is CH3. In some embodiments, R 3 is NH(CH3).

[0181] In some embodiments, R 3A and R 3B is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 cycloalkoxy, C1-C6 cycloalkylamino, C3-C8 cycloalkyl, or C2-C8 heterocyclyl.

[0182] In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0183] In some embodiments, L 2 is a bond. In some embodiments, L 2 is -C(=O)NR 4B -, -C1-C3 alkylene-, -C2-C3 alkynylene-, -NR 4A-(C1-C3 alkylene)-, -NR 4A -(C1-C3 alkylene)-C(=O)NR 4B , —O—(C1-C3 alkylene)-, or —O—(C1-C3 alkylene)-C(═O)NR 4B In some embodiments, L 2 is —C(═O)NH—, —CH—, —C≡C—, —NH—(CH)—, —NH—(CH)—C(═O)NH, —O—(CH)—, or —O—(CH)—C(═O)NH—. In some embodiments, L 2 is -C(=O)NR 4B -, -NR 4A -(C1-C3 alkylene)-C(=O)NR 4B - or -O-(C1-C3 alkylene)C(=O)NR 4B In some embodiments, L 2 is —C(═O)NH—, —NH—(CH)—C(═O)NH—, or —O—(CH)—C(═O)NH—. In some embodiments, L 2 is -NR 4A - or -O-.

[0184] In some embodiments, L 2 is —NH—. In some embodiments, L 2 is -O-.

[0185] In some embodiments, the DDB1 binding moiety B is a ligand A and / or a linker L 1 Not connected to.

[0186] In another embodiment, the DDB1 ligand is represented by formula (L-II):

[0187] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Ring Q is phenyl or a 5- or 6-membered monocyclic heteroaryl; R 1are independently hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , -OC(=O)R 4A , -N(R 4A )C(=O)R 4B , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 1 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; R 3 are independently hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 3 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 4A and R 4Bare each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B together with the atoms to which they are connected, and optionally C2-C 12 forming a heterocyclyl, p is 1, 2, 3, 4, or 5; q is 1, 2, 3, 4, or 5.

[0188] In some embodiments, ring Q is a 5-membered monocyclic heteroaryl. In some embodiments, ring Q is a 5-membered monocyclic heteroaryl selected from pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

[0189] In some embodiments, the DDB1 binding moiety of formula (L-II) is represented by formula (L-III-1) or (L-III-2):

[0190] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 1 is O, S, or NR 5 and X 2 and X 5 are independently N or CH; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl; R 1A and R 1B are independently hydrogen, halogen, CN, -NO2, -OR 4A, -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R 1A and R 1B together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0191] In some embodiments, X 1 is O or S, and X 2 is N. In some embodiments, R 2 is H.

[0192] In some embodiments, X 5 is CH. In some embodiments, X 5 is N.

[0193] In some embodiments, X 2 is N.

[0194] In some embodiments, the DDB1 binding moiety of formula (L-II) is represented by formula (L-IV-1) or (L-IV-2):

[0195] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0196] In some embodiments, R 1Ais selected from hydrogen, halogen, —NO2, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —CH3, —CF3, —CH2CH3, —CH(CH3)2, —C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. In some embodiments, R 1B is selected from hydrogen, halogen, —NO2, —OCH3, —NH2, —NHCH3, —N(CH3)2, —C(═O)CH3, —C(═O)OCH3, —C(═O)NH2, —C(═O)NHCH3, —C(═O)N(CH3)2, —CHF2, —CF3, or phenyl. 1B is selected from -CH3, -CH(CH3)2, -C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0197] In some embodiments, ring Q is phenyl or a 6-membered monocyclic heteroaryl. In some embodiments, ring Q is a 6-membered monocyclic heteroaryl selected from pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl.

[0198] In some embodiments, the DDB1 binding moiety of formula (L-II) has the formula (LVA):

[0199] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X 3 is N or CH, X 4 But, CR 1E or N, R 1C , R 1D , and R 1E are independently hydrogen, halogen, CN, -NO2, -OR 4A , -NR 4B R4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R 1C and R 1D , or R 1D and R 1E together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 Forming a heterocyclyl, aryl, or heteroaryl.

[0200] In some embodiments, the DDB1 binding moiety of formula (L-II) is represented by formula (LV-1) or (LV-2):

[0201] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0202] In some embodiments, R 2 is hydrogen. 3 is N. In some embodiments, X 3 is CH. In some embodiments, R 1C and R 1E are hydrogen, and R 1D is hydrogen, halogen, CN, -OR 4A , -NR 4B R 4A , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl.3 are each independently halogen, C-C alkyl, C-C haloalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C cycloalkoxy, C-C cycloalkylamino, C-C cycloalkyl, or C-C heterocyclyl. 3 is C1-C6 alkylamino. In some embodiments, R 3 is a C1-C6 alkylamide. In some embodiments, R 3 is a C1-C6 cycloalkylamide. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is CH3. In some embodiments, R 3 is F, Cl, Br, CH, CHF, CF, CHCH, CH(CH), cyclopropyl, CN, —NH, NH(CH), NH(i-Pr), NH(n-Bu), NH(t-Bu), or N(CH). In some embodiments, R 3 is NH(CH). In some embodiments, p is 1, 2, or 3. In some embodiments, q is 1, 2, or 3. R 1D may contain -H. 1D may contain -NH2. 1D may contain -NH(CH). 1D may contain -N(CH3)2. R 3 may contain CN, -NH2.

[0203] In another embodiment, the DDB1 ligand comprises a compound in Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0204] In some embodiments, the binding between the DDB1 protein and the DDB1 binding moiety comprises a binding affinity with an equilibrium dissociation constant (Kd) of less than 100 μM, a Kd of less than 90 μM, a Kd of less than 80 μM, a Kd of less than 70 μM, a Kd of less than 60 μM, a Kd of less than 50 μM, a Kd of less than 45 μM, a Kd of less than 40 μM, a Kd of less than 35 μM, a Kd of less than 30 μM, a Kd of less than 25 μM, a Kd of less than 20 μM, a Kd of less than 15 μM, a Kd of less than 14 μM, a Kd of less than 13 μM, a Kd of less than 12 μM, a Kd of less than 11 μM, a Kd of less than 10 μM, a Kd of less than 9 μM, a Kd of less than 8 μM, a Kd of less than 7 μM, a Kd of less than 6 μM, a Kd of less than 5 μM, a Kd of less than 4 μM, a Kd of less than 3 μM, a Kd of less than 2 μM, or a Kd of less than 1 μM. In some embodiments, the binding between the DDB1 protein and the DDB1 binding moiety comprises a binding affinity having a Kd value of about 100 μM, about 90 μM, about 80 μM, about 70 μM, about 60 μM, about 50 μM, about 45 μM, about 40 μM, about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 14 μM, about 13 μM, about 12 μM, about 11 μM, about 10 μM, about 9 μM, about 8 μM, about 7 μM, about 6 μM, about 5 μM, about 4 μM, about 3 μM, about 2 μM, or 1 μM, or a Kd value range defined by any two of the foregoing Kd values. In some embodiments, the binding between the DDB1 protein and the DDB1 binding moiety comprises a binding affinity having 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, about 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 Kd value range defined by any two of the foregoing Kd values.

[0205] In some embodiments, the binding between the DDB1 protein and the DDB1 binding moiety (DBM) comprises a binding affinity with a Kd of less than 100 μM. In some embodiments, the binding between the DDB1 protein and the DBM comprises a binding affinity with a Kd of less than 90 μM. In some embodiments, the binding between the DDB1 protein and the DBM comprises a binding affinity with a Kd of less than 80 μM. In some embodiments, the binding between the DDB1 protein and the DBM comprises a binding affinity with a Kd of less than 70 μM. In some embodiments, the binding between the DDB1 protein and the DBM comprises a binding affinity with a Kd of less than 60 μM. In some embodiments, the binding between the DDB1 protein and the DBM comprises a binding affinity with a Kd of less than 50 μM. In some embodiments, the binding between the DDB1 protein and the DBM comprises a binding affinity with a Kd of less than 45 μM. In some embodiments, the binding between the DDB1 protein and the DBM comprises a binding affinity with a Kd of less than 40 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 35 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 30 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 25 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 20 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 15 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 14 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 13 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 12 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 11 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity having a Kd of less than 10 μM.In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 9 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 8 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 7 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 6 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 5 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 4 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 3 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 2 μM. In some embodiments, the binding between the DDB1 protein and DBM comprises a binding affinity with a Kd of less than 1 μM.

[0206] In some embodiments, the binding between the DDB1 protein and the DDB1 binding moiety comprises a binding affinity having a Kd of less than 20 μM, a Kd of 20-100 μM, or a Kd of greater than 100 μM. In some embodiments, the binding between the DDB1 protein and the DDB1 binding moiety comprises a binding affinity having a Kd of less than 20 μM. In some embodiments, the binding between the DDB1 protein and the DDB1 binding moiety comprises a binding affinity having a Kd of 20-100 μM. In some embodiments, the binding between the DDB1 protein and the DDB1 binding moiety comprises a binding affinity having a Kd of greater than 100 μM.

[0207] In some embodiments, the bond between the DDB1 binding moiety and DDB1 is a non-covalent bond. In some embodiments, the bond between the DDB1 binding moiety and DDB1 is a covalent bond.

[0208] In some embodiments herein, a DDB1 binding moiety is disclosed. In some embodiments, the DDB1 binding moiety binds to a 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 is bound to the DDB1 protein. 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 comprises a beta-propeller domain. In some embodiments, the binding region on the DDB1 protein comprises a beta-propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein comprises the top surface of the BPC domain. In some embodiments, the binding region on the DDB1 protein is selected from the group consisting of the following DDB1 residues: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, A including one or more of LA834, 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 present: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, AL One or more of A869, 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 DDB1 binding moiety.In some embodiments, the binding region on the DDB1 protein comprises amino acid residues described herein, such as in the section entitled "Modified Proteins."

[0209] In some embodiments, the DDB1 binding moiety is selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof.

[0210] [Table 1-1]

[0211] [Table 1-2]

[0212] [Table 1-3]

[0213] [Table 1-4]

[0214] [Table 1-5]

[0215] [Table 1-6]

[0216] [Table 1-7]

[0217] [Table 1-8]

[0218] [Table 1-9]

[0219] [Table 1-10]

[0220] [Table 1-11]

[0221] [Table 1-12]

[0222] Linker The present specification describes compounds comprising a linker. In some embodiments, the linker is connected to the DDB1 binding moiety described herein. In some embodiments, the linker is connected to the target protein binding moiety described herein. In some embodiments, the linker is connected to the DDB1 binding moiety and the target protein binding moiety. In some embodiments, the connection is a covalent bond. In some embodiments, the linker is incorporated into the ligand described herein.

[0223] Described herein are compounds comprising a DDB1 binding moiety and a linker. In some embodiments, the linker comprises an optionally substituted polyethylene glycol (PEG). In some embodiments, the linker comprises an optionally substituted alkyl chain. In some embodiments, the linker is a straight-chain alkane. In some embodiments, the linker is an optionally substituted C2-C 30 , C2-C 25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20In some embodiments, the linker comprises an alkyl unit. In some embodiments, the linker comprises an optionally substituted carbocycle. In some embodiments, the linker comprises an optionally substituted heterocycle. In some embodiments, the linker comprises an optionally substituted aryl ring. In some embodiments, the linker comprises an optionally substituted heteroaryl ring. In some embodiments, the linker comprises an ether. In some embodiments, the linker comprises one or more C2-C 30 , C2-C 25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20 In some embodiments, the PEG is optionally substituted with 1 to 5, 2 to 7, 2 to 10, 2 to 20, 5 to 25, or 4 to 30 -(O-CH2CH2)- units in length. In some embodiments, the linker comprises an amine. In some embodiments, the linker comprises one or more C2-C 30 , C2-C 25 , C3-C 25 , C4-C 10 , C6-C 12 , C6-C 18 , or C4-C 20 In some embodiments, the linker comprises an alkylamino unit. In some embodiments, the linker comprises 1 to 5, 2 to 7, 2 to 10, 2 to 20, 5 to 25, or 4 to 30 optionally substituted -(NH-CH2CH2)- units. In some embodiments, the linker comprises an amide. In some embodiments, the linker comprises a sulfonamide. In some embodiments, the linker comprises a carbamide. In some embodiments, the linker comprises a carbamate. In some embodiments, the linker comprises a carbonate. In some embodiments, the compound comprises a DBB1-binding moiety, a linker, and / or a target protein-binding moiety.

[0224] In some embodiments, the linker L 1 is the formula (L)

[0225] [ka] or a pharmaceutically acceptable salt or solvate thereof; During the ceremony, A L , W L 1 , W L 2 , and B L When each appears, L a -R L b , R L a COR L b , R L a C(O)OR L b , R L a C(O)N(R L 1 )R L b , R L a C(S)N(R L 1 )R L b , R L a OR L b , R L a SR L b , R L a SOR L b , R L a SO2R L b , R L a SO2N(R L 1 )R L b , R L a N(R L 1 )R L b , R L a N(R L1 )COR L b , R L a N(R L 1 )CON(R L 2 )R L b , R L a N(R L 1 )C(S)R L b , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 1-8 membered heteroalkylene, optionally substituted 2-8 membered heteroalkenylene, optionally substituted 2-8 membered heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 a divalent moiety independently selected from the group consisting of cycloalkylene, optionally substituted 3- to 13-membered heterocyclene, optionally substituted arylene, and optionally substituted heteroarylene, wherein: R L a and R L b are each independently a bond, R L r , optionally substituted (C-C alkylene)-R L r , optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r-(C1-C8 alkylene), or optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 1-8 membered heteroalkylene, optionally substituted 2-8 membered heteroalkenylene, optionally substituted 2-8 membered heteroalkynylene, 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 C3-C 13 a divalent moiety consisting of cycloalkylene, optionally substituted 3- to 13-membered heterocyclene, optionally substituted arylene, or optionally substituted heteroarylene; R L r each independently represents an optionally substituted C-C 10 selected from cycloalkylene, optionally substituted 3- to 10-membered heterocyclene, optionally substituted arylene, and optionally substituted heteroarylene; R L 1 and R L 2 are each independently hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted C3-C 10 selected from cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or R L a and R L b , R L 1 and R L2 , R L a and R L 1 , R L a and R L 2 , R L b and R L 1 , or R L b and R L 2 together with the atoms to which they are attached, optionally C3-C 20 forming a carbocyclyl or 3- to 20-membered heterocyclyl ring, m L is an integer selected from 1 to 15.

[0226] In some embodiments, A L , W L 1 , W L 2 , and B L are, when they occur, a bond, R L a -R L b , R L a COR L b , R L a C(O)OR L b , R L a C(O)N(R L 1 )R L b , R L a C(S)N(R L 1 )R L b , R L a OR L b , R L a SR L b , R L a SORL b , R L a SO2R L b , R L a SO2N(R L 1 )R L b , R L a N(R L 1 )R L b , R L a N(R L 1 )COR L b , R L a N(R L 1 )CON(R L 2 )R L b , R L a N(R L 1 )C(S)R L b , optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 1-8 membered heteroalkylene, optionally substituted 2-8 membered heteroalkenylene, optionally substituted 2-8 membered heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 is a divalent moiety independently selected from the group consisting of cycloalkylene, optionally substituted 3- to 13-membered heterocyclene, optionally substituted arylene, and optionally substituted heteroarylene.

[0227] In some embodiments, A L , W L 1 , W L2 , and B L are, when they occur, a bond, R L a -R L b , R L a COR L b , R L a C(O)OR L b , R L a C(O)N(R L 1 )R L b , R L a C(S)N(R L 1 )R L b , R L a OR L b , R L a SR L b , R L a SOR L b , R L a SO2R L b , R L a SO2N(R L 1 )R L b , R L a N(R L 1 )R L b , R L a N(R L 1 )COR L b , R L a N(R L 1 )CON(R L 2 )R L b, or R L a N(R L 1 )C(S)RL. In some embodiments, A L , W L 1 , W L 2 , and B L each occurrence is optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 1-8 membered heteroalkylene, optionally substituted 2-8 membered heteroalkenylene, optionally substituted 2-8 membered heteroalkynylene, optionally substituted C1-C8 alkoxyC1-C8 alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C3-C 13 In some embodiments, A is a divalent moiety independently selected from the group consisting of cycloalkylene, optionally substituted 3- to 13-membered heterocyclene, optionally substituted arylene, and optionally substituted heteroarylene. L , W L 1 , W L 2 , and B L is independently selected at each occurrence from the group consisting of optionally substituted C1-C8 alkylene. L , W L 1 , W L 2 , and B L is independently selected at each occurrence from the group consisting of optionally substituted C-C alkenylene. L , W L 1 , W L 2 , and B L is independently selected at each occurrence from the group consisting of optionally substituted 1 to 8 membered heteroalkylene. L , WL 1 , W L 2 , and B L is independently selected at each occurrence from the group consisting of optionally substituted 2- to 8-membered heteroalkenylene. L , W L 1 , W L 2 , and B L is independently selected at each occurrence from the group consisting of optionally substituted 2- to 8-membered heteroalkynylene. L , W L 1 , W L 2 , and B L is independently selected at each occurrence from the group consisting of optionally substituted C1-C8 alkoxyC1-C8 alkylene. L , W L 1 , W L 2 , and B L is independently selected at each occurrence from the group consisting of optionally substituted C-C haloalkylene. L , W L 1 , W L 2 , and B L is independently selected at each occurrence from the group consisting of optionally substituted C1-C8 hydroxyalkylene. L , W L 1 , W L 2 , and B L Each occurrence is an optionally substituted C3-C 13 In some embodiments, A is independently selected from the group consisting of: L , W L 1 , W L 2 , and B Lis independently selected at each occurrence from the group consisting of optionally substituted 3- to 13-membered heterocyclene.

[0228] In some embodiments, R L a and R L b are each independently R L r , optionally substituted (C-C alkylene)-R L r , optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r -(C1-C8 alkylene), or optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted 1-8 membered heteroalkylene, optionally substituted 2-8 membered heteroalkenylene, optionally substituted 2-8 membered heteroalkynylene, 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 C3-C 13 In some embodiments, R is a divalent moiety comprised of cycloalkylene, optionally substituted 3- to 13-membered heterocyclene, optionally substituted arylene, or optionally substituted heteroarylene. L a and R L b are each independently a bond, R L r , optionally substituted (C-C alkylene)-R L r , optionally substituted R L r -(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)-R L r-(C1-C8 alkylene). In some embodiments, R L a and R L b are each independently an optionally substituted C1-C8 alkylene, an optionally substituted C2-C8 alkenylene, an optionally substituted C2-C8 alkynylene, an optionally substituted 1-8 membered heteroalkylene, an optionally substituted 2-8 membered heteroalkenylene, an optionally substituted 2-8 membered heteroalkynylene, an optionally substituted C1-C8 hydroxyalkylene, an optionally substituted C1-C8 alkoxyC1-C8 alkylene, an optionally substituted C1-C8 haloalkylene, an optionally substituted C3-C 13 is selected from a divalent moiety consisting of cycloalkylene, optionally substituted 3- to 13-membered heterocyclene, optionally substituted arylene, or optionally substituted heteroarylene.

[0229] In some embodiments, A L is a bond, —C(═O)—, —C(═O)NH—, —NH—, —NH—C(═O)—, —O—, —(C-C alkylene)-C(═O)NH—, —(C-C alkylene)-C(═O)—, —(C-C alkylene)NH—, —(C-C alkylene)-NH—C(═O)—, —(C-C alkylene)-O—, —C-C alkylene-, or —C-C alkynylene. L is a bond, —(C-C alkylene)-C(═O)NH—, —(C-C alkylene)-C(═O)—, —(C-C alkylene)NH—, —(C-C alkylene)-NH—C(═O)—, —(C-C alkylene)-O—, or —C-C alkylene-. L is a bond. L is —C(═O)—. In some embodiments, A L is —C(═O)NH—. In some embodiments, A L In some embodiments, A is —NH—. Lis —NH—C(═O)—. In some embodiments, A L is —O—. In some embodiments, A L is -(C1-C8 alkylene)-C(=O)NH-. In some embodiments, A L is -(C1-C8 alkylene)-C(=O)-. In some embodiments, A L is -(C1-C8 alkylene)NH-. In some embodiments, A L is -(C1-C8 alkylene)-NH-C(=O)-. In some embodiments, A L is -(C1-C8 alkylene)-O-. In some embodiments, A L is -C1-C8 alkylene-. In some embodiments, A L is -C2-C8 alkynylene-.

[0230] In some embodiments, B L is a bond, -C(=O)-, -C(=O)NH-, -NH-, -NH-C(=O)-, -O-, -(C-C alkylene)-, -C-C alkynylene-, -NH-(C-C alkylene)-, -O-(C-C alkylene)-, -C(=O)-(C-C alkylene), -C(=O)NH-(C-C alkylene), or -NH-C(=O)-(C-C alkylene)-. In some embodiments, B L is a bond, -(C1-C8 alkylene)-, -NH-(C1-C8 alkylene)-, -O-(C1-C8 alkylene)-, -C(=O)-(C1-C8 alkylene), -C(=O)NH-(C1-C8 alkylene), or -NH-C(=O)-(C1-C8 alkylene)-.

[0231] In some embodiments, B L is a bond. In some embodiments, B L is —C(═O)—. In some embodiments, B L is —C(═O)NH—. In some embodiments, B L In some embodiments, B is —NH—. Lis —NH—C(═O)—. In some embodiments, B L is —O—. In some embodiments, B L is -(C1-C8 alkylene)-. In some embodiments, B L is -C2-C8 alkynylene-. In some embodiments, B L is -NH-(C1-C8 alkylene)-. In some embodiments, B L is -O-(C1-C8 alkylene)-. In some embodiments, B L is -C(=O)-(C1-C8 alkylene)-. In some embodiments, B L is -C(=O)NH-(C1-C8 alkylene)-. In some embodiments, B L is -NH-C(=O)-(C1-C8 alkylene)-.

[0232] In some embodiments, W L 1 are each independently R L r or C1-C3 alkylene, W L 2 are each independently a bond, O, or NH. L 1 are each independently C1, C2, or C3 alkylene; W L 2 are each independently a bond, O, or NH. L 1 are each independently C1, C2, or C3 alkylene; W L 2 are each independently O or NH. In some embodiments, W L 1 are each independently C1, C2, or C3 alkylene; W L 2 are each independently O. In some embodiments, W L 1 are each independently C1, C2, or C3 alkylene; W L2 are each independently NH.

[0233] In some embodiments, W L 1 are each independently a bond, O, or NH, and W L 2 are each independently R L r or C1-C3 alkylene. In some embodiments, W L 1 are each independently a bond, O, or NH, and W L 2 are each independently C, C, or C alkylene. L 1 are each independently a bond or O, and W L 2 are each independently C, C, or C alkylene. L 1 are each independently O and W L 2 are each independently C, C, or C alkylene. L 1 are each independently NH and W L 2 are each independently C1, C2, or C3 alkylene.

[0234] In some embodiments, -W L 1 -W L 2 Each - is independently -CH2CH2O- or -CH2-. In some embodiments, -W L 1 -W L 2 Each - is independently -CH2CH2O-CH2. In some embodiments, -W L 1 -W L 2 Each - is independently -CH2-.

[0235] In some embodiments, R L r are each independently an optionally substituted C-C 10 It is selected from cycloalkylene or optionally 3- to 10-membered heterocyclene.

[0236] In some embodiments, R L r are each independently an optionally substituted C-C 10 In some embodiments, R is selected from cycloalkylene. L r are each independently selected from optionally substituted C-C cycloalkylene. L r are each independently selected from optionally substituted C-C cycloalkylene. L r are each independently selected from optionally substituted 3- to 10-membered heterocyclene. L r are each independently selected from optionally substituted 3- to 8-membered heterocyclenes. L r are each independently selected from optionally substituted 4- to 6-membered heterocyclenes. L r are each independently selected from optionally substituted arylene. In some embodiments, R L r are each independently selected from optionally substituted heteroarylene.

[0237] In some embodiments, m L is selected from 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. L is selected from 1 to 13. In some embodiments, m Lis selected from 1 to 12. In some embodiments, m L is selected from 1 to 11. In some embodiments, m L is selected from 1 to 10. In some embodiments, m L is selected from 1 to 9. In some embodiments, m L is selected from 1 to 8. In some embodiments, m L is selected from 1 to 7. In some embodiments, m L is selected from 1 to 6. In some embodiments, m L is selected from 1 to 5. In some embodiments, m L is selected from 1 to 4. In some embodiments, m L is selected from 1 to 3. In some embodiments, m L is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15.

[0238] In some embodiments, the linker L 1 are the formulas (L-1), (L-2), (L-3), (L-4), and (L-5)

[0239] [ka] and During the ceremony, X R ' and Y R 'But independently N, CR R b is selected from A R 1 , B R 1 , C R 1 , and D R 1 are null, O, CO, SO, SO2, and NR when they appear, respectively. R b , and C.R. R b selected independently from RRc, A R2 , B R 2 , C R 2 , D R 2 , and E R 2 are N and CR at their occurrence, respectively. R b are independently selected from A R 3 , B R 3 , C R 3 , D R 3 , and E R 3 are N, O, S, and NR when they appear, respectively. R b , and C.R. R b are independently selected from R R b and R R c is, at each occurrence, 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, optionally substituted C1- independently selected from C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3- to 10-membered carbocyclyl, optionally substituted 3- to 8-membered cycloalkoxy, optionally substituted 3- to 10-membered carbocyclylamino, optionally substituted 4- to 8-membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; m R 1 , nR 1 , o R 1 , and p R 1 is independently selected from 0, 1, 2, 3, 4, and 5.

[0240] In some embodiments, the linker L 1 Formula (L-1'), Formula (L-2'), Formula (L-3'), Formula (L-4'), and Formula (L-5')

[0241] [ka] The rings comprise one or more rings selected from the group consisting of:

[0242] In some embodiments, the linker L 1 teeth,

[0243] [ka] The compound includes one or more rings selected from:

[0244] In some embodiments, the linker L 1 teeth,

[0245] [ka] In some embodiments, the linker L 1 teeth,

[0246] [ka] In some embodiments, the linker L 1 teeth,

[0247] [ka] The compound includes one or more rings selected from:

[0248] In some embodiments, the linker L 1 is -(CH2) p1 C(=O)NH(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 C(=O)NH(CH2) p2 -, -(CH2) p1 NHC(=O)-(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 NHC(=O)-(CH2) p2 -, -(CH2) p1 C(=O)-(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 C(=O)-(CH2) p2 -, -(CH2) p1 NH(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 NH(CH2) p2 -, -(CH2CH2O) p2 -(CH2) p3 - or -(CH2) p2 -, where p1 is an integer selected from 0 to 8, p2 is an integer selected from 1 to 15, and p3 is an integer selected from 0 to 8. In some embodiments, the linker L 1 is -(CH2) p1 C(=O)NH(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 C(=O)NH(CH2) p2 -, -(CH2) p1 NH(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 NH(CH2) p2 -, -(CH2) p1 C(=O)-(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 C(=O)-(CH2)p2 -, -(CH2CH2O) p2 -(CH2) p3 - or -(CH2) p2 -, where p1 is an integer selected from 0 to 8, p2 is an integer selected from 1 to 15, and p3 is an integer selected from 0 to 8. In some embodiments, the linker L 1 is -(CH2) p1 C(=O)NH(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 C(=O)NH(CH2) p2 -, -(CH2) p1 NH(CH2CH2O) p2 -(CH2) p3 -, -(CH2) p1 C(=O)-(CH2CH2O) p2 -(CH2) p3 - or -(CH2) p1 C(=O)-(CH2) p2 -, where p1 is an integer selected from 0 to 8, p2 is an integer selected from 1 to 15, and p3 is an integer selected from 0 to 8. In some embodiments, the linker is -(CH2) p1 C(=O)NH(CH2CH2O) p2 -(CH2) p3 In some embodiments, the linker is (CH2) p1 NHC(=O)-(CH2CH2O) p2 -(CH2) p3 In some embodiments, the linker is (CH2) p1 NHC(=O)-(CH2CH2O) p2 -(CH2) p3 In some embodiments, the linker is -(CH) p1 NHC(=O)-(CH2) p2 In some embodiments, the linker is -(CH) p1 C(=O)-(CH2CH2O) p2 -(CH2) p3 In some embodiments, the linker is -(CH) p1 C(=O)-(CH2)p2 In some embodiments, the linker is -(CH) p1 NH(CH2CH2O) p2 -(CH2) p3 In some embodiments, the linker is -(CH) p1 NH(CH2) p2 In some embodiments, the linker is -(CH2CH2O) p2 -(CH2) p3 In some embodiments, the linker is -(CH) p2 -It is.

[0249] In some embodiments, the linker L 1 is -C(=O)-(CH2) 1-8 -, -(CH2) 1-9 -, -(CH2) 1-2 -C(=O)-NH-(CH2)2-9-, -(CH2) 1-2 -C(=O)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -, -(CH2) 0-1 -C(=O)-(CH2) 1-3 -(OCH2CH2) 1-7 -, -C(=O)-(CH2) 0-3 -(alkenylene)-(CH2) 0-3 -, -C(=O)-(CH2) 0-3 -(alkynylene)-(CH2) 0-3 -, -C(=O)-(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 -, -C(=O)-(CH2) 0-3 -(3-8 membered heterocarbocyclyl)-(CH2) 0-3 -, -(CH2) 0-3 -(alkenylene)-(CH2) 0-3 -, -(CH2) 0-3 -(alkynylene)-(CH2) 0-3 -, -(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 - or -(CH2) 0-3 -(3-8 membered heterocarbocyclyl)-(CH2) 0-3In some embodiments, the linker L 1 is -C(=O)-(CH2) 1-8 -, -(CH2) 1-9 -, -(CH2) 1-2 -C(=O)-NH-(CH2)2-9-, -(CH2) 1-2 -C(=O)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -, -(CH2) 0-1 -C(=O)-(CH2) 1-3 -(OCH2CH2) 1-7 -, -C(=O)-(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 -, -C(=O)-(CH2) 0-3 -(3-8 membered heterocarbocyclyl)-(CH2) 0-3 -, -(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 - or -(CH2) 0-3 -(3-8 membered heterocarbocyclyl)-(CH2) 0-3 In some embodiments, the linker L 1 is -C(=O)-(CH2) 1-8 -, -(CH2) 1-9 -, -(CH2) 1-2 -C(=O)-NH-(CH2)2-9-, -(CH2) 1-2 -C(=O)-NH-(CH2) 1-3 -(OCH2CH2) 1-7 -, -(CH2) 0-1 -C(=O)-(CH2) 1-3 -(OCH2CH2) 1-7 -, -C(=O)-(CH2) 0-3 -(3- to 6-membered carbocyclyl)-(CH2) 0-3 -, -C(=O)-(CH2) 0-3 -(3-6 membered heterocarbocyclyl)-(CH2) 0-3 -, -(CH2) 0-3 -(3-8 membered carbocyclyl)-(CH2) 0-3 - or -(CH2) 0-3 -(3-6 membered heterocarbocyclyl)-(CH2) 0-3 -It is.

[0250] In some embodiments, the linker has the structure -(CH) 1-12 -Has.

[0251] In some embodiments, the linker has the structure -(CH2)1-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 10 -, -(CH2) 11 - or -(CH2) 12 -Has.

[0252] In some embodiments, the linker has the structure -C(=O)(CH) 1-12 -Has.

[0253] In some embodiments, the linker has the structure -C(=O)(CH2)-, -C(=O)(CH2)2-, -C(=O)(CH2)3-, -C(=O)(CH2)4-, -C(=O)(CH2)5-, -C(=O)(CH2)6-, -C(=O)(CH2)7-, -C(=O)(CH2)8-, -C(=O(CH2)9-, C(=O)(CH2) 10 -, -C(=O)(CH2) 11 - or -C(=O)(CH2) 12 -Has.

[0254] In some embodiments, the linker has the structure -(CH) 0-12 NH(CH2) 1-12 -Has.

[0255] In some embodiments, the linker has the structure -(CH) 0-2 NH(CH2) 1-12 -Has.

[0256] In some embodiments, the linker has the structure -NH(CH2)-, -NH(CH2)2-, -NH(CH2)3-, -NH(CH2)4-, -NH(CH2)5-, -NH(CH2)6-, -NH(CH2)7-, -NH(CH2)8-, -NH(CH2)9-, -NH(CH2) 10 -, -NH(CH2) 11 - or -NH(CH2) 12 -Has.

[0257] In some embodiments, the linker has the structure -(CH2)NH(CH2)-, -(CH2)NH(CH2)2-, -(CH2)NH(CH2)3-, -(CH2)NH(CH2)4-, -(CH2)NH(CH2)5-, -(CH2)NH(CH2)6-, -(CH2)NH(CH2)7-, -(CH2)NH(CH2)8-, -(CH2)NH(CH2)9-, -(CH2)NH(CH2) 10 -, -(CH2)NH(CH2) 11 - or -(CH2)NH(CH2) 12 -Has.

[0258] In some embodiments, the linker has the structure -(CH2)2NH(CH2)-, -(CH2)2NH(CH2)2-, -(CH2)2NH(CH2)3-, -(CH2)2NH(CH2)4-, -(CH2)2NH(CH2)5-, -(CH2)2NH(CH2)6-, -(CH2)2NH(CH2)7-, -(CH2)2NH(CH2)8-, -(CH2)2NH(CH2)9-, -(CH2)2NH(CH2) 10 -, -(CH2)2NH(CH2) 11 - or -(CH2)2NH(CH2) 12 -Has.

[0259] In some embodiments, the linker has the structure -(CH) 0-12 NHC(=O)(CH2) 1-12 -Has.

[0260] In some embodiments, the linker has the structure -NHC(=O)(CH2)-, -NHC(=O)(CH2)2-, -NHC(=O)(CH2)3-, -NHC(=O)(CH2)4-, -NHC(=O)(CH2)5-, -NHC(=O)(CH2)6-, -NHC(=O)(CH2)7-, -NHC(=O)(CH2)8-, -NHC(=O)(CH2)9-, -NHC(=O)(CH2) 10 -, -NHC(=O)(CH2) 11 - or -NHC(=O)(CH2) 12 -Has.

[0261] In some embodiments, the linker has the structure -(CH2)NHC(=O)(CH2)-, -(CH2)NHC(=O)(CH2)2-, -(CH2)NHC(=O)(CH2)3-, -(CH2)NHC(=O)(CH2)4-, -(CH2)NHC(=O)(CH2)5-, -(CH2)NHC(=O)(CH2)6-, -(CH2)NHC(=O)(CH2)7-, -(CH2)NHC(=O)(CH2)8-, -(CH2)NHC(=O)(CH2)9-, -(CH2)NHC(=O)(CH2) 10 -, -(CH2)NHC(=O)(CH2) 11 - or -(CH2)NHC(=O)(CH2) 12 -Has.

[0262] In some embodiments, the linker has the structure -(CH2)2NHC(=O)(CH2)-, -(CH2)2NHC(=O)(CH2)2-, -(CH2)2NHC(=O)(CH2)3-, -(CH2)2NHC(=O)(CH2)4-, -(CH2)2NHC(=O)(CH2)5-, -(CH2)2NHC(=O)(CH2)6-, -(CH2)2NHC(=O)(CH2)7-, -(CH2)2NHC(=O)(CH2)8-, -(CH2)2NHC(=O)(CH2)9-, -(CH2)2NHC(=O)(CH2) 10 -, -(CH2)2NHC(=O)(CH2) 11 - or -(CH2)2NHC(=O)(CH2) 12 -Has.

[0263] In some embodiments, the linker has the structure -(CH) 0-12 C(=O)NH(CH2) 1-12 -Has.

[0264] In some embodiments, the linker has the structure -(CH) 0-3 C(=O)NH(CH2) 1-12 -Has.

[0265] In some embodiments, the linker has the structure -C(=O)NH(CH2)-, -C(=O)NH(CH2)2-, -C(=O)NH(CH2)3-, -C(=O)NH(CH2)4-, -C(=O)NH(CH2)5-, -C(=O)NH(CH2)6-, -C(=O)NH(CH2)7-, -C(=O)NH(CH2)8-, -C(=O)NH(CH2)9-, -C(=O)NH(CH2) 10 -, -C(=O)NH(CH2) 11 - or -C(=O)NH(CH2) 12 -Has.

[0266] In some embodiments, the linker has the structure -(CH2)C(=O)NH-(CH2)-, -(CH2)C(=O)NH-(CH2)2-, -(CH2)C(=O)NH(CH2)3-, -(CH2)C(=O)NH(CH2)4-, -(CH2)C(=O)NH(CH2)5-, -(CH2)C(=O)NH(CH2)6-, -(CH2)C(=O)NH(CH2)7-, -(CH2)C(=O)NH(CH2)8-, -(CH2)C(=O)NH(CH2)9-, -(CH2)C(=O)NH(CH2) 10 -, -(CH2)C(=O)NH(CH2) 11 - or -(CH2)C(=O)NH(CH2) 12 -Has.

[0267] In some embodiments, the linker has the structure -(CH2)2C(=O)NH(CH2)-, -(CH2)2C(=O)NH(CH2)2-, -(CH2)2C(=O)NH(CH2)3-, -(CH2)2C(=O)NH(CH2)4-, -(CH2)2C(=O)NH(CH2)5-, -(CH2)2C(=O)NH(CH2)6-, -(CH2)2C(=O)NH(CH2)7-, -(CH2)2C(=O)NH(CH2)8-, -(CH2)2C(=O)NH(CH2)9-, -(CH2)2C(=O)NH(CH2) 10 -, -(CH2)2C(=O)NH(CH2) 11 - or -(CH2)2C(=O)NH(CH2) 12 -Has.

[0268] In some embodiments, the linker has the structure -(CH2)3C(=O)NH(CH2)-, -(CH2)3C(=O)NH(CH2)2-, -(CH2)3C(=O)NH(CH2)3-, -(CH2)3C(=O)NH(CH2)4-, -(CH2)3C(=O)NH(CH2)5-, -(CH2)3C(=O)NH(CH2)6-, -(CH2)3C(=O)NH(CH2)7-, -(CH2)3C(=O)NH(CH2)8-, -(CH2)3C(=O)NH(CH2)9-, -(CH2)3C(=O)NH(CH2) 10 -, -(CH2)3C(=O)NH(CH2) 11 - or -(CH2)3C(=O)NH(CH2) 12 -Has.

[0269] In some embodiments, the linker has the structure -(CH) 0-12 (CH2CH2O) 1-12 (CH2) 0-12 -Has.

[0270] In some embodiments, the linker has the structure -(CH2CH2O) 1-12 (CH2) 0-12 -Has.

[0271] In some embodiments, the linker has the structure -(CH2CH2O) 1-12It has (CH2)2-.

[0272] In some embodiments, the linker has the structure -(CH2CHO)(CH2)2-, -(CH2CHO)2(CH2)2-, -(CH2CHO)3(CH2)2-, -(CH2CHO)4(CH2)2-, -(CH2CHO)5(CH2)2-, -(CH2CHO)6(CH2)2-, -(CH2CHO)7(CH2)2-, -(CH2CHO)8(CH2)2-, -(CH2CHO)9(CH2)2-, -(CH2CHO) 10 (CH2)2-, -(CH2CH2O) 11 (CH2)2-, or -(CH2CH2O) 12 It has (CH2)2-.

[0273] In some embodiments, the linker has the structure -(CH) 0-12 C(=O)(CH2CH2O) 1-12 (CH2) 0-12 -Has.

[0274] In some embodiments, the linker has the structure -C(=O)(CHCHO) 1-12 (CH2) 0-12 -Has.

[0275] In some embodiments, the linker has the structure -C(=O)(CHCHO) 1-12 It has (CH2)2-.

[0276] In some embodiments, the linker has the structure -C(=O)(CH2CHO)(CH2)2-, -C(=O)(CH2CHO)2(CH2)2-, -C(=O)(CH2CHO)3(CH2)2-, -C(=O)(CH2CHO)4(CH2)2-, -C(=O)(CH2CHO)5(CH2)2-, -C(=O)(CH2CHO)6(CH2)2-, -C(=O)(CH2CHO)7(CH2)2-, -C(=O)(CH2CHO)8(CH2)2-, -C(=O)(CH2CHO)9(CH2)2-, -C(=O)(CH2CHO) 10 (CH2)2-, -C(=O)(CH2CH2O)11 (CH2)2-, or -C(=O)(CH2CH2O) 12 It has (CH2)2-.

[0277] In some embodiments, the linker has the structure -(CH) 0-12 NH(CH2CH2O) 1-12 It has (CH2)2-.

[0278] In some embodiments, the linker has the structure -(CH) 0-2 NH(CH2CH2O) 1-12 It has (CH2)2-.

[0279] In some embodiments, the linker has the structure -NH(CH2CHO)(CH2)2-, -NH(CH2CHO)2(CH2)2-, -NH(CH2CHO)3(CH2)2-, -NH(CH2CHO)4(CH2)2-, -NH(CH2CHO)5(CH2)2-, -NH(CH2CHO)6(CH2)2-, -NH(CH2CHO)7(CH2)2-, -NH(CH2CHO)8(CH2)2-, -NH(CH2CHO)9(CH2)2-, -NH(CH2CHO) 10 (CH2)2-, -NH(CH2CH2O) 11 (CH2)2-, or -NH(CH2CH2O) 12 It has (CH2)2-.

[0280] In some embodiments, the linker has the structure -(CH2)NH(CH2CHO)(CH2)2-, -(CH2)NH(CH2CHO)2(CH2)2-, -(CH2)NH(CH2CHO)3(CH2)2-, -(CH2)NH(CH2CHO)4(CH2)2-, -(CH2)NH(CH2CHO)5(CH2)2-, -(CH2)NH(CH2CHO)6(CH2)2-, -(CH2)NH(CH2CHO)7(CH2)2-, -(CH2)NH(CH2CHO)8(CH2)2-, -(CH2)NH(CH2CHO)9(CH2)2-, -(CH2)NH(CH2CHO) 10 (CH2)2-, -(CH2)NH(CH2CH2O) 11(CH2)2-, or -(CH2)NH(CH2CH2O) 12 It has (CH2)2-.

[0281] In some embodiments, the linker has the structure -(CH2)2NH(CH2CHO)(CH2)2-, -(CH2)2NH(CH2CHO)2(CH2)2-, -(CH2)2NH(CH2CHO)3(CH2)2-, -(CH2)2NH(CH2CHO)4(CH2)2-, -(CH2)2NH(CH2CHO)5(CH2)2-, -(CH2)2NH(CH2CHO)6(CH2)2-, -(CH2)2NH(CH2CHO)7(CH2)2-, -(CH2)2NH(CH2CHO)8(CH2)2-, -(CH2)2NH(CH2CHO)9(CH2)2-, -(CH2)2NH(CH2CHO) 10 (CH2)2-, -(CH2)2NH(CH2CH2O) 11 (CH2)2-, or -(CH2)2NH(CH2CH2O) 12 It has (CH2)2-.

[0282] In some embodiments, the linker has the structure -(CH) 0-12 NHC(=O)(CH2CH2O) 1-12 It has (CH2)2-.

[0283] In some embodiments, the linker has the structure -NHC(=O)(CH2CHO)(CH2)2-, -NHC(=O)(CH2CHO)2(CH2)2-, -NHC(=O)(CH2CHO)3(CH2)2-, -NHC(=O)(CH2CHO)4(CH2)2-, -NHC(=O)(CH2CHO)5(CH2)2-, -NHC(=O)(CH2CHO)6(CH2)2-, -NHC(=O)(CH2CHO)7(CH2)2-, -NHC(=O)(CH2CHO)8(CH2)2-, -NHC(=O)(CH2CHO)9(CH2)2-, -NHC(=O)(CH2CHO) 10 (CH2)2-, -NHC(=O)(CH2CH2O) 11 (CH2)2-, or -NHC(=O)(CH2CH2O) 12It has (CH2)2-.

[0284] In some embodiments, the linker has the structure -(CH2)NHC(=O)(CH2CHO)(CH2)2-, -(CH2)NHC(=O)(CH2CHO)2(CH2)2-, -(CH2)NHC(=O)(CH2CHO)3(CH2)2-, -(CH2)NHC(=O)(CH2CHO)4(CH2)2-, -(CH2)NHC(=O)(CH2CHO)4(CH2)2-, -(CH2)NHC(=O)(CH2C H2O)5(CH2)2-, -(CH2)NHC(=O)(CH2CH2O)6(CH2)2-, -(CH2)NHC(=O)(CH2CH2O)7(CH2)2-, -(CH 2)NHC(=O)(CH2CH2O)8(CH2)2-, -(CH2)NHC(=O)(CH2CH2O)9(CH2)2-, -(CH2)NHC(=O)(CH2CH2O) 10 (CH2)2-, -(CH2)NHC(=O)(CH2CH2O) 11 (CH2)2-, or -(CH2)NHC(=O)(CH2CH2O) 12 It has (CH2)2-.

[0285] In some embodiments, the linker has the structure -(CH2)2NHC(=O)(CH2CH2O)(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)2(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)3(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)4(CH2)2-, -(CH2)2NHC(=O)(CH2C H2O)5(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)6(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)7(CH2)2-, -(CH2 )2NHC(=O)(CH2CH2O)8(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O)9(CH2)2-, -(CH2)2NHC(=O)(CH2CH2O) 10 (CH2)2-, -(CH2)2NHC(=O)(CH2CH2O) 11 (CH2)2-, or -(CH2)2NHC(=O)(CH2CH2O) 12 It has (CH2)2-.

[0286] In some embodiments, the linker has the structure -(CH) 0-12 C(=O)NH(CH2CH2O) 1-12 It has (CH2)2-.

[0287] In some embodiments, the linker has the structure -(CH) 0-2 C(=O)NH(CH2CH2O) 1-12 It has (CH2)2-.

[0288] In some embodiments, the linker has the structure -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO)(CH)-, -C(=O)NH(CHCHO) 10 (CH2)2-, -C(=O)NH(CH2CH2O) 11 (CH2)2-, or -C(=O)NH(CH2CH2O) 12 It has (CH2)2-.

[0289] In some embodiments, the linker has the structure -(CH2)C(=O)NH(CH2CHO)(CH2)2-, -(CH2)C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)C(=O)NH(CH2CHO)3(CH2)2-, -(CH2)C(=O)NH(CH2CHO)4(CH2)2-, -(CH2)C(=O)NH(CH2CHO)4(CH2)2-, -(CH2)C(=O)NH(CH2C H2O)5(CH2)2-, -(CH2)C(=O)NH(CH2CH2O)6(CH2)2-, -(CH2)C(=O)NH(CH2CH2O)7(CH2)2-, -(CH 2)C(=O)NH(CH2CH2O)8(CH2)2-, -(CH2)C(=O)NH(CH2CH2O)9(CH2)2-, -(CH2)C(=O)NH(CH2CH2O) 10(CH2)2-, -(CH2)C(=O)NH(CH2CH2O) 11 (CH2)2-, or -(CH2)C(=O)NH(CH2CH2O) 12 It has (CH2)2-.

[0290] In some embodiments, the linker has the structure -(CH2)2C(=O)NH(CH2CHO)(CH2)2-, -(CH2)2C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)2C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)2C(=O)NH(CH2CHO)3(CH2)2-, -(CH2)2C(=O)NH(CH2CHO)4(CH2)2-, -(CH2)2C(=O)NH(CH2C H2O)5(CH2)2-, -(CH2)2C(=O)NH(CH2CH2O)6(CH2)2-, -(CH2)2C(=O)NH(CH2CH2O)7(CH2)2-, -(CH2 )2C(=O)NH(CH2CH2O)8(CH2)2-, -(CH2)2C(=O)NH(CH2CH2O)9(CH2)2-, -(CH2)2C(=O)NH(CH2CH2O) 10 (CH2)2-, -(CH2)2C(=O)NH(CH2CH2O) 11 (CH2)2-, or -(CH2)2C(=O)NH(CH2CH2O) 12 It has (CH2)2-.

[0291] In some embodiments, the linker has the structure -(CH2)3C(=O)NH(CH2CHO)(CH2)2-, -(CH2)3C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)3C(=O)NH(CH2CHO)2(CH2)2-, -(CH2)3C(=O)NH(CH2CHO)3(CH2)2-, -(CH2)3C(=O)NH(CH2CHO)4(CH2)2-, -(CH2)3C(=O)NH(CH2C H2O)5(CH2)2-, -(CH2)3C(=O)NH(CH2CH2O)6(CH2)2-, -(CH2)3C(=O)NH(CH2CH2O)7(CH2)2-, -(CH2 )3C(=O)NH(CH2CH2O)8(CH2)2-, -(CH2)3C(=O)NH(CH2CH2O)9(CH2)2-, -(CH2)3C(=O)NH(CH2CH2O) 10 (CH2)2-, -(CH2)3C(=O)NH(CH2CH2O)11 (CH2)2-, or -(CH2)3C(=O)NH(CH2CH2O) 12 It has (CH2)2-.

[0292] In some embodiments, the linker L 1 is the structure -(CH2) 0-12 NH(CH2) 2-12 In some embodiments, the linker has the structure -NH(CH2)2NH-, -NH(CH2)3NH-, -NH(CH2)4NH-, -NH(CH2)5NH-, -NH(CH2)6NH-, -NH(CH2)7NH-, -NH(CH2)8NH-, -NH(CH2)9NH-, -NH(CH2) 10 NH-, -NH(CH2) 11 NH- or -NH(CH2) 12 In some embodiments, the linker has the structure -(CH) 0-12 NHC(=O)(CH2) 2-12 In some embodiments, the linker has the structure -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 In some embodiments, the linker has the structure -(CH) 0-12 NH(CH2) 2-12 It has C(=O)NH-. In some embodiments, 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 (=O)NH-. In some embodiments, the linker has the structure -(CH) 0-12 C(=O)NH(CH2) 2-12 It has 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)N H-, -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 It has (=O)NH-. In some embodiments, 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) 12It has (=O)NH-. In some embodiments, 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) 10 C(=O)NH-, -(CH2)2C(=O)NH(CH2) 11 C(=O)NH-, or -(CH2)2C(=O)NH(CH2) 12 It has (=O)NH-. In some embodiments, 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 Has (=O)NH-.

[0293] In some embodiments, the linker L 1 is the structure -(CH2) 0-12 NH(CH2CH2O) 1-12In some embodiments, the linker has the structure -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO)(CH)NH-, -NH(CHCHO) 10 (CH2)2NH-, -NH(CH2CH2O) 11 (CH2)2NH-, or -NH(CH2CH2O) 12 In some embodiments, the linker has the structure -(CH)NH-. 0-12 NHC(=O)(CH2CH2O) 1-12 In some embodiments, the linker has the structure -(CH)NH-. 0-12 NH(CH2CH2O) 1-12 In some embodiments, the linker has the structure -NH(CHCHO)(CH)C(=O)NH-, -NH(CHCHO)(CH)C(=O)NH-, -NH(CHCHO)(CH)C(=O)NH-, -NH(CHCHO)(CH)C(=O)NH-, -NH(CHCHO)4(CH)C(=O)NH-, -NH(CHCHO)5(CH)C(=O)NH-, -NH(CHCHO)6(CH)C(=O)NH-, -NH(CHCHO)7(CH)C(=O)NH-, -NH(CHCHO)8(CH)C(=O)NH-, -NH(CHCHO)9(CH)C(=O)NH-, -NH(CHCHO) 10 (CH2)2C(=O)NH-, -NH(CH2CH2O) 11 (CH2)2C(=O)NH-, or -NH(CH2CH2O) 12 (CH2)2C(=O)NH-. In some embodiments, the linker has the structure -(CH2) 0-12 C(=O)NH(CH2CH2O) 1-12In some embodiments, the linker has the structure -C(=O)NH(CHCHO)(CH)C(=O)NH-, -C(=O)NH(CHCHO)(CH)C(=O)NH-, -C(=O)NH(CHCHO)(CH)C(=O)NH-, -C(=O)NH(CHCHO)(CH)C(=O)NH-, -C(=O)NH(CHCHO)(CH)C(=O)NH-, -C(=O)NH(CHCHO)(CH)C(=O)NH-, -C(=O)NH(CHCHO) )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 In some embodiments, the linker has the structure -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH- )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) 12In some embodiments, the linker has the structure -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO)(CH)C(=O)NH-, -(CH)C(=O)NH(CHCHO) )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-, -(C H2)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 In some embodiments, the linker has the structure -(CH2)3C(=O)NH(CH2CHO)(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CHO)2(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CHO)2(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CHO)3(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CHO)4(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CHO)4(CH2)2C(=O)NH-, -(CH2)3C(=O)NH(CH2CHO) )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-, -(C H2)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(CH2C H2O) 11 (CH2)2C(=O)NH-, or -(CH2)3C(=O)NH(CH2CH2O) 12 It has (CH2)2C(=O)NH-.

[0294] In some embodiments, representative DDB1 binding moieties with linker components are set forth in Table 2.

[0295] [Table 2-1]

[0296] [Table 2-2]

[0297] [Table 2-3]

[0298] [Table 2-4]

[0299] [Table 2-5]

[0300] [Table 2-6]

[0301] [Table 2-7]

[0302] [Table 2-8]

[0303] Table 2-9

[0304] Table 2-10

[0305] Table 2-11

[0306] Table 2-12

[0307] Table 2-13

[0308] Table 2-14

[0309] Table 2-15

[0310] Table 2-16

[0311] Table 2-17

[0312] Table 2-18

[0313] Table 2-19

[0314] [Table 2-20]

[0315] [Table 2-21]

[0316] [Table 2-22]

[0317] [Table 2-23]

[0318] Target protein binding moiety In some embodiments, disclosed herein are compounds comprising a target protein binding moiety. The compounds may comprise heterobifunctional molecules comprising the target protein binding moiety.

[0319] In some embodiments, a target protein is disclosed herein. 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 comprises CDK4. In some embodiments, the target protein comprises CDK6. In some embodiments, the target protein comprises CDK9. In some embodiments, the target protein comprises a CDK, CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CDK12, or CDK13.

[0320] In some embodiments, A is a target protein binding moiety that comprises a cyclin-dependent kinase 4 (CDK4) binding moiety or a cyclin-dependent kinase 6 (CDK6) binding moiety.

[0321] In some embodiments, A is a target protein binding moiety comprising a CBP and / or p300 binding moiety or a BRD4 binding moiety. In some embodiments, A is a target protein binding moiety comprising a CBP and / or p300 binding moiety. In some embodiments, A is a target protein binding moiety comprising a BRD4 binding moiety.

[0322] In some embodiments, A is a group of formula (A):

[0323] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X A 1 , X A 2 , Y A 1 , and Y A 2 However, each is independently CR A 4 or N, R A 1 But NR A 5 R A 6 , N(R A 5 )C(=O)R A 6 , aryl, or heteroaryl; R A 2 is hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C heteroalkyl, C-C cycloalkyl, or C-C heterocyclyl; or R A1 and R A 2 optionally, taken together with the atom to which they are attached, form an optionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl; L 3 But -R A 3A_ R A 3B -, and R A 3A and R A 3B are each independently a bond, -O-, -S-, or -NR A 7 -, -C(=O)-, -C(=O)NR A 7 -, -S(=O)-, -S(=O)NR A 7 -, -S(=O)2-, -S(=O)2NR A 7 -, C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, C2-C 12 heterocyclene, arylene, or heteroarylene; R A 4 are independently hydrogen, halogen, CN, NO2, NR A 8 R A 9 , -C(=O)R A 10 , -C(=O)OR A 10 , -C(=O)NR A 8 R A 9 , -NR A 8 C(=O)R A 10, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R A 5 and R A 6 is independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or R A 5 and R A 6 optionally, together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; R A 7 , R A 8 , R A 9 , and R A 10 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 hetero, aryl, or heteroaryl; R A 8 and R A 9 taken together with the atom to which they are attached optionally form a 3- to 20-membered heterocyclyl ring.

[0324] In some embodiments, R A 1 and RA2 together with the atom to which they are attached form an optionally substituted heterocyclyl or heteroaryl.

[0325] In some embodiments, the target protein binding moiety of Formula (A) is represented by Formula (A1), (A2), or (A3):

[0326] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Y A 3 But, CR A 19 or N, R A 11 , R A 14 , and R A 18 are each independently selected from hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxyalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or C-C heterocyclyl, aryl, or heteroaryl; R A 12 and R A 15 However, each independently, R A 20 , C.O.R. A 20 , CO2R A 20 , or CONR A 20 R A 21 Selected from R A 20 and R A 21 are each independently selected from hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxyalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or C-C heterocyclyl; or R A 20 and R A 21optionally, together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; R A 13 is hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 heteroalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl; R A 16 and R A 17 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl, aryl, or heteroaryl; or R A 16 and R A 17 taken together with the atom to which they are attached optionally form a 3- to 8-membered cycloalkyl or a 3- to 8-membered heterocyclyl; R A 19 is independently selected from hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxyalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or C-C heterocyclyl; m A is 0, 1, or 2.

[0327] In some embodiments, the target protein binding moiety of Formula (A) has the structure of Formula (A1), or a pharmaceutically acceptable salt or solvate thereof:

[0328] In some embodiments, the target protein binding moiety of Formula (A) has the structure of Formula (A2), or a pharmaceutically acceptable salt or solvate thereof:

[0329] In some embodiments, the target protein binding moiety of Formula (A) has the structure of Formula (A3), or a pharmaceutically acceptable salt or solvate thereof:

[0330] In some embodiments, m A is 1.

[0331] In some embodiments, R A 1 is aryl or heteroaryl.

[0332] In some embodiments, the target protein binding moiety of Formula (A) has Formula (A4):

[0333] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, X A 3 But, CR A 25 or N, R A 22 is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R A 23 , R A 24 , and R A 25are each independently selected from hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C alkoxyalkyl, C-C heteroalkyl, C-C alkoxy, C-C alkylamino, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, or C-C heterocyclyl;

[0334] In some embodiments, X A 1 , X A 2 , and X A 3 are each N. In some embodiments, X A 1 is N. In some embodiments, X A 2 is N. In some embodiments, X A 3 is N.

[0335] In some embodiments, X A 1 is CR A 4 In some embodiments, X A 2 is CR A 4 In some embodiments, X A 3 is CR A 4 In some embodiments, X A 1 is CH. In some embodiments, X A 2 is CH. In some embodiments, X A 3 is CH.

[0336] In some embodiments, Y A 1 , Y A 2 , and Y A 3 are each N. In some embodiments, YA 1 is N. In some embodiments, Y A 2 is N. In some embodiments, Y A 3 is N.

[0337] In some embodiments, Y A 1 is CR A 4 In some embodiments, Y A 2 is CR A 4 In some embodiments, Y A 3 is CR A 4 In some embodiments, Y A 1 , Y A 2 , and Y A 3 are CH, respectively.

[0338] In some embodiments, R A 2 , R A 4 , R A 13 , R A 19 , R A 23 , and R A 24 are each independently selected from hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl. A 2 , R A 4 , R A 13 , R A 19 , R A 23 , and R A 24are each independently selected from hydrogen, F, Cl, CH3, CH2CH3, CH(CH3)2, CF3, CH2F, cyclopropyl, or cyclobutyl.

[0339] In some embodiments, R A 11 and R A 14 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl. A 11 and R A 14 are each independently selected from C1-C8 alkyl or C3-C8 cycloalkyl. A 11 and R A 14 are each independently selected from C1-C8 alkyl. A 11 and R A 14 are each independently selected from C3-C8 cycloalkyl.

[0340] In some embodiments, R A 12 and R A 15 are each independently R A 20 , C.O.R. A 20 , or CONR A 20 R A 21 Selected from R A 20 and R A 21 are each independently selected from C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl. A 12 and R A 15 are independently COR A 20 or CONRA 20 R A 21 Selected from R A 20 and R A 21 are each independently selected from C1-C8 alkyl.

[0341] In some embodiments, R A 16 and R A 17 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl. A 16 and R A 17 are each independently selected from C1-C8 alkyl. A 16 and R A 17 are each independently selected from C-C cycloalkyl. A 16 and R A 17 are each independently selected from C2-C8 heterocyclyl.

[0342] In some embodiments, R A 16 and R A 17 are taken together with the atoms to which they are attached optionally to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl ring. In some embodiments, R A 16 and R A 17 optionally form a 3- to 6-membered cycloalkyl together with the atom to which they are attached. In some embodiments, R A 16 and R A 17 are taken together with the atoms to which they are attached optionally to form a 3- to 6-membered heterocyclyl ring. A18 and R A 22 are each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclyl. A 18 and R A 22 are each independently selected from H, CH3, CH2CH3, CH(CH3)2, CF3, CHF2, cyclopropyl, or cyclobutyl.

[0343] In some embodiments, L 3 -R A 3A_ R A 3B -, and R A 3A and R A 3B each independently represents a bond, -O-, -S-, or -NR A 7 -, -C(=O)-, -C(=O)NR A 7 -, -S(=O)-, -S(=O)NR A 7 -, -S(=O)2-, -S(=O)2NR A 7 -, C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, C2-C 12 In some embodiments, R is a heterocyclene, an arylene, or a heteroarylene. A 3A and R A 3B each independently represents a bond, -O-, -S-, or -NR A 7 -, -C(=O)-, -C(=O)NR A 7 -, -S(=O)-, -S(=O)NR A 7 -, -S(=O)2-, -S(=O)2NR A7 In some embodiments, R A 3A and R A 3B are each independently C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, C3-C 13 It is heterocyclene, arylene, or heteroarylene.

[0344] In some embodiments, R A 3A is a bond, -O-, -S-, -NR A 7 -, -C(=O)-, -C(=O)NR A 7 -, -S(=O)-, -S(=O)NR A 7 -, -S(=O)2-, -S(=O)2NR A 7 - selected from R A 3B is C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, C3-C 13 In some embodiments, R is selected from heterocyclene, arylene, or heteroarylene. A 3B is a bond, -O-, -S-, -NR A 7 -, -C(=O)-, -C(=O)NR A 7 -, -S(=O)-, -S(=O)NR A 7 -, -S(=O)2-, -S(=O)2NR A 7 - selected from R A 3Ais C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, C3-C 13 It is selected from heterocyclene, aryl, or heteroarylene.

[0345] In some embodiments, L 3 is a bond, C1-C3 alkylene, C3-C8 cycloalkylene, C2-C8 heteroalkylene, C2-C8 heterocyclene, -(C1-C3 alkylene)-(C3-C8 cycloalkylene)-, -(C1-C3 alkylene)-(C2-C8 heterocyclene)-, or -(C1-C3 alkylene)-(C2-C8 heteroalkylene).

[0346] In some embodiments, L 3 is a bond. In some embodiments, L 3 is C1-C3 alkylene. In some embodiments, L 3 is C-C cycloalkylene. In some embodiments, L 3 is C2-C8 heteroalkylene. 3 is a C2-C8 heterocyclene. 3 is -(C1-C3 alkylene)-(C3-C8 cycloalkylene)-. In some embodiments, L 3 is -(C1-C3 alkylene)-(C2-C8 heterocyclene)-. In some embodiments, L 3 is -(C1-C3 alkylene)-(C2-C8 heteroalkylene).

[0347] In some embodiments, L 3 is a bond,

[0348] [ka] In some embodiments, L 3 teeth,

[0349] [ka] In some embodiments, L 3 teeth,

[0350] [ka] In some embodiments, L 3 teeth,

[0351] [ka] In some embodiments, L 3 teeth,

[0352] [ka] is.

[0353] In some embodiments, the target protein binding moiety of formula (A) is

[0354] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0355] In some embodiments, A is a group represented by formula (B-1):

[0356] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, Y B 1 But CHR B 4 or NR B4 and Y B 2is CH or N, Y B 3 But, CR B 2 or N, R B 1 is an optionally substituted 5-6 membered heteroaryl; R B 2 are each independently hydrogen, halogen, CN, NO, C-C alkyl, C-C haloalkyl, C-C alkoxy, C-C heteroalkyl, C-C cycloalkyl, or C-C heterocyclyl; R B 4 But -C(=O)R B 8 , -C(=O)OR B 8 , -C(=O)NR B 6 R B 7 , or -NR B 6 C(=O)R B 8 and L 4 But -R B 3A_ R B 3B -, and R B 3A and R B 3B are each independently absent, a bond, -O-, -S-, or -NR B 5 -, -C(=O)-, -C(=O)NR B 5 -, -S(=O)-, -S(=O)NR B 5 -, -S(=O)2-, -S(=O)2NR B 5 -, C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, C2-C13 heterocyclene, arylene, or heteroarylene; R B 5 , R B 6 , R B 7 , and R B 8 are each independently selected from C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R B 6 and R B 7 optionally, together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; x 3B is 0, 1, or 2.

[0357] In some embodiments, Y B 2 is CH. In some embodiments, Y B 2 is N.

[0358] In some embodiments, x 3B is 1 or 2. In some embodiments, x 3B is 0. In some embodiments, x 3B is 1. In some embodiments, x 3B is 2.

[0359] In some embodiments, Y B 2 is N and x 3B is 1.

[0360] In some embodiments, Y B 1 is C(R B 4 )2. In some embodiments, Y B 1 is NR B4is.

[0361] In some embodiments, Y B 3 is CR B 2 In some embodiments, Y B 2 is N.

[0362] In some embodiments, A is a group represented by formula (B-2):

[0363] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0364] In some embodiments, R B 4 is -C(=O)R B 8 , -C(=O)OR B 8 , or -C(=O)NR B 6 R B 7 is.

[0365] In some embodiments, R B 4 is -C(=O)R B 8 and R B 8 is C1-C8 alkyl.

[0366] In some embodiments, R B 4 is -C(=O)NHR B 8 and R B 8 is C1-C8 alkyl.

[0367] In some embodiments, R B 2is halogen, CN, NO, C-C alkyl, C-C haloalkyl, or C-C alkoxy. B 2 is halogen, C-C alkyl, or C-C haloalkyl. B 2 is Cl, F, Br, CH3, CF3, or CHF2.

[0368] In some embodiments, R B 1 is an optionally substituted 5-membered heteroaryl selected from pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. B 1 is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, or tetrazolyl. B 1 is an optionally substituted pyrazolyl. In some embodiments, R B 1 is a methyl-substituted pyrazolyl.

[0369] In some embodiments, L 4 is a bond, C1-C3 alkylene, C3-C8 cycloalkylene, C2-C8 heteroalkylene, C2-C8 heterocyclene, -(C1-C3 alkylene)-(C3-C8 cycloalkylene)-, -(C1-C3 alkylene)-(C2-C8 heterocyclene)-, or -(C1-C3 alkylene)-(C2-C8 heteroalkylene)-.

[0370] In some embodiments, L 4 is a bond,

[0371] [ka] In some embodiments, L 4 teeth,

[0372] [ka] In some embodiments, L 4 is a bond.

[0373] In some embodiments, the target protein binding moiety is

[0374] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0375] In some embodiments, the target protein binding moiety is

[0376] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0377] In some embodiments, A is of formula (C-1), (C-2), (C-3), (C-4), (C-5), or (C-6):

[0378] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony,

[0379] [ka] but,

[0380] [ka] and X C 1 and X C 2However, each is independently CR C 3 or N, Y C 1 is O, S, or -C(R C 2 )=C(R C 2 )- and Y C 2 However, C(R C 7 )2 or NR C 7 and R C 1 is hydrogen or optionally substituted C6-C 10 aryl or 5- to 10-membered heteroaryl; R C 2 are independently hydrogen, halogen, CN, NO2, NR C 4 R C 5 , -C(=O)R C 6 , -C(=O)OR C 4 , -C(=O)NR C 4 R C 5 , -OC(=O)R C 6 , -N(R C 4 )C(=O)R C 6 , C1-C8 alkyl, C1-C8 heteroalkyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, or C1-C8 alkylaryl; R C 3 are independently hydrogen, halogen, CN, NO2, NR C 4 R C 5, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, aryl, or heteroaryl; R C 4 , R C 5 , and R C 6 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R C 4 and R C 5 optionally, together with the atoms to which they are attached, form a 3- to 20-membered heterocyclyl ring; R C 7 are independently hydrogen, NR C 4 R C 5 , OR C 4 , -C(=O)R C 6 , -C(=O)OR C 6 , -C(=O)NR C 4 R C 5 , -(C1-C8 alkyl)-C(=O)NR C 4 R C , -OC(=O)R C 6 , -N(R C 8 )C(=O)R C 6 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, or R C 7 two of which, together with the atom to which they are attached, optionally form a C3-C8 cycloalkyl or a C2-C8 heterocyclyl; x 4C is 1, 2, or 3.

[0381] In some embodiments,

[0382] [ka] teeth,

[0383] [ka] In some embodiments,

[0384] [ka] teeth,

[0385] [ka] is.

[0386] In some embodiments, X C 1 and X C 2 are each independently N. In some embodiments, X C 1 and X C 2 are each independently CR C 3 In some embodiments, X C 1 is N and X C 2 is CR C 3 In some embodiments, X C 2 is N and X C 1 is CR C 3 is.

[0387] In some embodiments, Y C 1is S. In some embodiments, Y C 1 is O. In some embodiments, Y C 1 is -C=C-. In some embodiments, Y C 1 is -C(R C 2 )=C(R C 2 )-. In some embodiments, Y C 2 is C(R C 7 )2. In some embodiments, Y C 2 is NR C 7 In some embodiments, R C 3 is hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl. C 2 are each independently hydrogen, halogen, C-C alkyl, C-C alkynyl, C-C haloalkyl, C-C alkoxy, C-C alkoxyalkyl, aryl, or heteroaryl. C 1 is H. In some embodiments, R C 1 is an optionally substituted C6-C 10 aryl, optionally 1 to 4 halogens, CN, NO2, NR C 4 R C 5 , -C(=O)R C 6 , -C(=O)OR C 6 , -C(=O)NR C 4 R C 5 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl. 4C is 2 and RC 2 are each independently C1-C8 alkyl. 4C is 2 and R C 2 are each independently C1-C8 alkoxy.

[0388] In some embodiments, R C 2 are each independently halogen, C-C alkyl, C-C alkynyl, C-C haloalkyl, C-C alkoxy, C-C alkoxyalkyl, aryl, or heteroaryl. C 2 are each independently halogen, C-C alkyl, C-C haloalkyl, C-C alkoxy, or C-C alkoxyalkyl. C 2 are each independently a halogen. C 2 are each independently CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH(CH2)2, CH2Ph. In some embodiments, R C 2 are each independently C1-C8 alkoxy. C 2 are each independently OCH, OCHCH, OCH(CH), OC(CH), or OCH(CH). In some embodiments, R C 2 are each independently C2-C8 alkynyl.

[0389] In some embodiments, R C 2 are each independently -C≡C-, or

[0390] [ka] In some embodiments, R C 2are each independently heteroaryl. In some embodiments, R C 2 are each independently a 5-membered heteroaryl. C 2 are each independently pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. C 2 are each independently a 6-membered heteroaryl. C 2 are each independently pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, or triazinyl. 4 is 2 and R C 2 are each independently C1-C8 alkyl. 4 is 2 and R C 2 are each independently C1-C8 alkoxy. C 2 are each independently C1-C8 alkyl. In some embodiments, R C 2 are each independently CH3, CH2CH3, CH(CH3)2, or C(CH3)3.

[0391] In some embodiments, R C 3 is halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl. C 3 are each independently a halogen. C 3 are each independently C1-C8 alkyl. In some embodiments, R C 3are each independently CH3, CH2CH3, CH(CH3)2, or C(CH3)3.

[0392] In some embodiments, R C 1 is H. In some embodiments, R C 1 is an optionally substituted C6-C 10 aryl, optionally 1 to 4 halogens, CN, NO2, NR C 4 R C 5 , -C(=O)R C 6 , -C(=O)OR C 6 , -C(=O)NR C 4 R C 5 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl. C 1 is an optionally substituted C6 aryl, optionally containing 1 to 4 halogens, CN, NO2, NR C 4 R C 5 , substituted with C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl.

[0393] In some embodiments, R C 1 optionally 1 to 4 halogens, CN, NO2, NR C 4 R C 5 , an optionally substituted 5-10 membered heteroaryl substituted with C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl.

[0394] In some embodiments, the target protein binding moiety is

[0395] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0396] In some embodiments, the target protein binding moiety is

[0397] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0398] In some embodiments, the target protein is described in International Publication WO2020173440, which is incorporated by reference in its entirety.

[0399] In some embodiments, the target protein comprises cyclin D. In some embodiments, the target protein is cyclin D1. In some embodiments, the target protein is cyclin D2. In some embodiments, the target protein is cyclin D3.

[0400] In some embodiments, the target protein comprises a retinoblastoma (RB) protein. In some embodiments, the target protein is RB1. In some embodiments, the target protein is p107 (RBL1). In some embodiments, the target protein is p130 (RBL2).

[0401] Further examples of target protein binding moieties include haloalkane halogenase 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 the aryl hydrocarbon receptor (AHR). Some compounds comprise small molecule target protein binding moieties. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates, and polymorphs of these compositions, as well as other small molecules that can target proteins of interest.

[0402] In some embodiments, the target protein binding moiety comprises a heat shock protein (HSP; e.g., HSP90) binder or inhibitor. HSP90 inhibitors used herein include, but are not limited to, N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide, 8-[(2,4-dimethylphenyl)sulfanyl]-3-pent-4-yn-1-yl-3H-purin-6-amine, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxid These include, but are not limited to, sazol-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 any of its derivatives (e.g., 17-alkylamino-17-desmethoxygeldanamycin).

[0403] In some embodiments, N-[4-(3H-imidazo[4,5-C]pyridin-2-yl)-9H-fluoren-9-yl]-succinamide is bonded to a linker described herein via its terminal amide group. In some embodiments, 8-[(2,4-dimethylphenyl)sulfanyl]-3-pent-4-yn-1-yl-3H-purin-6-amine is bonded to a linker described herein via its terminal amide group. In some embodiments, 5-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide is bonded to a linker described herein via its terminal amide group (e.g., at the amine or alkyl group on the amine). In some embodiments, PU3 is bonded to a 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 any of its derivatives is attached to a linker described herein by an amide group.

[0404] In some embodiments, the target protein binding moiety comprises a kinase inhibitor or a phosphatase inhibitor. In some embodiments, the target protein binding moiety comprises 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, the kinase inhibitor is a Met inhibitor. In some embodiments, the kinase inhibitor is an Abl inhibitor. In some embodiments, the kinase inhibitor is a B-Raf / Mek inhibitor.

[0405] Non-limiting examples of kinase inhibitors include erlotinib, sunitinib, sorafenib, dasatinib, lapatinib, U09-CX-5279, Y1W, Y1X, 1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea, 2,6-naphthyridine, 07U, YCF, XK9, NXP, N-{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 foretinib.

[0406] In some embodiments, erlotinib is coupled to a linker described herein through its ether group. In some embodiments, sunitinib is coupled to a linker described herein through its pyrrole moiety. In some embodiments, sorafenib is coupled to a linker described herein through its phenyl moiety. In some embodiments, dasatinib is coupled to a linker described herein through its pyrimidine. In some embodiments, lapatinib is coupled to a linker described herein through the terminal methyl of its sulfonylmethyl group. In some embodiments, U09-CX-5279 is coupled to a linker described herein through its amine (aniline), carboxylic acid, or amine alpha to a cyclopropyl group, or through a cyclopropyl group. In some embodiments, 1-ethyl-3-(2-{[3-(1-methylethyl)[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl}benzyl)urea is coupled to a linker described herein through its propyl group. In some embodiments, Y1W is bonded to a linker described herein through its propyl group or butyl group. In some embodiments, 6TP is bonded to an amide moiety through a terminal methyl group bonded to the amide moiety. In some embodiments, 07U is bonded to a linker described herein through its secondary amine or terminal amino group. In some embodiments, YCF is bonded to a linker described herein through an ether of its terminal hydroxyl group. In some embodiments, XK9 is bonded to a linker described herein through its terminal hydroxyl group. In some embodiments, NXP is bonded to a linker described herein through its terminal hydrazone group (NXP). In some embodiments, afatinib is bonded to a linker described herein through its aliphatic amine group. In some embodiments, fostamatinib is bonded to a linker described herein through its methoxy group. In some embodiments, gefitinib is bonded to a linker described herein through its methoxy group or its ether group. In some embodiments, lenvatinib is bonded to a linker described herein through its cyclopropyl group.In some embodiments, vandetanib is coupled to a linker described herein through its methoxy group or hydroxyl group. In some embodiments, vemurafenib is coupled to a linker described herein through its sulfonylpropyl group. In some embodiments, Gleevec is coupled to a linker described herein through its amide group or its aniline amine group. In some embodiments, pazopanib is coupled to a linker described herein through its phenyl group or its aniline amine group. In some embodiments, AT-9283 is coupled to a linker described herein through its phenyl moiety. In some embodiments, TAE684 is coupled to a linker described herein through its phenyl moiety. In some embodiments, nilotinib is coupled to a linker described herein through its phenyl moiety or aniline amine group. In some embodiments, crizotinib is coupled to a linker described herein through its phenyl moiety or diazole group. In some embodiments, crizotinib is coupled to a linker described herein through its phenyl moiety or diazole group. In some embodiments, JNJ FMX is coupled to a linker described herein through its phenyl moiety.

[0407] In some embodiments, the target protein binding moiety comprises 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 a tyrosine phosphatase. Non-limiting examples of phosphatase inhibitors include PTP1B.

[0408] 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 Nutlin-3, Nutlin-2, Nutlin-1, or trans-4-iodo-4'-boranyl-chalcone. In some embodiments, Nutlin-3, Nutlin-2, or Nutlin-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.

[0409] In some embodiments, the target protein binding moiety comprises a compound that targets a human BET bromodomain-containing protein. In some embodiments, the compound that targets a human BET bromodomain-containing protein is 3,5-dimethylisoxazole. In some embodiments, the target protein binding moiety comprises a compound that inhibits HDAC. 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 azacytidine. In some embodiments, azacytidine is attached to a linker described herein via a hydroxy group or an amino group. In some embodiments, the lysine methyltransferase inhibitor is decitabine. In some embodiments, decitabine is attached to a linker described herein via a hydroxy group or an amino group. In some embodiments, the target protein binding moiety comprises an angiogenesis inhibitor. Non-limiting examples of angiogenesis inhibitors include GA-1, estradiol, testosterone, DHT, ovalicin, or fumagillin. In some embodiments, the target protein binding moiety comprises an immunosuppressant compound. Non-limiting examples of immunosuppressant compounds include AP21998, glucocorticoids (e.g., hydrocortisone, prednisone, prednisolone, or methylprednisolone), beclomethasone dipropionate, methotrexate, cyclosporine, tacrolimus, rapamycin, or actinomycin. In some embodiments, the glucocorticoid is coupled to a linker described herein via a hydroxyl. In some embodiments, beclomethasone dipropionate is coupled to a linker described herein via a propionate. In some embodiments, methotrexate is coupled to a linker described herein via an ether of its terminal hydroxyl. In some embodiments, cyclosporine is coupled to a linker described herein via a butyl group. In some embodiments, tacrolimus is coupled to a linker described herein via a methoxy group.In some embodiments, rapamycin is attached to a linker described herein via a methoxy group. In some embodiments, actinomycin is attached to a linker described herein via an isopropyl group. In some embodiments, the target protein binding moiety comprises a compound that targets the aryl hydrocarbon receptor (AHR). Non-limiting examples of compounds that target the AHR include apigenin, SR1, or LGC006. In some embodiments, the target protein binding moiety comprises a compound that targets the RAF receptor. In some embodiments, the target protein binding moiety comprises a compound that targets FKBP. In some embodiments, the target protein binding moiety comprises 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. In some embodiments, the target protein binding moiety comprises a compound that targets the estrogen receptor. In some embodiments, the target protein binding moiety comprises a compound that targets the thyroid hormone receptor. In some embodiments, the target protein binding moiety comprises a compound that inhibits HIV. In some embodiments, the target protein binding moiety comprises a compound that inhibits HIV integrase. In some embodiments, the target protein binding moiety comprises a compound that targets HCV protease. In some embodiments, the target protein binding moiety comprises a compound that targets acyl-protein thioesterase-1 and / or -2. Some examples of target protein binding moieties are shown in Table 3. In this table, an "R" or a wavy line indicates an optional point of attachment to a linker or other molecule, such as a DDB1 binding moiety.

[0410] [Table 3-1]

[0411] [Table 3-2]

[0412] Table 3-3

[0413] Table 3-4

[0414] Table 3-5

[0415] Table 3-6

[0416] Table 3-7

[0417] Table 3-8

[0418] Table 3-9

[0419] Table 3-10

[0420] Table 3-11

[0421] Table 3-12

[0422] compound In one aspect herein, a compound of formula (I)

[0423] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, A is a target protein binding moiety; L 1 is the linker, B is a compound of formula (II):

[0424] [ka] is a DDB1 binding moiety having the structure During the ceremony, Ring Q is phenyl or a 5- or 6-membered monocyclic heteroaryl; L 2 is a bond, -O-, -NR 4A -, -NR 4B -C(=O)-, -NR 4B -C(=O)-(C1-C3 alkylene)-NR 4A -, -NR 4B -C(=O)-(C1-C3 alkylene)-O-, -(C1-C3 alkylene)-NR 4B -C(=O)-, -C(=O)NR 4A -, -C1-C3 alkylene-, -C2-C3 alkenylene-, -C2-C3 alkynylene-, C3-C8 cycloalkylene, or C2-C8 heterocyclene; R 1 However, hydrogen, halogens, -CN, NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 1 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 2 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, OH, or O-C1-C4 alkyl; R 3 are independently hydrogen, halogen, -CN, -NO2, -OR 4A , -NR 4A R 4B , -C(=O)R 4A , -C(=O)OR 4A , -C(=O)NR 4B R 4A , -OC(=O)R 4A , -N(R 4A )C(=O)R 4B , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; or The Two R's 3 together with the atoms to which they are connected, and optionally C3-C 13 Cycloalkyl, C2-C 12 forming a heterocyclyl, aryl, or heteroaryl; R 4A and R 4B are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocyclyl, aryl, or heteroaryl; R 4A and R 4B together with the atoms to which they are connected, and optionally C2-C 12 forming a heterocyclyl, p is 1, 2, or 3; Heterobifunctional compounds are provided wherein q is 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof.

[0425] In some embodiments, the compound comprises a heterobifunctional compound. In some embodiments, the heterobifunctional compound is a compound set forth in Table 4, or a pharmaceutically acceptable salt or solvate thereof.

[0426] [Table 4-1]

[0427] [Table 4-2]

[0428] [Table 4-3]

[0429] [Table 4-4]

[0430] [Table 4-5]

[0431] [Table 4-6]

[0432] [Table 4-7]

[0433] [Table 4-8]

[0434] Table 4-9

[0435] Table 4-10

[0436] Table 4-11

[0437] Table 4-12

[0438] Table 4-13

[0439] Table 4-14

[0440] Table 4-15

[0441] Table 4-16

[0442] Table 4-17

[0443] Table 4-18

[0444] Table 4-19

[0445] Table 4-20

[0446] Table 4-21

[0447] Table 4-22

[0448] Table 4-23

[0449] Table 4-24

[0450] Table 4-25

[0451] Table 4-26

[0452] Table 4-27

[0453] Table 4-28

[0454] Table 4-29

[0455] Table 4-30

[0456] Table 4-31

[0457] Table 4-32

[0458] Table 4-33

[0459] Table 4-34

[0460] Table 4-35

[0461] Table 4-36

[0462] Table 4-37

[0463] Table 4-38

[0464] Table 4-39

[0465] Table 4-40

[0466] Table 4-41

[0467] Table 4-42

[0468] Table 4-43

[0469] Table 4-44

[0470] Table 4-45

[0471] Table 4-46

[0472] Table 4-47

[0473] Table 4-48

[0474] Table 4-49

[0475] Table 4-50

[0476] Table 4-51

[0477] Table 4-52

[0478] Table 4-53

[0479] Table 4-54

[0480] Table 4-55

[0481] Table 4-56

[0482] Table 4-57

[0483] Table 4-58

[0484] Table 4-59

[0485] Table 4-60

[0486] Table 4-61

[0487] Table 4-62

[0488] Table 4-63

[0489] Table 4-64

[0490] Table 4-65

[0491] Table 4-66

[0492] Table 4-67

[0493] Table 4-68

[0494] Table 4-69

[0495] Table 4-70

[0496] Table 4-71

[0497] Table 4-72

[0498] Table 4-73

[0499] Table 4-74

[0500] Table 4-75

[0501] Table 4-76

[0502] Table 4-77

[0503] Table 4-78

[0504] Table 4-79

[0505] Table 4-80

[0506] Table 4-81

[0507] Table 4-82

[0508] Table 4-83

[0509] Table 4-84

[0510] Table 4-85

[0511] Table 4-86

[0512] Table 4-87

[0513] Table 4-88

[0514] Table 4-89

[0515] [Table 4-90]

[0516] [Table 4-91]

[0517] In some embodiments, the heterobifunctional compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, binds to the DDB1 protein via a DDB1 binding moiety. In some embodiments, the heterobifunctional compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is bound to the DDB1 protein via the DDB1 binding moiety. In some embodiments, the heterobifunctional compound or DDB1 binding moiety does not inhibit DDB1 function. For example, binding of DDB1 to the DDB1 binding moiety may, in some embodiments, not prevent or reduce the association of DDB1 with cullin proteins, such as cullin 4A and cullin 4B. In some embodiments, the DDB1 binding moiety is a small molecule.

[0518] Modified or engineered proteins In some embodiments, modified proteins, such as in vivo modified proteins, are disclosed herein. In some embodiments, the in vivo modified protein comprises 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 bond between the DDB1 protein and the ligand is a non-covalent bond. In some embodiments, the bond between the DDB1 protein and the ligand is a covalent bond. The ligand may be any ligand described herein. In some embodiments, the ligand comprises a compound disclosed herein, or a salt or variant thereof. 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 covalently connected to a target protein binding moiety described herein by a linker. In some embodiments, the DDB1 protein is modified in vivo by binding to a ligand administered to a subject.

[0519] Modified protein can include engineered protein.In some embodiments herein, engineered DDB1 protein, such as in vivo engineered DDB1 protein, is disclosed.Engineered DDB1 protein can be bound to ligand.Engineered DDB1 protein can be bound to ligand in vivo.For example, when ligand is administered to a subject, it can be bound to DDB1 protein or engineered DDB1 protein in vivo.

[0520] In some embodiments, the present disclosure provides an in vivo modified protein. In some embodiments, the in vivo modified protein comprises a DDB1 protein directly bound to a ligand comprising a DDB1 binding moiety. In some embodiments, the in vivo modified protein comprises a DDB1 protein directly bound to a ligand, i.e., a ligand comprising a DDB1 binding moiety. In some embodiments, the in vivo modified protein comprises a DDB1 protein directly bound to a heterobifunctional compound, i.e., a heterobifunctional compound comprising a DDB1 binding moiety covalently linked to a target protein binding moiety by a linker.

[0521] In some embodiments, in vivo modified proteins are disclosed herein. In some embodiments, the ligand comprises a DDB1 binding moiety. In some embodiments, the ligand comprises a linker. In some embodiments, the ligand comprises a target protein binding moiety. In some embodiments, the DDB1 binding moiety is covalently connected to a 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 by a 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 comprises a compound described herein. For example, the ligand can comprise 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 more than just a bond. In some embodiments, the ligand is a small molecule. In some embodiments, the ligand is a heterobifunctional compound comprising a DDB1 binding moiety covalently connected to a target protein binding moiety by a linker.

[0522] In some embodiments, disclosed herein are in vivo modified proteins. 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 comprises a beta-propeller domain. In some embodiments, the beta-propeller domain comprises a beta-propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein comprises a BPC domain. In some embodiments, the binding region on the DDB1 protein comprises the top surface of the BPC domain. In some embodiments, disclosed herein are in vivo modified proteins. In some embodiments, the binding region on the DDB1 protein comprises 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: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, One or more of 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 a ligand. An in vivo engineered DDB1 protein can include a DDB1 protein bound to a ligand at any of the aforementioned residues.

[0523] In some embodiments, in vivo modified proteins are disclosed herein. In some embodiments, the binding region on the DDB1 protein comprises ARG327 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LEU328 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises PRO358 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ILE359 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises VAL360 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ASP361 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises GLY380 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA381 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises PHE382 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER720 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ARG722 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LYS723 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER738 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ILE740 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises GLU787 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises TYR812 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LEU814 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER815 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA834 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises VAL836 of the DDB1 protein.In some embodiments, the binding region on the DDB1 protein comprises ALA841 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA869 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises TYR871 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER872 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises MET910 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LEU912 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises TYR913 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises LEU926 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises TRP953 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises SER955 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA956 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ASN970 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ALA971 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises PHE972 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises PHE1003 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises ASN1005 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises VAL1006 of the DDB1 protein. In some embodiments, the binding region on the DDB1 protein comprises VAL1033 of the DDB1 protein.

[0524] In some embodiments, the bond between the DDB1 protein and the ligand comprises one or more of a salt bridge, a Coulombic interaction, a hydrogen bond, a stereoelectronic interaction, and a dispersed contact. In some embodiments, the bond between the DDB1 protein and the ligand comprises a salt bridge. In some embodiments, the bond between the DDB1 protein and the ligand comprises a Coulombic interaction. In some embodiments, the bond between the DDB1 protein and the ligand comprises one or more hydrogen bonds. In some embodiments, the bond between the DDB1 protein and the ligand comprises a stereoelectronic interaction. In some embodiments, the bond between the DDB1 protein and the ligand comprises a dispersed contact.

[0525] In some embodiments, the DDB1 protein comprises a BPC domain comprising a central cavity. In some embodiments, a ligand binds to the DDB1 protein within the central cavity of the BPC domain. In some embodiments, the DDB1 protein comprises a WD40-motif. In some embodiments, the WD40-motif comprises a center. In some embodiments, the ligand is anchored toward the center of the WD40-motif. In some embodiments, the ligand is anchored toward the center of the WD40-motif by a salt bridge. In some embodiments, the ligand comprises a nitro group. In some embodiments, the salt bridge is between a primary amine of an amino acid of the DDB1 protein and a nitro group of the ligand. In some embodiments, the salt bridge is between a primary amine of a lysine (e.g., LYS723) of the DDB1 protein and a nitro group of the ligand.

[0526] In some embodiments, the ligand is anchored toward the center of the WD40-motif by Coulombic interactions. In some embodiments, the ligand comprises an electron-deficient nitrogen. In some embodiments, a nitro group comprises an electron-deficient nitrogen. In some embodiments, the Coulombic interaction is between the electron-deficient nitrogen and the lone pair of nearby water. In some embodiments, nearby waters are ordered between backbone carbonyl oxygen atoms of one or more amino acids of the DDB1 protein. In some embodiments, nearby waters are ordered between backbone carbonyl oxygen atoms of arginines (e.g., ARG722) of the DDB1 protein. In some embodiments, nearby waters are ordered between backbone carbonyl oxygen atoms of valines (e.g., VAL360) of the DDB1 protein. In some embodiments, nearby waters are ordered between primary amines of lysines, such as LYS723. In some embodiments, nearby waters are ordered between backbone carbonyl oxygen atoms of arginines, backbone carbonyl oxygen atoms of valines, and / or primary amines of lysines. In some embodiments, nearby waters are ordered between the backbone carbonyl oxygen atoms of ARG722 and VAL360 as well as the primary amine of LYS723. In some embodiments, the ligand is anchored towards the center of the WD40-motif by Coulombic interactions and salt bridges.

[0527] 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 the pi-face of a thiazole. In some embodiments, the ligand comprises the pi-face of an amide. In some embodiments, the pi-faces of the thiazole and amide are on an amino acid side chain. In some embodiments, the pi-faces of the thiazole and amide are on a valine (e.g., VAL360) side chain. In some embodiments, the amide forms an intermolecular hydrogen bond with the side chain of an amino acid of the DDB1 protein. In some embodiments, the amide forms a hydrogen bond with the side chain of an asparagine (e.g., ASN1005) 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 side chain of an asparagine and an intramolecular hydrogen bond with an acetate. In some embodiments, the ligand comprises a sulfur-containing thiophene. In some embodiments, the sulfur of the thiophene is geometrically stabilized by stereoelectronic interactions with an amino acid side chain of the DDB1 protein. In some embodiments, the sulfur of the thiophene is geometrically stabilized by stereoelectronic interactions with a side chain of asparagine (e.g., ASN1005). In some embodiments, the acetate comprises a methyl group that forms dispersed contacts with ordered water. In some embodiments, the acetate comprises a methyl group that forms dispersed contacts with an amino acid side chain of the DDB1 protein. In some embodiments, the acetate comprises a methyl group that forms dispersed contacts with an arginine (e.g., ARG722) side chain of the DDB1 protein. In some embodiments, the acetate comprises a methyl group that forms dispersed contacts with an arginine side chain of the DDB1 protein and ordered water. In some embodiments, the ligand comprises a benzene ring. In some embodiments, the benzene ring forms dispersed contacts with an amino acid side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with an alanine (e.g., ALA381) side chain of the DDB1 protein.In some embodiments, the benzene ring forms dispersed contacts with a leucine (e.g., LEU328) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with a proline (e.g., PRO358) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with a valine (e.g., VAL1033) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with alanine, leucine, proline, and valine side chains of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with ALA381, LEU328, PRO358, and VAL1033 side chains of the DDB1 protein.

[0528] In some embodiments, in vivo modified proteins are disclosed herein. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) of less than 100 μM, a Kd of less than 90 μM, a Kd of less than 80 μM, a Kd of less than 70 μM, a Kd of less than 60 μM, a Kd of less than 50 μM, a Kd of less than 45 μM, a Kd of less than 40 μM, a Kd of less than 35 μM, a Kd of less than 30 μM, a Kd of less than 25 μM, a Kd of less than 20 μM, a Kd of less than 15 μM, a Kd of less than 14 μM, a Kd of less than 13 μM, a Kd of less than 12 μM, a Kd of less than 11 μM, a Kd of less than 10 μM, a Kd of less than 9 μM, a Kd of less than 8 μM, a Kd of less than 7 μM, a Kd of less than 6 μM, a Kd of less than 5 μM, a Kd of less than 4 μM, a Kd of less than 3 μM, a Kd of less than 2 μM, or a Kd of less than 1 μM. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity having a Kd of less than 20 μM, a Kd of 20-100 μM, or a Kd of greater than 100 μM. An in vivo engineered DDB1 protein can comprise a DDB1 protein bound to a ligand having any of the foregoing binding affinities.

[0529] In some embodiments, in vivo modified proteins are disclosed herein. In some embodiments, the bond between the DDB1 binding moiety and the DDB1 protein is a non-covalent bond. The bond can include a non-covalent bond. The bond can include more than one non-covalent bond. Some non-limiting examples of non-covalent bonds include salt bridges, Coulomb force interactions, hydrogen bonds, stereoelectronic interactions, or dispersion contacts. The bond can include a combination of non-covalent bonds. In some embodiments, the bond between the DDB1 binding moiety and the DDB1 protein is a covalent bond.

[0530] Ligand-protein complexes In some embodiments, a ligand-protein complex is disclosed herein. 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 a DDB1 ligand. In some embodiments, binding is direct 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. In some embodiments, the ligand comprises a compound disclosed herein, or a salt or variant thereof. 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 covalently connected to a target protein binding moiety described herein by a linker.

[0531] In some embodiments, a ligand-protein complex is disclosed herein. In some embodiments, the ligand-DDB1 complex is formed by non-covalently directly binding the DDB1 protein to a ligand, i.e., a ligand comprising a DDB1 binding moiety. In some embodiments, the ligand-DDB1 complex is formed by covalently directly binding the DDB1 protein to a ligand, i.e., a ligand comprising a DDB1 binding moiety. In some embodiments, the ligand-DDB1 complex is formed by non-covalently directly binding to a heterobifunctional compound, i.e., a heterobifunctional compound comprising a DDB1 binding moiety covalently linked to a target protein binding moiety by a linker. In some embodiments, the ligand-DDB1 complex is formed by covalently directly binding to a heterobifunctional compound, i.e., a heterobifunctional compound comprising a DDB1 binding moiety covalently linked to a target protein binding moiety by a linker.

[0532] In some embodiments, a ligand-protein complex is disclosed herein. In some embodiments, the ligand comprises a DDB1 binding moiety. In some embodiments, the ligand comprises a linker. In some embodiments, the ligand comprises a target protein binding moiety. In some embodiments, the DDB1 binding moiety is covalently connected to a 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 by a 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 comprises a compound described herein. For example, the ligand can comprise 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 comprising a DDB1 binding moiety covalently connected to the target protein binding moiety by a linker.

[0533] In some embodiments, a ligand-protein complex is disclosed herein. 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 comprises a beta-propeller domain. In some embodiments, the beta-propeller domain comprises a beta-propeller C (BPC) domain. In some embodiments, the binding region on the DDB1 protein comprises a BPC domain. In some embodiments, the binding region on the DDB1 protein comprises the top surface of the BPC domain.

[0534] In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the binding region on the DDB1 protein comprises 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: ARG327, LEU328, PRO358, ILE359, VAL360, ASP361, GLY380, ALA381, PHE382, SER720, ARG722, LYS723, SER738, ILE740, GLU787, TYR812, LEU814, SER815, ALA834, VAL836, ALA841, One or more of 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 a ligand. In some embodiments, the binding region on the DDB1 protein comprises an amino acid residue described herein, such as in the section entitled "Modified Proteins."

[0535] In some embodiments, the bond between the DDB1 protein and the ligand comprises one or more of a salt bridge, a Coulombic interaction, a hydrogen bond, a stereoelectronic interaction, and a dispersed contact. In some embodiments, the bond between the DDB1 protein and the ligand comprises a salt bridge. In some embodiments, the bond between the DDB1 protein and the ligand comprises a Coulombic interaction. In some embodiments, the bond between the DDB1 protein and the ligand comprises one or more hydrogen bonds. In some embodiments, the bond between the DDB1 protein and the ligand comprises a stereoelectronic interaction. In some embodiments, the bond between the DDB1 protein and the ligand comprises a dispersed contact.

[0536] In some embodiments, the DDB1 protein comprises a BPC domain comprising a central cavity. In some embodiments, a ligand binds to the DDB1 protein within the central cavity of the BPC domain. In some embodiments, the DDB1 protein comprises a WD40-motif. In some embodiments, the WD40-motif comprises a center. In some embodiments, the ligand is anchored toward the center of the WD40-motif. In some embodiments, the ligand is anchored toward the center of the WD40-motif by a salt bridge. In some embodiments, the ligand comprises a nitro group. In some embodiments, the salt bridge is between a primary amine of an amino acid in the DDB1 protein and a nitro group of the ligand. In some embodiments, the salt bridge is between a primary amine of a lysine (e.g., LYS723) in the DDB1 protein and a nitro group of the ligand.

[0537] In some embodiments, the ligand is anchored toward the center of the WD40-motif by Coulombic interactions. In some embodiments, the ligand comprises an electron-deficient nitrogen. In some embodiments, a nitro group comprises an electron-deficient nitrogen. In some embodiments, the Coulombic interaction is between the electron-deficient nitrogen and the lone pair of nearby water. In some embodiments, nearby waters are ordered between backbone carbonyl oxygen atoms of one or more amino acids of the DDB1 protein. In some embodiments, nearby waters are ordered between backbone carbonyl oxygen atoms of arginines (e.g., ARG722) of the DDB1 protein. In some embodiments, nearby waters are ordered between backbone carbonyl oxygen atoms of valines (e.g., VAL360) of the DDB1 protein. In some embodiments, nearby waters are ordered between primary amines of lysines, such as LYS723. In some embodiments, nearby waters are ordered between backbone carbonyl oxygen atoms of arginines, backbone carbonyl oxygen atoms of valines, and / or primary amines of lysines. In some embodiments, nearby waters are ordered between the backbone carbonyl oxygen atoms of ARG722 and VAL360 as well as the primary amine of LYS723. In some embodiments, the ligand is anchored towards the center of the WD40-motif by Coulombic interactions and salt bridges.

[0538] 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 thiazole pi face. In some embodiments, the ligand comprises an amide pi face. In some embodiments, the thiazole and amide pi faces are on an amino acid side chain. In some embodiments, the thiazole and amide pi faces are on a valine (e.g., VAL360) side chain. In some embodiments, the amide forms an intermolecular hydrogen bond with the side chain of an amino acid in the DDB1 protein. In some embodiments, the amide forms a hydrogen bond with the side chain of an asparagine (e.g., ASN1005) in 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 side chain of an asparagine and an intramolecular hydrogen bond with an acetate. In some embodiments, the ligand comprises a sulfur-containing thiophene. In some embodiments, the sulfur of the thiophene is geometrically stabilized by stereoelectronic interactions with an amino acid side chain of the DDB1 protein. In some embodiments, the sulfur of the thiophene is geometrically stabilized by stereoelectronic interactions with a side chain of asparagine (e.g., ASN1005). In some embodiments, the acetate comprises a methyl group that forms dispersed contacts with ordered water. In some embodiments, the acetate comprises a methyl group that forms dispersed contacts with an amino acid side chain of the DDB1 protein. In some embodiments, the acetate comprises a methyl group that forms dispersed contacts with an arginine (e.g., ARG722) side chain of the DDB1 protein. In some embodiments, the acetate comprises a methyl group that forms dispersed contacts with an arginine side chain of the DDB1 protein and ordered water. In some embodiments, the ligand comprises a benzene ring. In some embodiments, the benzene ring forms dispersed contacts with an amino acid side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with an alanine (e.g., ALA381) side chain of the DDB1 protein.In some embodiments, the benzene ring forms dispersed contacts with a leucine (e.g., LEU328) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with a proline (e.g., PRO358) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with a valine (e.g., VAL1033) side chain of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with alanine, leucine, proline, and valine side chains of the DDB1 protein. In some embodiments, the benzene ring forms dispersed contacts with ALA381, LEU328, PRO358, and VAL1033 side chains of the DDB1 protein.

[0539] In some embodiments herein, ligand-protein complexes are disclosed. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity with an equilibrium dissociation constant (Kd) of less than 100 μM, a Kd of less than 90 μM, a Kd of less than 80 μM, a Kd of less than 70 μM, a Kd of less than 60 μM, a Kd of less than 50 μM, a Kd of less than 45 μM, a Kd of less than 40 μM, a Kd of less than 35 μM, a Kd of less than 30 μM, a Kd of less than 25 μM, a Kd of less than 20 μM, a Kd of less than 15 μM, a Kd of less than 14 μM, a Kd of less than 13 μM, a Kd of less than 12 μM, a Kd of less than 11 μM, a Kd of less than 10 μM, a Kd of less than 9 μM, a Kd of less than 8 μM, a Kd of less than 7 μM, a Kd of less than 6 μM, a Kd of less than 5 μM, a Kd of less than 4 μM, a Kd of less than 3 μM, a Kd of less than 2 μM, or a Kd of less than 1 μM. In some embodiments, the binding between the DDB1 protein and the ligand comprises a binding affinity having a Kd of less than 20 μM, a Kd of 20-100 μM, or a Kd of greater than 100 μM.

[0540] In some embodiments, the present disclosure provides a ligand-protein complex.In some embodiments, the bond between DDB1 binding moiety and DDB1 protein is a non-covalent bond.In some embodiments, the bond between DDB1 binding moiety and DDB1 protein is a covalent bond.

[0541] In some embodiments, disclosed herein are ligand-protein complexes. In one embodiment, the complex is formed in vivo. In one embodiment, the complex is formed in vitro.

[0542] IV. Methods of Treatment and Pharmaceutical Compositions Disclosed herein in some embodiments are heterobifunctional compounds (e.g., compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof) for use in methods, such as methods of treatment. Some embodiments include heterobifunctional compounds for use in methods of degrading, inhibiting, or modulating a protein or target protein (e.g., a cyclin or cyclin-dependent kinase). Some embodiments include heterobifunctional compounds for use in methods of treating a disease or disorder mediated by a target protein (e.g., a cyclin or cyclin-dependent kinase (CDK)), particularly cancer.

[0543] In certain embodiments, the compounds described herein are used to treat a subject. In certain embodiments, the compounds described herein are used to degrade a target protein. Some embodiments include administering a compound described herein to a subject. Some embodiments include administering a pharmaceutical composition comprising a heterobifunctional compound described herein to a subject. Some embodiments include providing a heterobifunctional compound or pharmaceutical composition described herein for administration to a subject.

[0544] In one aspect herein, there is provided a method for treating abnormal cell growth (e.g., cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a heterobifunctional compound described herein, or a pharmaceutically acceptable salt thereof. The heterobifunctional compound may be administered as a single agent or in combination with other therapeutic agents, particularly standard of care agents, appropriate for the disease or disorder.

[0545] In another aspect herein, provided is a heterobifunctional compound described herein, or a pharmaceutically acceptable salt thereof, for use in treating abnormal cell growth (e.g., cancer). In another aspect herein, provided is the use of a heterobifunctional compound described herein, or a pharmaceutically acceptable salt thereof, in the treatment of abnormal cell growth (e.g., cancer). In another aspect herein, provided is a heterobifunctional compound described herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of abnormal cell growth (e.g., cancer).

[0546] In another aspect herein, there is provided a method for treating a cyclin D-mediated disorder, particularly the aforementioned disorder, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a heterobifunctional compound described herein, or a pharmaceutically acceptable salt thereof.

[0547] In some embodiments provided herein are methods for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a heterobifunctional compound described herein, or a pharmaceutically acceptable salt thereof.

[0548] In some embodiments of each of the methods and uses herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, endometrial cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma, or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer, thyroid cancer, and melanoma.

[0549] In some embodiments, a method for treatment comprises administering to a subject in need thereof an effective amount of a heterobifunctional compound of Formula (I), wherein the target protein binding moiety binds to a CDK, preferably CDK4 and / or CDK6. In some such embodiments, the heterobifunctional compound comprises a structure of Formula (A), (A1), (A2), (A3), or (A4). In preferred embodiments, the heterobifunctional compound comprises a structure of Formula (A-67), (A-70), (A-71), or (A72).

[0550] In some embodiments of each of the methods and uses herein, the cancer is a cyclin D-mediated cancer. In some such embodiments, the cancer is characterized by amplification or overexpression of cyclin D (CCND), CDK4, and / or CDK6. In some such embodiments, the cancer is characterized by amplification or overexpression of cyclin D (CCND). In some embodiments, the cancer is characterized by amplification or overexpression of CDK4. In some embodiments, the cancer is characterized by amplification or overexpression of CDK6. In some embodiments, the cancer is characterized by amplification or overexpression of both CCND and CDK4.

[0551] In some embodiments of each of the methods and uses herein, the cancer is characterized by primary or acquired resistance to treatment with a CDK4 and / or CDK6 inhibitor or endocrine therapy. In some embodiments, the cancer is breast cancer that demonstrates such primary or acquired resistance. In some such embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is hormone receptor positive (HR+) HER2-negative breast cancer. In some embodiments, the breast cancer is HR+ HER2-negative advanced or metastatic breast cancer. In some such embodiments, the breast cancer is triple-negative breast cancer (TNBC). In some embodiments, the subject's cancer progresses during prior treatment with a CDK4 / 6 inhibitor and / or endocrine therapy. In some embodiments, the subject's cancer demonstrates primary or acquired resistance to treatment with a CDK4 / 6 inhibitor and / or endocrine therapy.

[0552] In some embodiments of the methods and uses herein, the heterobifunctional compound is administered as a first-line therapy. In other embodiments, the heterobifunctional compound is administered as a second- (or later)-line therapy. In some embodiments, the heterobifunctional compound is administered as a second- (or later)-line therapy after treatment with an endocrine therapeutic agent and / or a CDK4 / 6 inhibitor. In some embodiments, the heterobifunctional compound is administered as a second- (or later)-line therapy after treatment with an endocrine therapeutic agent, such as an aromatase inhibitor, a SERM, or a SERD. In some embodiments, the heterobifunctional compound is administered as a second- (or later)-line therapy after treatment with a CDK4 / 6 inhibitor. In some embodiments, the heterobifunctional compound is administered as a second- (or later)-line therapy after treatment with one or more chemotherapy regimens, for example, including a taxane or a platinum agent.

[0553] An effective dosage can be administered in one or multiple doses.For the purposes of the present invention, an effective dosage of a drug, compound or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventive or therapeutic treatment.As understood from a clinical point of view, an effective dosage of a drug, compound or pharmaceutical composition may or may not be achieved in combination with another drug, compound or pharmaceutical composition.

[0554] In frequent embodiments of the compounds, compositions, methods, and uses herein, the methods and uses result in one or more of the following effects: (1) inhibition of cancer cell proliferation, (2) inhibition of cancer cell invasion, (3) induction of apoptosis in cancer cells, (4) inhibition of cancer cell metastasis, or (5) inhibition of angiogenesis.

[0555] In some embodiments, the modified proteins disclosed herein are formed in vivo after administration of a heterobifunctional compound or pharmaceutical composition to a subject. In some embodiments, the ligand-protein complex is formed by administration of the heterobifunctional compound or pharmaceutical composition to a subject.

[0556] In certain embodiments, the heterobifunctional compounds described herein are administered as pure chemicals. In other embodiments, the heterobifunctional compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier), selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, 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 or solvate thereof, and a pharmaceutically acceptable excipient.

[0557] Provided herein are pharmaceutical compositions comprising at least one heterobifunctional compound described herein, or its stereoisomer, pharmaceutically acceptable salt, or N-oxide, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and not harmful to the recipient of the composition (i.e., subject or patient). In some embodiments, the excipient comprises a buffer or solution.

[0558] In certain embodiments, the heterobifunctional compounds described herein are substantially pure in that they contain less than about 5%, preferably less than about 1%, or more preferably less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthetic by-products arising from, for example, one or more of the steps of the synthetic method.

[0559] Some embodiments include the use of a compound such as a ligand described herein, a ligand-DDB1 complex, or an in vivo modified DDB1 protein. The use may include use as an antiviral drug. The use may include use as a molecular glue. The use may include use as a targeted proteolytic agent. In some embodiments, the use includes administering the compound to a subject. In some embodiments, the use includes contacting a sample with the compound.

[0560] Some embodiments herein provide methods for degrading a target protein in a subject. Some embodiments include administering a ligand described herein to the subject. Some embodiments include administering to the subject a ligand comprising a DNA damage binding protein 1 (DDB1) binding moiety covalently linked to the target protein binding moiety by a linker. In some embodiments, the subject is a subject in need of administration of a ligand or in need of treatment with a ligand. Some embodiments include a method of modulating a target protein, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) to a subject in need thereof. In some embodiments, the target protein is decreased in the subject compared to a baseline measurement. After administering a heterobifunctional compound described herein to a subject, the target protein measurement may be decreased in a tissue or fluid sample from the subject compared to a baseline target protein measurement in a first tissue or fluid sample from the subject. Some embodiments include measuring the decrease in CDK after administration.

[0561] Some embodiments include methods of activating apoptosis, comprising administering a therapeutically effective amount of a compound (e.g., a heterobifunctional compound) described herein to a subject in need thereof. Some embodiments include activating a caspase, such as caspase 3.

[0562] Some embodiments include obtaining a baseline measurement of the target protein. The baseline measurement may be obtained in a first sample obtained before administering a compound described herein to the subject. The first sample may include a fluid sample. The first sample may include a tissue sample. The baseline measurement may be obtained directly from the subject. The baseline measurement may include a concentration. The baseline measurement may be normalized to, for example, sample weight, sample volume, total sample protein measurement, or housekeeping protein measurement.

[0563] Some embodiments include obtaining a measurement of a target protein. The measurement may be obtained in a second sample obtained after administering a compound described herein to a subject. The measurement may be obtained in a second sample obtained during administration of a compound described herein to a subject. The second sample may include a fluid sample. The second sample may include a tissue sample. The measurement may be obtained directly from the subject. The measurement may be normalized to, for example, sample weight, sample volume, total sample protein measurement, or housekeeping protein measurement.

[0564] The measurement or baseline measurement of the target protein may include any method known in the art. For example, the measurement or baseline measurement may be obtained using an assay such as an immunoassay, a colorimetric assay, a lateral flow assay, a fluorescent assay, a proteomics assay, or a cell-based analysis. The immunoassay may include an immunoblot such as a Western blot or a dot blot, an enzyme-linked immunosorbent assay, or immunostaining. The proteomics assay may include mass spectrometry. The measurement or baseline measurement may be obtained using flow cytometry. The measurement or baseline measurement may be obtained using chromatography, for example, high-performance liquid chromatography.

[0565] The target protein may be or include any of the target proteins included herein, as well as other target proteins not specified. Some embodiments include methods of degrading cyclin-dependent kinases (CDKs). Some embodiments include methods of degrading target proteins including CDKs. Some examples of such cyclin-dependent kinases include, but are not limited to, CDK4 or CDK6. Some embodiments include methods of modulating CDKs, comprising administering a therapeutically effective amount of a compound (e.g., a heterobifunctional compound) described herein to a subject in need thereof. In some embodiments, CDK is decreased in the subject compared to baseline measurements. Some embodiments include measuring the decrease in CDK after administration.

[0566] Some embodiments include methods of degrading a cyclin. Some embodiments include methods of degrading a target protein that includes a cyclin. Some examples of such cyclins include cyclin D, such as cyclin D1, cyclin D2, cyclin D3, or cyclin E. Some embodiments include methods of modulating a cyclin, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) to a subject in need thereof. Some embodiments include methods of modulating cyclin D, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) to a subject in need thereof. In some embodiments, the cyclin is decreased in the subject compared to baseline measurements. Some embodiments include measuring the decrease in the cyclin after administration.

[0567] Some embodiments include methods of degrading a transcription factor. Non-limiting examples of transcription factors include CBP and P300. Some embodiments include methods of degrading a target protein comprising CBP or P300. Some embodiments include methods of degrading a target protein comprising CBP. Some embodiments include methods of degrading a target protein comprising P300. Some embodiments include methods of modulating a transcription factor, comprising administering a therapeutically effective amount of a compound described herein (e.g., a heterobifunctional compound) to a subject in need thereof. In some embodiments, the transcription factor is decreased in the subject compared to baseline measurements. Some embodiments include measuring the decrease in the transcription factor after administration. Additional examples of target proteins are included herein.

[0568] Examples of subjects include vertebrates, animals, mammals, dogs, cats, cows, rodents, mice, rats, primates, monkeys, and humans. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0569] In some embodiments, administering the ligand to the subject comprises administering an effective amount of the ligand sufficient to degrade the target protein. In some embodiments, after administering 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 comprises injection. In some embodiments, the administration comprises dermal administration. In some embodiments, the administration comprises subcutaneous administration. In some embodiments, the administration comprises intraperitoneal administration. In some embodiments, the administration comprises oral administration. In some embodiments, the route of administration is intravenous, oral, subcutaneous, intraperitoneal, ocular, intraocular, intramuscular, intrainterstitial, intraarterial, intracranial, intraventricular, intrasynovial, transepithelial, transdermal, inhalation, ophthalmic, sublingual, buccal, topical, cutaneous, rectal, nasal, insufflation, or nebulization. In some embodiments, the administration is intramuscular. In some embodiments, the administration is intrathecal. 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 intravaginal. In some embodiments, administration is ocular. In some embodiments, administration is otic. In some embodiments, administration is nasal. In some embodiments, administration is inhalation. In some embodiments, administration is nebulization. In some embodiments, administration is dermal. In some embodiments, administration is topical. In some embodiments, administration is transdermal. In some embodiments, administration is systemic.

[0570] In some embodiments herein, a method for degrading target protein in a sample is provided.Some embodiments comprise contacting target protein with the ligand described herein.Some embodiments comprise contacting target protein with the ligand comprising DNA damage binding protein 1 (DDB1) binding moiety, which is covalently connected to target protein binding moiety by a linker.

[0571] In some embodiments, the sample is a biological sample. In some embodiments, the biological sample comprises tissue, cells, or bodily fluid. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo. In some embodiments, the target protein is ubiquitinated after contact with the ligand to form a ubiquitinated target protein.

[0572] In some embodiments, after administration or contact, the ubiquitinated target protein is degraded. 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 undergoes proteasomal degradation. In some embodiments, the target protein is degraded by the proteasome.

[0573] 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 directly binds to the DDB1 protein via the DDB1 binding moiety of the ligand. In some embodiments, the bond between the DDB1 binding moiety and the DDB1 protein is a non-covalent bond. In some embodiments, the bond between the DDB1 binding moiety and the DDB1 protein is a covalent bond. In some embodiments, the target protein is ubiquitinated by a ubiquitin E3 ligase complex comprising 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 protein degrader. In some embodiments, the ligand is synthetic. In some embodiments, the ligand comprises a ligand described herein.

[0574] The target protein degraded using the methods described herein can be or include any of the target proteins described herein. In some embodiments, the target protein is a transcription factor, CBP, p300, kinase, receptor, TRK, TrkA, TrkB, TrkC, cyclin-dependent kinase, CDK4, CDK6, B7.1, B7, TINFRlm, TNFR2, NADPH oxidase, apoptosis pathway partner, 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, trypanosomal 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-alphaR, 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 converting enzyme, 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 transfer protein inhibitor, bile acid transport inhibitor, 5-alpha 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, purinergic receptor, P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7, farnesyltransferase, geranylgeranyltransferase, NGF receptor, beta-amyloid, tyrosine kinase Flk-IIKDR, vitronectin receptor, integrin receptor, Her2 neu, telomerase inhibition, cytosolic phospholipase A2, EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, GABA-gated chloride channel ion channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium release channel, chloride channel, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, or enoylpyruvinylshikimate-phosphate synthase. Some embodiments include multiple target proteins, such as a combination of any two or more of the target proteins disclosed herein.

[0575] The heterobifunctional compounds described herein (e.g., compounds comprising a DDB1-binding moiety) may be useful for several purposes, including, but not limited to, use as: 1) antiviral agents; 2) DDB1 protein level modulators (e.g., increasing or decreasing DDB1 protein levels); 3) DDB1 function modulators (e.g., activating or inhibiting DDB1); 4) molecular binders (e.g., increasing protein-protein interactions between DDB1 and a second protein, such as a target protein); 5) to affect the activity or protein levels of a second protein via molecular binder function (e.g., by functioning as a targeted proteolytic agent); 6) to decrease the protein levels of a second protein via molecular binder function; 7) to increase the protein levels of a second protein via molecular binder function; 8) to decrease the activity of a second protein via molecular binder function; or 9) to increase the activity of a second protein via molecular binder function.

[0576] In some embodiments, the heterobifunctional compounds described herein can compete with one or more viral proteins or virus-derived peptides for binding to DDB1. In some embodiments, the heterobifunctional compounds competitively bind to the same binding site on DBB1 as the viral proteins or virus-derived peptides. Such competitive binding can be measured by competitive binding assays and can be used to identify and characterize residues comprising the DBB1-binding site of the heterobifunctional compounds.

[0577] The heterobifunctional compounds described herein can be useful for treating diseases or disorders. For example, the compounds can be administered to a subject with a disease or disorder. Administration can reduce the severity of the subject's disease or disorder compared to baseline measurements. The compounds can bind to a target protein involved in a disease or disorder, resulting in the inhibition or degradation of the target protein. The compounds can be heterobifunctional compounds and can include a DDB1 binding moiety and a target protein binding moiety, where the target protein is involved in a disease or disorder. The target protein can exacerbate the disease or disorder. The target protein can prevent or reduce the inhibition of the disease or disorder.

[0578] In some embodiments, the compounds described herein are used as antibacterial agents. For example, the compounds can be administered to a subject with a microbial infection. Administration can reduce the severity of the subject's microbial infection from baseline measurements. The compounds can bind to a target protein involved in the microbial infection, resulting in the inhibition or degradation of the target protein. The microbial infection can include a viral infection. The microbial infection can include a bacterial infection. The compounds can be heterobifunctional compounds and can include a DDB1-binding moiety and a target protein-binding moiety, where the target protein is a microbial protein. The microbial protein can include a viral protein. The microbial protein can include a bacterial protein. The target protein can be a non-microbial protein that exacerbates the microbial infection. The target protein can be a non-microbial protein that prevents or reduces the inhibition of the microbial infection. In some embodiments, the compounds enter a subject's cells, bind to a cellular microbial protein via its target protein-binding moiety, bind to DDB1 via its DDB1-binding moiety, and induce ubiquitin-mediated degradation of the microbial protein. Such an effect can be useful against microorganisms, such as bacteria or viruses, that infect or reside within cells.

[0579] 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 comprising a 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 comprising a 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 comprise a DDB1-binding moiety linked (directly or via a linker) to a second moiety that increases or decreases the degradation of DDB1 protein. The second moiety may accomplish this by binding to a target protein. In some such embodiments, the target protein may comprise an E3 ubiquitin ligase protein that enhances the degradation of DDB1 protein. In some embodiments, the heterobifunctional compound comprises or consists of a DDB1-binding moiety. In some embodiments, the heterobifunctional compound comprises or consists of the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, a compound provided in Table 4, or a pharmaceutically acceptable salt thereof. In some embodiments, the heterobifunctional compound is administered to a subject to increase the subject's DDB1 protein level. The administration may increase the subject's DDB1 activity above baseline measurements. In some embodiments, the heterobifunctional compound is administered to a subject to decrease the subject's DDB1 protein level. The administration may decrease the subject's DDB1 activity below baseline measurements.

[0580] The heterobifunctional compounds described herein can be useful for modulating DDB1 function. For example, the compounds can be used to activate or inhibit DDB1. In some embodiments, compounds comprising a DDB1-binding moiety described herein are used to increase DDB1 activity. For example, a compound can bind to and activate DDB1. A compound can allosterically activate DDB1. A compound can activate DDB1 by binding to a protein binding site on DDB1. In some embodiments, heterobifunctional compounds comprising a DDB1-binding moiety described herein are used to decrease DDB1 activity. For example, a compound can bind to and inhibit DDB1. A compound can allosterically inhibit DDB1. A compound can inhibit DDB1 by binding to the active site of DDB1. A compound can inhibit DDB1 by binding to a protein binding site on DDB1. The compound may be a heterobifunctional compound and may include a DDB1 binding moiety linked (directly or via a linker) to a second moiety that increases the activity of the DDB1 protein or decreases the activity of the DDB1 protein. The second moiety may accomplish this by binding to the target protein. In some embodiments, the compound is administered to a subject to increase the subject's DDB1 activity. The administration may increase the subject's DDB1 activity above baseline measurements. In some embodiments, the compound is administered to a subject to decrease the subject's DDB1 activity. The administration may decrease the subject's DDB1 activity below baseline measurements.

[0581] The heterobifunctional compounds described herein can be useful as molecular glues. For example, the compounds can bind to multiple molecules and hold them together. In some embodiments, the molecular glue binds to DDB1 and a target protein. The compound can accomplish this as a heterobifunctional compound containing a DDB1-binding portion and a target protein-binding portion. The compound can increase the protein-protein interaction between DDB1 and the target protein. The compound can function as a molecular glue to regulate the activity or amount of the target protein. As a molecular glue, the compound can decrease the amount of the target protein. As a molecular glue, the compound can increase the amount of the target protein. As a molecular glue, the compound can decrease the activity of the target protein. As a molecular glue, the compound can increase the activity of the target protein.

[0582] Some embodiments disclosed herein are methods for degrading a target protein in a cell. The method may include degrading the target protein through direct binding of an intermediate protein (e.g., a first protein) that interacts with the target protein. This is sometimes referred to as cross-link degradation. Some embodiments include administering a binding molecule to a cell. The binding molecule may include a ligand or compound 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 to a subject a binding molecule that binds to a first protein that interacts with the target protein, 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 the cell. Some embodiments include measuring the first protein in the cell. 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 a target protein described herein. The first protein may include another target protein 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 cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell.In some embodiments, the cells are cancer cells. In some embodiments, administering the binding molecule to the cells comprises administering the binding molecule to a subject comprising the 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). 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 by a linker. The first protein binding moiety can comprise a target protein binding moiety disclosed herein. In some embodiments, the binding molecule comprises a structure disclosed herein.

[0583] In some embodiments, disclosed herein are methods (e.g., cross-linking degradation methods) that include administering to cells a binding molecule that binds to a cyclin-dependent kinase (CDK), thereby degrading a cyclin that interacts with a CDK. 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.

[0584] In some embodiments, compounds of Formula (I) selectively degrade cyclin D relative to CDK4. In some such embodiments, CDK4 is degraded more slowly than cyclin D. In some such embodiments, CDK4 is degraded to a lesser extent than cyclin D. In some embodiments, compounds of Formula (I) degrade cyclin D but not CDK4.

[0585] Some embodiments include measuring a cyclin in the cell. Some embodiments include measuring a CDK in the cell. 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, the cyclin D includes cyclin D1, cyclin D2, or cyclin D3. The cyclin D may include cyclin D1. The cyclin D may include cyclin D2. The cyclin D may include cyclin D3. In some embodiments, the CDK includes CDK4 or CDK6. The CDK may include CDK4. The CDK may include CDK6. In some embodiments, the binding molecule reduces cell viability. In some embodiments, the cell is a eukaryotic cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a cancer cell. In some embodiments, administering the binding molecule to the cell comprises administering the binding molecule to a subject comprising the cell. In some embodiments, the binding molecule recruits a ubiquitin E3 ligase that ubiquitinates a cyclin. In some embodiments, the E3 ubiquitin ligase comprises DNA damage-binding protein 1 (DDB1). In some embodiments, the binding molecule comprises a heterobifunctional compound comprising an E3 ubiquitin ligase binding moiety covalently connected to a CDK binding moiety by a linker. In some embodiments, the E3 ubiquitin ligase binding moiety comprises a chemical structure disclosed herein. In some embodiments, the CDK binding moiety comprises a target protein binding moiety disclosed herein. In some embodiments, the binding molecule comprises a ligand disclosed herein.

[0586] Preparation of compounds The compounds used in the chemical reactions described herein are made according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "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 (Lancarshire, 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, UK), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CT), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hannover, 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).

[0587] Suitable references and papers detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing their preparation include, for example, "Synthetic Organic Chemistry," John Wiley & Sons, Inc., New York; "Organic Functional Group Preparations," by S.R. Sandler et al., 2nd ed., Academic Press, New York, 1983; "Modern Synthetic Reactions," by H.O. House, 2nd ed., W.A. Benjamin, Inc., Menlo Park, Calif., 1972; "Heterocyclic Chemistry," by T.L.G. Gilchrist, 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. Additional suitable references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide references to articles describing their preparation include, for example, "Organic Synthesis: Concepts, Methods, Starting Materials" by Fuhrhop, J. and Penzlin G., 2nd Edition, Revised and Enlarged Edition (1994) John Wiley & Sons, ISBN: 3-527-29074-5; "Organic Chemistry, An Intermediate Text" by Hoffman, RV (1996) Oxford University Press, ISBN 0-19-509618-5; "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" by Larock, RC, 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4;"Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2, "Modern Carbonyl Chemistry" by Otera, J. (ed.) (2000) Wiley-VCH, ISBN: 3-527-29871-1, "Patai's 1992 Guide to the Chemistry of Functional Groups" by Patai, S. (1992) Interscience ISBN: 0-471-93022-9, "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0, "Intermediate Organic Chemistry" by Stowell, JC "Chemistry," 2nd 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.

[0588] Alternatively, specific and similar reactants can be identified by indexes of known chemicals and reactants prepared by the Chemical Abstract Service of the American Chemical Society, available through most public and university libraries, as well as through online databases (contact the American Chemical Society in Washington, D.C., for further information). Chemicals that are known but not commercially available in catalogs are optionally prepared by specialized chemical synthesis laboratories, where many standard chemical supply facilities (e.g., those listed above) offer specialized synthesis services. Regarding the preparation and selection of pharmaceutical salts of the compounds described herein, see "Handbook of Pharmaceutical Salts" by P.H. Stahl & C.G. Wermuth, Verlag Helvetica Chimica Acta, Zurich, 2002. The compounds described herein are prepared using common methods in the field of organic synthesis, as described in the Examples section. Alternative synthetic methods may also be used to produce the compounds described herein. Some embodiments include methods of making the heterobifunctional compounds disclosed herein.

[0589] Characterization of examples of heterobifunctional compounds Disclosed herein are heterobifunctional compounds that modulate cyclin D, P300 / CBP, or BRD4 protein levels. These compounds are designed and synthesized by incorporating three moieties: a DDB1 ligand, a linker, and a CDK4 / 6, P300 / CBP, or BRD4 binder.

[0590] To determine whether the addition of a linker and target binder to the DDB1 ligand affected binding to the DDB1 E3 ligase, the binding affinity of heterobifunctional compounds to DDB1 was assessed using a surface plasmon resonance (SPR) assay. Purified DDB1ΔBPB protein was immobilized on a CM5 sensor chip, and compound solutions over a range of doses were injected in a kinetic format over multiple cycles. The data were fitted to a steady-state model to obtain equivalent dissociation constants (Kd). As illustrated in Figure 1A-1B, exemplary heterobifunctional compounds, namely CPD-004 and CPD-031, bound to DDB1 in a concentration-dependent manner, with binding affinities (Kd) of 9.4 μM and 5.7 μM, respectively (Figure 1A-1B). As illustrated in Table 5, additional exemplary heterobifunctional compounds exhibited binding affinities (Kd) of less than 20 μM.

[0591] Specific exemplary heterobifunctional compounds were characterized in Calu-1, BT-549, and other cells. Cells expressing cyclin D1-3 and CDK4 / 6 proteins were treated for 16 hours with the indicated concentrations of the heterobifunctional compounds disclosed herein. Cells were harvested, lysed, and subjected to immunoblotting using antibodies specific for cyclin D1, cyclin D2, cyclin D3, CDK4, CDK6, or phosphorylated Rb proteins. Tubulin or GAPDH was used as a loading control. DMSO treatment was used as a negative control. As illustrated in Tables 6A and 6B, after 16 hours of treatment with the indicated concentrations of various heterobifunctional compounds, cyclin D1 and CDK4 protein levels in Calu-1 cells were significantly reduced.

[0592] Heterobifunctional compounds exemplified by CPD-002, CPD-004, and CPD-031 were found to be particularly effective in reducing cyclin D1, cyclin D2, and cyclin D3 protein levels in a concentration-dependent manner (Figures 2A-B and 3; CPD-002 reduced DC 50 for CPD-031 was less than 50 nM, and for CPD-031 it was DC 50Palbociclib, a CDK4 / 6 inhibitor, had no significant effect on cyclin D and CDK4 / 6 protein levels (Figures 2A-B). The heterobifunctional compound also inhibited downstream Rb phosphorylation and induced caspase-3 (a marker of cell apoptosis) cleavage in a concentration-dependent manner in Calu-1 cells (Figures 2A-B). In a time course study, Calu-1 cells were treated with 500 nM CPD-002 or 100 nM CPD-031 for the indicated periods, followed by immunoblotting (Figures 4A-B). Significant degradation of cyclin D protein was observed within 0.5 h after treatment with CPD-002, with complete proteolysis achieved within 2 h, whereas CDK4 and CDK6 degradation occurred significantly later (Figure 4A). Interestingly, in CPD-031, the degradation of cyclin D3 was observed to be slower than that of cyclins D1 and D2 (Fig. 4B).

[0593] Heterobifunctional compound-mediated degradation relied on the ubiquitin-proteasome system and cullin E3 ligase. Pretreatment of Calu-1 cells with the proteasome inhibitor MG-132, the cullin E3 ligase inhibitor MLN4924, or the ubiquitin-activating enzyme (UAE) inhibitor TAK-243 completely abolished the cyclin D downregulation effects of CPD-002 or CPD-031 (Figure 5A-B). Furthermore, DDB1 E3 ligase was critical for degrader-induced cyclin D downregulation. Depletion of DDB1 using CRISPR-Cas9 technology attenuated CPD-031-induced cyclin D degradation (Figure 5C). Collectively, these findings demonstrated that these heterobifunctional compounds downregulated cyclin D protein through mechanisms mediated by DDB1, cullin E3 ligase, and the proteasome.

[0594] To verify that heterobifunctional compound-mediated degradation is due to binding to the CDK4-cyclin D complex, we designed three negative control compounds, CPD-042, CPD-049, and CPD-380, which are derived from CPD-002, CPD-031, and CPD-343, respectively. These three control compounds have the same DDB1 ligand and linker as their corresponding active heterobifunctional compounds, but the warhead is modified to impair binding of the control compounds to CDK4. As shown in Figures 6A-6D and 10, compared with the corresponding active heterobifunctional compounds, the negative control compounds exhibited significantly weaker degradation potencies (>10-fold reduction for CPD-042, >100-fold reduction for CPD-049, and >15-fold reduction for CPD-380) and cellular antiproliferative activity (>20-fold reduction for CPD-042, >100-fold reduction for CPD-049, and >20-fold reduction for CPD-380). These results confirm that heterobifunctional compound-mediated degradation of cyclin D and CDK4 / 6 is due to direct binding to CDK4. However, binding to CDK4 is not sufficient for cyclin D degradation. Two cereblon (CRBN)-supplemented reference heterobifunctional compounds, CP-10 (Su, J Med Chem, 2019, CAS No.: 2366268-80-4) and BSJ-03-123 (Brand, Cell Chem Biol, 2019, CAS No.: 2361493-16-3), were analyzed on Calu-1 cells. Consistent with reported data, these two reference heterobifunctional compounds significantly reduced CDK4 and CDK6 protein levels but did not affect cyclin D1 protein levels (Figure 11A) or suppress Calu-1 cell proliferation (Figure 11B).

[0595] To demonstrate the superiority of our cyclin D degraders over FDA-approved CDK4 / 6 drugs in inhibiting cancer cell proliferation, Calu-1, NCI-H522, BT-549, Hs578T, MIA PaCa-2, or other cells were plated in 96-well plates and treated with the CDK4 / 6 inhibitors palbociclib, ribociclib, or abemaciclib, or the heterobifunctional compounds CPD-002, CPD-031, CPD-043, or CPD-044, according to nine-point serial dilutions, three days after treatment. As illustrated in Figure 7 and Table 7, CPD-002 and CPD-031 are significantly more potent than palbociclib, ribociclib, and abemaciclib in inhibiting multiple cancer cell lines.

[0596] Furthermore, flow cytometry analysis of T47D cells stained with Annexin V / 7-AAD demonstrated that our cyclin D degrader inhibited tumor cell proliferation through a mechanism of action (MoA) different from that of CDK4 / 6 inhibitors. + Breast cancer T47D cells were cultured with DMSO, palbociclib, the heterobifunctional compound CPD-343, or the negative control compound CPD-380, as determined in Figure 10A and Figure 13. 50 and IC 90 The cells were treated for 6 days with doses approximating the concentration of 7-AAD-. Cells were harvested by trypsinization and stained using an Annexin V apoptosis detection kit. The percentages of early apoptosis (Annexin V + 7-AAD-, lower right quadrant), late apoptosis (Annexin V + 7-AAD+, upper right quadrant), and necrotic cells (Annexin V - 7-AAD+, upper left quadrant) are shown in dot plots. As illustrated in Figure 12, the heterobifunctional compound CPD-343 exhibited an IC 50 and IC 90Although both concentrations were found to induce cell apoptosis in T47D cells at doses approaching those of 10 nM and 200 nM (Annexin V+ population, 26.9% at 10 nM and 52.6% at 200 nM), the CDK4 / 6 inhibitor palbociclib ("palbo") or the negative control compound CPD-380 had significantly less effect on cell apoptosis at concentrations up to 1 μM compared to cells treated with DMSO (palbo: 15.9% at 100 nM, 26.1% at 1 μM; CPD-380: 7.1% at 10 nM, 28.6% at 200 nM). Furthermore, we found that 1 μM palbociclib (IC 90 One ER with acquired resistance after prolonged treatment with + A breast cancer T47D model was developed. Cells were considered resistant if they grew in the presence of palbo at the same rate as parental cells. Palbo resistance was determined by CellTiter-Lumi cell viability assay. The heterobifunctional compound CPD-343 was found to remain effective against the T47D palbo-resistant model compared to parental cells (Figure 13).

[0597] Collectively, these results demonstrate that cyclin D protein degradation can be therapeutically targeted in multiple cancer types beyond breast cancer, demonstrating greater potency than CDK4 / 6 inhibitors.

[0598] Additional exemplary heterobifunctional compounds were designed to modulate either P300 / CBP or BRD4 protein levels and characterized in multiple cell lines. As illustrated in Figure 8, heterobifunctional compound CPD-191 inhibited the expression of P300 / CBP in LNCaP, Calu-1, NCI-H1703, or MM.1R cell lines (DCs). 50DDB1 significantly reduced the protein levels of P300 and CBP in a concentration-dependent manner at concentrations below 10 nM. Furthermore, the specific heterobifunctional compound CPD-253 was found to dramatically reduce the protein levels of BRD4 in Daudi, SU-DHL-4, or MDA-MB-231 cell lines (Figure 9). Collectively, DDB1 ligands conjugated with different targeting ligands can regulate the cellular target protein levels of cyclin D, CDK4 / 6, P300 / CBP, and BRD4. This data demonstrates the broad utility of DDB1 ligands in targeted protein degradation techniques. [Example]

[0599] The following examples are set forth to more clearly illustrate the principles and practice of the examples disclosed herein to those skilled in the art, and should not be construed as limiting the scope of any examples claimed. Unless otherwise specified, all parts and percentages are by weight.

[0600] General Chemical Methods

[0601] All chemicals and reagents were purchased from commercial suppliers and used without further purification. LCMS spectra for all compounds were acquired using a Waters LC-MS AcQuity H UPLC Classification System. The Waters LC-MS AcQuity H UPLC Classification System is equipped with a pump (Quaternary Solvent Manager), a degasser, an autosampler (FTN), a column oven (40 °C unless otherwise specified), and a photodiode array PDA detector. Chromatography was performed on an AcQuity UPLC BEH C18 (1.7 μm, 2.1 × 50 mm) column using water containing 0.1% formic acid as solvent A and acetonitrile containing 0.1% formic acid as solvent B at a flow rate of 0.6 mL / min. The column flow was split to an MS spectrometer. The MS detector was configured with an electrospray ionization source. Nitrogen was used as the nebulizer gas. Data acquisition was performed using a MassLynx data system. Nuclear magnetic resonance spectra were recorded on a Bruker Avance III 400 spectrometer. Chemical shifts are expressed in parts per million (ppm) and reported as δ values ​​(chemical shift δ). Coupling constants are reported in hertz (J values, Hz; integration and splitting patterns: s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet). Purification of intermediates or final products was performed on an Agilent Prep 1260 series with UV detection set at 254 nm or 220 nm. Samples were injected and loaded onto a Phenomenex Luna C18 column (5 μm, 30 × 75 mm) at room temperature. The flow rate was 40 mL / min. A linear gradient was used, with 10% or 50% MeOH in HO containing 0.1% TFA as solvent A and 100% MeOH as solvent B. Alternatively, products were purified on a CombiFlash® NextGen 300 system with the UV detector set at 254 nm, 220 nm, or 280 nm. The flow rate was 40 mL / min. A linear gradient was used with HO containing 0.05% TFA as solvent A and 100% MeOH containing 0.05% TFA as solvent B.All compounds were greater than 95% pure using the LCMS method described above.

[0602] The following are non-limiting examples of the synthesis of ligands.

[0603] Example 001. 4-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl)amino)-2-methylbenzoic acid (BL1-1)

[0604] [ka]

[0605] Step 1. Synthesis of methyl 4-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl)amino)-2-methylbenzoate

[0606] A solution of tert-butyl (17-amino-3,6,9,12,15-pentaoxaheptadecyl)carbamate (2.00 g, 5.26 mmol), L-proline (605 mg, 5.26 mmol), K2CO3 (1.45 g, 10.5 mmol), CuI (1.00 g, 5.26 mmol), and methyl 4-iodo-2-methylbenzoate (1.74 g, 6.31 mmol) in DMF (20 mL) was stirred at 110 °C for 2 h under microwave irradiation in an argon atmosphere. After cooling to room temperature, the mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 5:1) to give the desired product (1.20 g, 43% yield) as a colorless oil. MS (ESI) m / z = 529.2 [M+H] + .

[0607] Step 2. Synthesis of 4-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl)amino)-2-methylbenzoic acid

[0608] A solution of methyl 4-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl)amino)-2-methylbenzoate (1.20 g, 2.27 mmol) and LiOH·HO (477 mg, 11.4 mmol) in MeOH (10 mL) and HO (1 mL) was stirred at 50 °C for 16 h. After cooling to room temperature, the mixture was diluted with water (50 mL) and the pH was adjusted to 4 with 1 N HCl. The mixture was extracted with EtOAc (2 x 50 mL). The combined organic phase was washed with brine (2 x 50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude title compound (1.05 g, 90% yield) as a brown oil. 1 HNMR(400MHz,DMSO-d6)δ 11.77(s,1H),7.66(d,J=8.4Hz,1H),6.74(t,J=5.2Hz,1H),6.43-6.41(m,2H),6.25(t,J=5.6Hz,1H),3.56- 3.48(m,18H),3.36(t,J=6.0Hz,2H),3.23(q,J=5.6Hz,2H),3.05(q,J=5.6Hz,2H),2.43(s,3H),1.36(s,9H). MS(ESI)m / z=515.3[M+H] + .

[0609] Example 002.N 4 -(5-aminopentyl)-2-methyl-N 1 -(5-methylthiazol-2-yl)terephthalamide (BL1-2)

[0610] [ka]

[0611] Step 1. Synthesis of tert-butyl 4-bromo-2-methylbenzoate

[0612] A solution of 4-bromo-2-methylbenzoic acid (10 g, 46.5 mmol), DMAP (567 mg, 4.65 mmol), and BocO (15.2 g, 69.8 mmol) in t-BuOH (100 mL) was stirred overnight at 50° C. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (petroleum ether / EtOAc = 10:1) to give the title compound (8.0 g, 64% yield) as a colorless oil.

[0613] Step 2. Synthesis of 1-(tert-butyl) 4-methyl 2-methyl terephthalate

[0614] A solution of tert-butyl 4-bromo-2-methylbenzoate (8.00 g, 29.5 mmol), Pd(dppf)Cl (2.16 g, 2.95 mmol), and TEA (5.96 g, 59.0 mmol) in MeOH (80 mL) was heated at 70 °C overnight under a carbon monoxide atmosphere (15 psi). After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with brine (2 x 30 mL). The organic phase was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10:1) to give the desired product (6.0 g, 81% yield) as a colorless oil.

[0615] Step 3. Synthesis of 4-(methoxycarbonyl)-2-methylbenzoic acid

[0616] A solution of 1-(tert-butyl) 4-methyl 2-methyl terephthalate (6.00 g, 24.0 mmol) in DCM (20 mL) and TFA (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and lyophilized to give the title compound (4.20 g, 90% yield) as a white solid. MS (ESI) m / z = 193.0 [MH] - .

[0617] Step 4. Synthesis of methyl 3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)benzoate

[0618] A solution of 4-(methoxycarbonyl)-2-methylbenzoic acid (4.20 g, 21.6 mmol), 5-methylthiazol-2-amine (3.69 g, 32.4 mmol), HATU (12.3 g, 32.4 mmol), and DIEA (8.36 g, 64.8 mmol) in DMF (50 mL) was stirred at 80 °C for 2 hours. After cooling to room temperature, the mixture was diluted with water (200 mL) and acidified with 1N HCl to pH = 5. The mixture was filtered, and the filter cake was washed with MeOH (100 mL). The solid was dried under high vacuum to give the title compound (3.00 g, 48% yield) as a pale yellow solid. MS (ESI) m / z = 291.1 [M+H] + .

[0619] Step 5. Synthesis of 3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)benzoic acid

[0620] A solution of methyl 3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)benzoate (3.00 g, 10.3 mmol) and LiOH·HO (2.16 g, 51.5 mmol) in THF (50 mL) and HO (20 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove THF. The residue was diluted with water (100 mL) and acidified with 1 N HCl to pH = 2. The mixture was filtered, and the filter cake was lyophilized to give the title compound (2.50 g, 88% yield) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ 12.8(brs,2H),7.87(s,1H),7.83(dd,J=8.0,0.8Hz,1H),7.61(d,J=8.0Hz,1H),7.20(d,J=1.2Hz,1H),2.42(s,3H),2.38(s,3H). MS(ESI)m / z=277.0[M+H] + .

[0621] Step 6. Synthesis of tert-butyl (5-(3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)benzamido)pentyl)carbamate

[0622] A solution of 3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)benzoic acid (200 mg, 0.725 mmol), tert-butyl(5-aminopentyl)carbamate (184 mg, 0.906 mmol), HATU (413 mg, 1.09 mmol), and DIEA (280 mg, 2.18 mmol) in DMF (8 mL) was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (150 mg, 45% yield) as a yellow oil. MS (ESI) m / z = 461.2 [M+H] + .

[0623] Process 7.N 4 -(5-aminopentyl)-2-methyl-N 1 Synthesis of 5-methylthiazol-2-yl terephthalamide

[0624] A solution of tert-butyl (5-(3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)benzamido)pentyl)carbamate (150 mg, 0.326 mmol) in DCM (5 mL) and TFA (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and lyophilized to give the title compound (130 mg, TFA salt, 84% yield) as a yellow solid. 1 HNMR(400MHz,DMSO-d6)δ 12.39(brs,1H),8.54(t,J=5.2Hz,1H),7.76-7.67(m,4H),7.59(d,J=8.0Hz,1H),7.20(d,J=1.2Hz,1H) ,3.29-3.25(m,2H),2.81-2.77(m,2H),2.42(s,3H),2.38(s,3H),1.59-1.53(m,4H),1.37-1.33(m,2H). MS(ESI)m / z=361.2[M+H] + .

[0625] Example 003.N 4-(7-aminoheptyl)-2-methyl-N 1 -(5-methylthiazol-2-yl)terephthalamide (BL1-3)

[0626] [ka]

[0627] BL1-3 was synthesized following the standard procedure for the preparation of BL1-2 (120 mg, 36% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 12.39(brs,1H),8.54(t,J=5.2Hz,1H),7.76(s,1H),7.71-7.70(m,1H),7.65-7.56(m,3H),7.20(d,J=1.2Hz ,1H),3.27-3.24(m,2H),2.79-2.74(m,2H),2.42(s,3H),2.38(s,3H),1.54-1.51(m,4H),1.31-1.28(m,6H). MS(ESI)m / z=389.1[M+H] + .

[0628] Example 004.N 4 -(9-aminononyl)-2-methyl-N 1 -(5-methylthiazol-2-yl)terephthalamide (BL1-4)

[0629] [ka]

[0630] BL1-4 was synthesized following the standard procedure for the preparation of BL1-2 (150 mg, 41% yield over two steps). 1HNMR(400MHz,DMSO-d6)δ 12.42(brs,1H),8.53(t,J=5.6Hz,1H),7.75(s,1H),7.72-7.70(m,1H),7.64-7.58(m,3H),7.20(d,J=1.2Hz,1H),3.28-3.23(m,2H),2.79 -2.74(m,2H),2.41(s,3H),2.38(s,3H),1.52-1.49(m,4H),1.28-1.22(m,10H). MS(ESI)m / z=417.2[M+H] + .

[0631] Example 005.N 4 -(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-methyl-N 1 -(5-methylthiazol-2-yl)terephthalamide (BL1-5)

[0632] [ka]

[0633] BL1-5 was synthesized following the standard procedure for the preparation of BL1-2 (65 mg, 23% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 12.44(brs,1H),8.63(t,J=5.6Hz,1H),7.79-7.72(m,4H),7.60(d,J=8.0Hz,1H),7.21(d,J=1 .2Hz,1H),3.60-3.56(m,8H),3.46-3.42(m,2H),2.98-2.95(m,2H),2.42(s,3H),2.38(s,3H). MS(ESI)m / z=407.2[M+H] + .

[0634] Example 006.N 4 -(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-2-methyl-N 1 -(5-methylthiazol-2-yl)terephthalamide (BL1-6)

[0635] [ka]

[0636] BL1-6 was synthesized following the standard procedure for the preparation of BL1-2 (140 mg, 34% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 12.42(brs,1H),8.62(t,J=5.2Hz,1H),7.70-7.68(m,4H),7.60(d,J=8.0Hz,1H),7.20(d,J=1. 2Hz, 1H), 3.59-3.54 (m, 12H), 3.46-3.43 (m, 2H), 2.99-2.95 (m, 2H), 2.42 (s, 3H), 2.38 (s, 3H). MS(ESI)m / z=451.3[M+H] + .

[0637] Example 007.N 4 -(14-amino-3,6,9,12-tetraoxatetradecyl)-2-methyl-N 1 -(5-methylthiazol-2-yl)terephthalamide (BL1-7)

[0638] [ka]

[0639] BL1-7 was synthesized following the standard procedure for the preparation of BL1-2 (91 mg, 21% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 12.39(brs,1H),8.61(t,J=5.6Hz,1H),7.77-7.61(m,4H),7.60(d,J=8.0Hz,1H),7.20(d,J=1. 2Hz, 1H), 3.60-3.52 (m, 16H), 3.45-3.41 (m, 2H), 2.99-2.96 (m, 2H), 2.42 (s, 3H), 2.38 (s, 3H). MS(ESI)m / z=495.2[M+H] + .

[0640] Example 008.N 4-(17-amino-3,6,9,12,15-pentaoxaheptadecyl)-2-methyl-N 1 -(5-methylthiazol-2-yl)terephthalamide (BL1-8)

[0641] [ka]

[0642] BL1-8 was synthesized following the standard procedure for the preparation of BL1-2 (240 mg, 51% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 12.4(brs,1H),8.62(t,J=5.6Hz,1H),7.78-7.72(m,4H),7.59(d,J=8.0Hz,1H),7.21(s, 1H), 3.60-3.50 (m, 20H), 3.46-3.41 (m, 2H), 2.99-2.95 (m, 2H), 2.42 (s, 3H), 2.38 (s, 3H). MS(ESI)m / z=539.3[M+H] + .

[0643] Example 009. 4-((2-((5-aminopentyl)amino)-2-oxoethyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-9)

[0644] [ka]

[0645] Step 1. Synthesis of 2-methyl-N-(5-methylthiazol-2-yl)-4-nitrobenzamide

[0646] To a solution of 2-methyl-4-nitrobenzoic acid (5.00 g, 27.6 mmol) in DMF (100 mL) were added 5-methylthiazol-2-amine (3.20 g, 28.0 mmol), HATU (11.4 g, 30.0 mmol), and DIPEA (7.74 g, 60.0 mmol). The reaction mixture was stirred at 80 °C for 2 h. After cooling to room temperature, the solution was poured into ice water (500 mL). The solid was collected by filtration, washed with HO, and dried under vacuum to give the title compound (7.0 g, 92% yield) as a yellow solid. MS (ESI) m / z = 278.0 [M+H] + .

[0647] Step 2. Synthesis of 4-amino-2-methyl-N-(5-methylthiazol-2-yl)benzamide

[0648] To a solution of 2-methyl-N-(5-methylthiazol-2-yl)-4-nitrobenzamide (7.00 g, 25.2 mmol) in AcOH (50 mL) was added iron powder (11.2 g, 200 mmol). After stirring at 70 °C for 2 h, the reaction mixture was diluted with HO (20 mL), filtered, and concentrated under reduced pressure. The residue was adjusted to pH = 6 with aqueous NaHCO. The solid was collected by filtration, washed with HO, and dried in vacuo to give the title compound (6.00 g, 96% yield) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ 11.17 (s, 1H), 7.38-7.36 (m, 1H), 7.14 (s, 1H), 6.40 (s, 2H), 5.62 (s, 2H), 2.36 (s, 6H). MS(ESI)m / z=248.0[M+H] + .

[0649] Step 3. Synthesis of (3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)phenyl)glycine

[0650] To a solution of 4-amino-2-methyl-N-(5-methylthiazol-2-yl)benzamide (2.5 g, 7.20 mmol) in MeOH (50 mL) was added NaBH(OAc) (3.04 g, 14.4 mmol) and 2-oxoacetic acid (50%, 2 mL). After stirring overnight at room temperature, the solid was collected by filtration, washed with MeOH, and dried in vacuo to give the title compound (1.7 g, 77% yield) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ 12.58 (brs, 1H), 11.86 (brs, 1H), 7.45-7.44 (m, 1H), 7.14 (s, 1H), 6.45-6.44 (m, 3H), 3.87 (s, 2H), 2.36 (s, 6H). MS(ESI)m / z=306.0[M+H] + .

[0651] Step 4. Synthesis of tert-butyl (5-(2-((3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)phenyl)amino)acetamido)pentyl)carbamate

[0652] To a solution of (3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)phenyl)glycine (200 mg, 0.656 mmol) in DMF (2 mL) was added N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (TCFH) (277 mg, 0.984 mmol), N-methylimidazole (81 mg, 0.984 mmol), and tert-butyl(5-aminopentyl)carbamate (74 mg, 0.722 mmol). The mixture was stirred at room temperature for 3 h, then diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (310 mg, crude) as a brown oil.

[0653] Step 5. Synthesis of 4-((2-((5-aminopentyl)amino)-2-oxoethyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide

[0654] To a solution of tert-butyl (5-(2-((3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)phenyl)amino)acetamido)pentyl)carbamate (310 mg, crude) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 5 h, then concentrated and purified by preparative HPLC (0.1% TFA) to give the title compound (74.8 mg, TFA salt, 29% yield over two steps) as a white solid. 1 HNMR(400MHz,DMSO-d6)δ 11.87(brs,1H),7.96(t,J=11.6Hz,1H),7.75(brs,3H),7.45(d,J=8.4Hz 1H),7.14(d,J=1.2Hz,1H),6.41-6.38(m,2H),3.67(s,2H),3.10-3.05(m,2H),2.76-2.71( m,2H),2.36(s,3H),2.35(s,3H),1.53-1.49(m,2H),1.42-1.37(m,2H),1.30-1.24(m,2H). MS(ESI)m / z=390.2[M+H] + .

[0655] Example 010. 4-((2-((7-aminoheptyl)amino)-2-oxoethyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-10)

[0656] [ka]

[0657] BL1-10 was synthesized following the standard procedure for the preparation of BL1-9 (130 mg, 37% yield over two steps). 1HNMR(400MHz,DMSO-d6)δ 11.85(brs,1H),7.90(t,J=11.6Hz,1H),7.61(brs,3H),7.44(d,J=8.4Hz,1H),7.14(d,J=1.2Hz,1H),6.40-6.38(m,2H),3.86(s ,2H),3.09-3.05(m,2H),2.77-2.72(m,2H),2.36(s,3H),2.35(s,3H),1.53-1.49(m,2H),1.42-1.37(m,2H),1.30-1.24(m,6H). MS(ESI)m / z=418.2[M+H] + .

[0658] Example 011. 4-((2-((9-aminononyl)amino)-2-oxoethyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-11)

[0659] [ka]

[0660] BL1-11 was synthesized following the standard procedure for the preparation of BL1-9 (48 mg, 14% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 11.85(brs,1H),7.88(t,J=11.6Hz,1H),7.63(brs,3H),7.44(d,J=8.4Hz,1H),7.14(d,J=1.2Hz,1H),6.40-6.38(m,2H),3.66(s ,2H),3.09-3.05(m,2H),2.77-2.72(m,2H),2.36(s,3H),2.34(s,3H),1.53-1.47(m,2H),1.42-1.37(m,2H),1.36-1.24(m,10H). MS(ESI)m / z=446.2[M+H] + .

[0661] Example 012. 4-((2-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-oxoethyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-12)

[0662] [ka]

[0663] BL1-12 was synthesized following the standard procedure for the preparation of BL1-9 (168 mg, 59% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 11.86(brs,1H),7.95(t,J=5.6Hz,1H),7.77(brs,3H),7.44(d,J=8.4Hz,1H),7.14(s,1H),6.41-6.37(m,2H),3. 69(s,2H),3.58-3.52(m,6H),3.42-3.39(m,2H),3.27-3.22(m,2H),2.98-2.96(m,2H),2.36(s,3H),2.34(s,3H). MS(ESI)m / z=480.2[M+H] + .

[0664] Example 013. 4-((14-amino-2-oxo-6,9,12-trioxa-3-azatetradecyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-13)

[0665] [ka]

[0666] BL1-13 was synthesized following the standard procedure for the preparation of BL1-9 (130 mg, 44% yield over two steps). 1HNMR(400MHz,DMSO-d6)δ 11.86(brs,1H),7.95(t,J=5.6Hz,1H),7.77(brs,3H),7.44(d,J=8.4Hz,1H),7.14(s,1H),6.41-6.37(m,2H),3.69(s,2 H),3.58-3.52(m,6H),3.49(s,4H),3.42-3.39(m,2H),3.27-3.22(m,2H),2.98-2.96(m,2H),2.36(s,3H),2.34(s,3H). MS(ESI)m / z=480.2[M+H] + .

[0667] Example 014. 4-((18-amino-2-oxo-6,9,12,15-tetraoxa-3-azaoctadecyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-14)

[0668] [ka]

[0669] BL1-14 was synthesized following the standard procedure for the preparation of BL1-9 (320 mg, 55% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 11.88(brs,1H),7.96(t,J=5.4Hz,1H),7.75(brs,3H),7.46-7.44(d,1H),7.14(d,J=1.2Hz,1H),6.42-6.38(m,2H), 3.70(s,2H),3.59-3.48(m,14H),3.42-3.39(m,2H),3.27-3.22(m,2H),2.99-2.95(m,2H),2.37(s,3H),2.35(s,3H). MS(ESI)m / z=524.2[M+H] + .

[0670] Example 015. 4-((20-amino-2-oxo-6,9,12,15,18-pentaoxa-3-azaicosyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-15)

[0671] [ka]

[0672] BL1-15 was synthesized following the standard procedure for the preparation of BL1-9 (248 mg, 55% yield over two steps). 1 HNMR(400MHz,DMSO-d6)δ 11.86(brs,1H),7.95(t,J=5.4Hz,1H),7.75(brs,3H),7.46-7.44(d,J=8.4Hz,1H),7.14(d,J=1.2Hz,1H),6.42-6.38(m, 2H),3.69(s,2H),3.59-3.48(m,18H),3.42-3.39(m,2H),3.26-3.22(m,2H),2.99-2.95(m,2H),2.36(s,3H),2.34(s,3H). MS(ESI)m / z=568.3[M+H] + .

[0673] Example 016. 4-(2-((5-aminopentyl)amino)-2-oxoethoxy)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-16)

[0674] [ka]

[0675] Step 1. Synthesis of tert-butyl 4-hydroxy-2-methylbenzoate

[0676] To a solution of 4-hydroxy-2-methylbenzoic acid (3.00 g, 19.6 mmol) in THF (15 mL) and t-BuOH (15 mL) was added DCC (4.06 g, 19.6 mmol). The reaction mixture was stirred at room temperature for 12 hours. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 5:1) to give the title compound (1.5 g, 37% yield) as a yellow solid.

[0677] Step 2. Synthesis of tert-butyl 4-(2-ethoxy-2-oxoethoxy)-2-methylbenzoate

[0678] To a solution of tert-butyl 4-hydroxy-2-methylbenzoate (1.50 g, 7.20 mmol) in DMF (10 mL) were added ethyl 2-bromoacetate (1.20 g, 7.20 mmol) and K2CO3 (1.20 g, 7.20 mmol). The reaction mixture was stirred at 25 °C for 12 hours. The solution was then poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (petroleum ether / EtOAc = 5:1) to give the title compound (1.00 g, 48% yield) as a white solid. MS (ESI) m / z = 295.1 [M+H] + .

[0679] Step 3. Synthesis of 4-(2-ethoxy-2-oxoethoxy)-2-methylbenzoic acid

[0680] To a solution of 2-ethoxy-6-methylbenzoic acid (1.0 g, 3.3 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated in vacuo to give the title compound (950 mg, crude) as a yellow solid, which was used in the next step without further purification. MS (ESI) m / z = 239.1 [M+H] + .

[0681] Step 4. Synthesis of ethyl 2-(3-methyl-4-((5-methylthiazol-2-yl)carbamoyl)phenoxy)acetate

[0682] To a solution of 4-(2-ethoxy-2-oxoethoxy)-2-methylbenzoic acid (950 mg, crude...

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, A is a target protein binding moiety; L １ is the linker, B is a compound of formula (II): 【Chemistry 2】 is a DDB1 binding moiety having the structure During the ceremony, Ring Q is a 5-membered monocyclic heteroaryl; L ２ is a bond, —O—, —NR ４Ａ -, -NR ４Ｂ -C(=O)-, -NR ４Ｂ -C(=O)-(C １ -C ３ alkylene)-NR ４Ａ -, -NR ４Ｂ -C(=O)-(C １ -C ３ alkylene)-O-, -(C １ -C ３ alkylene)-NR ４Ｂ -C(=O)-, -C(=O)NR ４Ａ -, -C １ -C ３ Alkylene-, -C ２ -C ３ Alkenylene-, -C ２ -C ３ Alkynylene-, C ３ -C ８ Cycloalkylene, or C ２ -C ８ Heterocyclene, R １ are each independently hydrogen, halogen, -CN, NO ２ , -OR ４Ａ , -NR ４Ａ R ４Ｂ , -C(=O)R ４Ａ , -C(=O)OR ４Ａ , —C(═O)NR ４Ｂ R ４Ａ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ３ -C ８ Cycloalkyl, C ２ -C ８ heterocyclyl, aryl, or heteroaryl; or Two R's １ together with the atoms to which they are connected, and optionally C ３ -C １３ Cycloalkyl, C ３ -C １２ forming a heterocyclyl, aryl, or heteroaryl; R ２ But hydrogen, C １ -C ６ Alkyl, C ３ -C ８ Cycloalkyl, OH, or O—C １ -C ４ is alkyl, R ３ are each independently hydrogen, halogen, —CN, —NO ２ , -OR ４Ａ , -NR ４Ａ R ４Ｂ , -C(=O)R ４Ａ , -C(=O)OR ４Ａ , —C(═O)NR ４Ｂ R ４Ａ , —OC(═O)R ４Ａ , -N(R ４Ａ ) C(=O)R ４Ｂ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ３ -C ８ Cycloalkyl, C ２ -C ８ heterocyclyl, aryl, or heteroaryl; or Two R's ３ together with the atoms to which they are connected, and optionally C ３ -C １３ Cycloalkyl, C ２ -C １２ forming a heterocyclyl, aryl, or heteroaryl; R ４Ａ and R ４Ｂ are each independently hydrogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C １ -C ６ Haloalkyl, C １ -C ６ Heteroalkyl, C ３ -C ８ Cycloalkyl, C ２ -C ８ heterocyclyl, aryl, or heteroaryl; or R ４Ａ and R ４Ｂ together with the atoms to which they are connected, and optionally C ２ -C １２ forming a heterocyclyl, p is 1, 2, or 3; q is 1, 2, or 3; A heterobifunctional compound, or a pharmaceutically acceptable salt thereof.

2. The DDB1 binding moiety of formula (II) is represented by formula (III-1) or (III-2): 【Chemistry 3】 having the structure During the ceremony, X 1 is O, S, or NR 5 ; X 2 and X 5 are independently N or CH; R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, or C 2 -C 8 heterocyclyl; R 1A and R 1B are independently selected from hydrogen, halogen, CN, NO 2 , —OR 4A , —NR 4B R 4A , —C(═O)R 4A , —C(═O)OR 4A , —C(═O)NR 4B R 4A , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl; 2. The heterobifunctional compound of claim 1, wherein R 1A and R 1B together with the atoms to which they are attached optionally form a C 3 -C 13 cycloalkyl, C 2 -C 12 heterocyclyl, aryl, or heteroaryl, or a pharmaceutically acceptable salt thereof.

3. The DDB1 binding moiety of formula (II) is represented by formula (IV-1): 【Chemistry 4】 3. The heterobifunctional compound of claim 2 having the structure: or a pharmaceutically acceptable salt thereof.

4. The heterobifunctional compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R 1A is selected from hydrogen, halogen, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3 ) 2 , -CH 3 , -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl.

5. The heterobifunctional compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R 1B is selected from —CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

6. The heterobifunctional compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is F, Cl, Br, CH3, CHF2, CF3, CH2CH3, CH(CH3)2, cyclopropyl, CN, -NH2, NH(CH3), NH(i-Pr), NH(n-Bu), NH(t-Bu), or N(CH3)2.

7. The heterobifunctional compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

8. The heterobifunctional compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L 2 is —NH—.

9. The heterobifunctional compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L 2 is —O—.

10. The linker L 1 is -(CH 2 ) p1 C(=O)NH(CH 2 CH 2 O) p2 -(CH 2 ) p3 -, -(CH 2 ) p1 C(=O)NH(CH 2 ) p2 -, -(CH 2 ) p1 NHC(=O)-(CH2CH2O) p2-(CH2) p3-,-(CH2) p1 NHC(=O)-(CH2) p2-,-(CH2) p1 C(=O)-(CH2CH2O) p2-(CH2) p3 -, -(CH 2 ) p1 C(=O)-(CH 2 ) p2 -, -(CH 2) p1 NH(CH 2 CH 2 O) p2 -(CH 2 ) p3 -, -(CH 2 ) p1 NH(CH 2 ) p2 -, -(CH 2 CH 2 O) p2 -(CH 2 ) p3 -, or -(CH 2 ) p2 -, wherein p1 is an integer selected from 0 to 8, p2 is an integer selected from 1 to 15, and p3 is an integer selected from 0 to 8, or a pharmaceutically acceptable salt thereof.

11. The heterobifunctional compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the linker L 1 is —(CH 2 ) p1 NH(CH 2 CH 2 O) p2 —(CH 2 ) p3 —.

12. The heterobifunctional compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein the linker L 1 is —(CH 2 ) 0-2 NH(CH 2 CH 2 O) 1-12 (CH 2 ) 2 —.

13. The heterobifunctional compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is a target protein binding moiety comprising a BRD4 binding moiety.

14. A is represented by formula (C-1), (C-2), (C-3), (C-4), (C-5), or (C-6): 【Chemistry 5】 or a pharmaceutically acceptable salt thereof, During the ceremony, 【Chemistry 6】 but, 【Chemistry 7】 and X C 1 and X C 2 are each independently CR C 3 or N; Y C 1 is O, S, or —C(R C 2 )═C(R C 2 )—; Y C 2 is C(R C 7 ) 2 or NR C 7 ; R C 1 is hydrogen or optionally substituted C 6 -C 10 aryl or 5-10 membered heteroaryl; R C 2 are each independently hydrogen, halogen, CN, NO 2 , NR C 4 R C 5 , —C(═O)R C 6 , —C(═O)OR C 4 , —C(═O)NR C 4 R C 5 , —OC(═O)R C 6 , —N(R C 4 )C(═O)R C 6 , C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, C 2 -C 8 alkynyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, or C 1 -C 8 alkylaryl; R C 3 are each independently hydrogen, halogen, CN, NO 2 , NR C 4 R C 5 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, aryl, or heteroaryl; R C4 , R C5 , and R C6 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocyclyl, aryl, or heteroaryl; R C 4 and R C 5 together with the atoms to which they are attached optionally form a 3- to 20-membered heterocyclyl ring; R C 7 is each independently hydrogen, NR C 4 R C 5 , OR C 4 , —C(═O)R C 6 , —C(═O)OR C 6 , —C(═O)NR C 4 R C 5 , —(C 1 -C 8 alkyl)-C(═O)NR C 4 R C , —OC(═O)R C 6 , —N(R C 8 )C(═O)R C 6 , C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocyclyl; two of R C 7 together with the atom to which they are attached optionally form a C 3 -C 8 cycloalkyl or a C 2 -C 8 heterocyclyl; 2. The heterobifunctional compound of claim 1, wherein x 4C is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

15. The heterobifunctional compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein X C 1 and X C 2 are each independently N.

16. The heterobifunctional compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein Y C 1 is S.

17. The heterobifunctional compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R C3 is hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 1 -C 8 alkoxy, or C 1 -C 8 alkoxyalkyl.

18. The heterobifunctional compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein x 4C is 2 and each R C 2 is independently C 1 -C 8 alkyl or C 1 -C 8 alkoxy.

19. The heterobifunctional compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R C1 is an optionally substituted C6 aryl, optionally substituted with 1 to 4 halogen, CN, NO 2 , NR C4 R C5 , C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl.

20. The target protein binding moiety, 【Chemistry 8】 15. The heterobifunctional compound of claim 14, wherein:

21. The DDB1-binding moiety of formula (IV-1), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methyl-N-(5-phenylthiazol-2-yl)benzamide (BL1-23), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-24), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methyl-N-(5-(trifluoromethyl)thiazol-2-yl)benzamide (BL1-25), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methyl-N-(thiazol-2-yl)benzamide (BL1-26), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(5-chlorothiazol-2-yl)-2-methylbenzamide (BL1-27), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(5-isopropylthiazol-2-yl)-2-methylbenzamide (BL1-28), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methyl-N-(4-phenylthiazol-2-yl)benzamide (BL1-29), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(5-fluorothiazol-2-yl)-2-methylbenzamide (BL1-33), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(5-cyclopropylthiazol-2-yl)-2-methylbenzamide (BL1-34), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(5-methoxythiazol-2-yl)-2-methylbenzamide (BL1-35), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (BL1-36), Methyl 2-(4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methylbenzamido)thiazole-5-carboxylate (BL1-37), Methyl 2-(4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methylbenzamido)-5-methylthiazole-4-carboxylate (BL1-38), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methyl-N-(5-methyl-4-phenylthiazol-2-yl)benzamide (BL1-39), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(4-isopropyl-5-methylthiazol-2-yl)-2-methylbenzamide (BL1-40), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(4-bromo-5-methylthiazol-2-yl)-2-methylbenzamide (BL1-41), N-(4-acetyl-5-methylthiazol-2-yl)-4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methylbenzamide (BL1-42), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(4-cyclopropyl-5-methylthiazol-2-yl)-2-methylbenzamide (BL1-43), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-N-(4-ethyl-5-methylthiazol-2-yl)-2-methylbenzamide (BL1-44), 4-((8-aminooctyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-189), 4-((9-aminononyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-190), 4-((2-(2-aminoethoxy)ethyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-191), 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-192), 4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-193), 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-194), 4-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-195), and 4-((20-amino-3,6,9,12,15,18-hexaoxaicosyl)amino)-2-methyl-N-(5-methylthiazol-2-yl)benzamide (BL1-196) 4. The heterobifunctional compound of claim 3, selected from the group consisting of:

22. (S)-2-(5-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)pentanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-219), (S)-3-((2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-220), (S)-3-((3-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)propyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-221), (S)-3-((4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)butyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-222), (S)-3-((5-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)pentyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-223), (S)-3-((6-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)hexyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-224), (S)-3-((7-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)heptyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-225), (S)-3-((8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)octyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-226), (S)-3-((2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-227), (S)-3-((2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-228), (S)-3-((1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-229), (S)-3-((1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-17-yl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-230), (S)-3-((1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15,18-pentaoxa-3-azaeicosan-20-yl)amino)-N-(4,5-dimethylthiazol-2-yl)-2-methylbenzamide (CPD-231), (S)-2-(3-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)propanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-232), (S)-2-(4-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)butanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-233), (S)-2-(6-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)hexanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-234), (S)-2-(7-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)heptanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-235), (S)-2-(3-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)propanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-236), (S)-2-(3-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)propanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-237), (S)-2-(1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azapentadecan-15-amido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-238), (S)-2-(1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaoctadecan-18-amido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-239), (S)-2-(1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15,18-pentaoxa-3-azaheneicosan-21-amide)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-240), (S)-2-(1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15,18,21-hexaoxa-3-azatetracosan-24-amide)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-241), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 3 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)malonamide (CPD-242), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 4 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)succinamide (CPD-243), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 5 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)glutaramide (CPD-244), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 6 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)adipamide (CPD-245), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 7 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)heptanediamide (CPD-246), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 8 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)octanediamide (CPD-247), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 9 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)nonanediamide (CPD-248), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 10 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)decanediamide (CPD-249), (S)-2-(1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2,7-dioxo-10,13-dioxa-3,6-diazahexadecan-16-amido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-250), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 16 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)-4,7,10,13-tetraoxahexadecanediamide (CPD-251), (S)—N 1 -(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)-N 19 -(2-((4,5-dimethylthiazol-2-yl)carbamoyl)phenyl)-4,7,10,13,16-pentaoxanonadecanediamide (CPD-252), (S)-2-(12-((2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)amino)dodecanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-253), (S)-2-(1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-9,12,15-trioxa-3,6-diazaoctadecan-18-amido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-254), (S)-2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)acetamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-255), (S)-2-(8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)octanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-256), (S)-2-(3-(3-((2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethyl)amino)-3-oxopropoxy)propanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-257), (S)-2-(9-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)nonanamido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-258), (S)-2-((9-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)nonyl)amino)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-259), (S)-2-(1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2,7-dioxo-10,13,16-trioxa-3,6-diazanonadecan-19-amido)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-260), (S)-2-(1-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-2-oxo-6,9,12,15,18,21-hexaoxa-3-azatetracosan-24-amide)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-261), (S)-2-((3-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)propyl)amino)-N-(4,5-dimethylthiazol-2-yl)benzamide (CPD-262), (S)-2-acetamido-4-((3-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)propyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide (CPD-263), (S)-2-acetamido-4-((5-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)pentyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide (CPD-264), (S)-2-acetamido-4-((9-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)nonyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide (CPD-265), or (S)-2-acetamido-4-((11-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)undecyl)amino)-N-(4-methyl-5-nitrothiazol-2-yl)benzamide (CPD-266) 2. The heterobifunctional compound of claim 1, wherein:

23. A method for degrading a target protein, comprising contacting the target protein with the heterobifunctional compound of claim 1, or a pharmaceutically acceptable salt thereof.

24. Use of the heterobifunctional compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject in need thereof.

25. The use of claim 24, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, endometrial cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colon cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, thyroid cancer, and melanoma.

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