Compounds and methods for treating cancer

Abstract

Provided herein are hetero-bifunctional compounds of any of Formulae (I)-(XII), and pharmaceutically acceptable salts, pharmaceutical compositions and uses thereof, which can be used for targeted degradation of a protein of interest. Also provided are E3 ligase binding compounds of Formula (XIII), and salts, compositions and uses thereof.

Description

[0001] Cross-references

[0002] This application claims the benefits of PCT application No. PCT / CN2023 / 080134 filed on March 7, 2023 and PCT application No. PCT / CN2023 / 141582 filed on December 25, 2023, each of which is incorporated herein by reference in its entirety.

[0003] sequence list

[0004] This application contains a sequence of documents electronically submitted in XML file format and hereby incorporated herein by reference in its entirety. The XML copy is named 54922_723_603_SL.xml, created on March 1, 2024, and is 6,844 bytes in size. Technical Field

[0005] This document provides heterobifunctional compounds and methods for regulating cyclin D (CCND), cyclin-dependent kinase 4 (CDK4), and / or cyclin-dependent kinase 6 (CDK6) through ubiquitination and / or targeting protein degradation. Pharmaceutically acceptable salts of such compounds, pharmaceutical compositions comprising such compounds and salts, and their uses are also provided. The compounds, salts, and compositions described herein can be used to treat a variety of diseases associated with CCND, CDK4, and / or CDK6, including abnormal cell proliferative disorders such as cancer. Background Technology

[0006] The ubiquitin (Ub) proteasome system (UPS) plays a crucial role in intracellular protein turnover and maintaining protein homeostasis by selectively eliminating abnormally folded or damaged proteins. Targeted protein degradation, which utilizes UPS to selectively degrade disease-associated proteins of interest (“POIs”), has emerged as a promising drug discovery strategy (M. Békés, D.R.Langley, and C.M.Crews, PROTAC targeted protein degraders: the past is prologue, Nature Reviews (2022), 21:181-200.).

[0007] Targeted protein degradation agents are heterobifunctional compounds comprising a protein binding moiety (“PBM”) directed to a target protein, which is covalently attached via a linker to an E3 ligase binding moiety. By binding to the target protein and the corresponding E3 ligase, such heterobifunctional degrader molecules can induce ubiquitination and degradation of the POI by the UPS. Typically, the POI is the target protein that binds to the PBM. Recently, examples of heterobifunctional compounds that degrade proteins that are not directly bound to the PBM have been reported. Sometimes referred to as “bridging” or “bystander” degradation, this off-target degradation can occur unpredictably when the relevant protein is ubiquitinated and degraded as part of the degrader-POI complex. Exploiting this phenomenon to selectively target relevant proteins of interest can enable degradation of otherwise undruggable proteins associated with the degrader-target protein complex.

[0008] The specificity of the UPS is largely achieved through the function of E3 ubiquitin ligases (E3), which promote the covalent transfer of Ub onto lysine residues of substrate proteins in a highly regulated manner, leading to polyubiquitination and protein degradation by the 26S proteasome. More than 600 E3s have been identified, classified into four families: HECT (homologous to the E6AP C terminus) type, U-box type, RING (Really Interesting New Gene) type, and RBR (RING-between-RING) type (G. Kleiger & T. Mayor, Perilous Journey: a Tour of the Ubiquitin Proteasome System. Trends Cell Biol. (2014), 24:352-359.). However, only a few E3s have been widely used to make degraders, most commonly cereblon (CRBN) and von Hippel-Lindau tumor suppressor (VHL) (A. Bricelj et al., E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Attachment Points, Front. Chem. (2021) 9:1-46.). The discovery of degraders that work through different E3 ligases can be used to address resistance to or overcome potential liabilities of CRBN- and VHL-based degraders (K. Moreau et al., Proteolysis-targeting chimeras in drug development: A safety perspective, Br J Pharmacol (2019), 177:1709-1718.).

[0009] DDB1 (DNA damage binding protein 1) was first identified as a subunit of a heterodimeric complex involved in DNA repair. DDB1 was later found to act as a linker protein to link substrate receptor proteins to CUL4 to assemble multiple CUL4-RING E3 ligase complexes (CRL4). Perhaps due to the inherent flexibility of CRL ligases, the CRL family of E3 ligases is frequently hijacked by various viruses to degrade diverse host restriction factors. In particular, DDB1 is among the most frequently hijacked E3 factors. Structural analysis of DDB1 in complex with HBx or SV5-V H-Box motif provides key insights into the binding site of DDB1 with viral proteins.

[0010] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that perform important functions in regulating cell division and proliferation. CDK1-4, 6, 10, and 11 have been reported to play a direct role in cell cycle progression, while CDK3, 5, and 7-9 can play indirect roles (e.g., by activating other CDKs, regulating transcription, or neuronal function). The catalytic unit of CDKs is activated by binding to regulatory subunits, called cyclins, which can be divided into four general classes (G1, G1 / S, S, and M cyclins) whose expression levels vary at different points in the cell cycle. Cyclin B / CDK1, Cyclin A / CDK2, Cyclin E / CDK2, Cyclin D / CDK4, Cyclin D / CDK6, and other possible Cyclin / CDK heterodimers are important regulators of cell cycle progression.

[0011] CDK4 and CDK6 have proven to be tractable targets for the development of traditional small molecule inhibitors. Three CDK4 / 6 inhibitors (palbociclib, ribociclib, and abemaciclib) have been approved in combination with endocrine therapy for the treatment of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative, advanced or metastatic breast cancer, and one (trilaciclib) has been approved for mitigating chemotherapy-induced myelosuppression. As with other kinase inhibitors, resistance to CDK4 / 6 inhibitors develops over time, leading to disease progression. Resistance mechanisms to CDK4 / 6 inhibitors have been identified as RB1 deletion, amplification or overexpression of CDK4 or CDK6, and amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2) (M. Alvarez-Fernandez & M. Malumbres, Mechanisms of Sensitivity and Resistance to CDK4 / 6 Inhibition, Cancer Cell (2020), 37:514-529.).

[0012] Degraders of CDK4 and CDK6 have been reported, but none appear to have entered clinical development (see, e.g., B. Jiang et al., Development of Dual and Selective Degraders of Cyclin-Dependent Kinases 4 and 6, Angew Chem Int Ed Engl (2019), 58(19):6321-6326; B. Zhao & K. Burgess, PROTACs suppression of CDK4 / 6, crucial kinases for cell cycle regulation in cancer, Chem Commun (Camb.) (2019), 55(18):2704-2707; S. Rana et al., Selective degradation of CDK6 by a palbociclib based PROTAC, Bioorg Med Chem Lett (2019), 29:1375-1379.).

[0013] Cyclin D (CCND) includes three closely related isoforms, Cyclin D1 (CCND1), Cyclin D2 (CCND2), and Cyclin D3 (CCND3), which heterodimerize with CDK4 and CDK6 to form CCND-CDK4 / 6 complexes that can phosphorylate and inactivate the retinoblastoma (Rb). D-cyclins are activated by mitogenic and oncogenic signals and promote the G1 -to-S transition, leading to cell proliferation. Amplification or overexpression of CCND1 has been observed in solid and hematological cancers, including breast cancer, bone cancer, central nervous system (CNS) cancer, non-small cell lung cancer (NSCLC), ovarian cancer, endometrial cancer, gastric cancer, oral cancer, esophageal cancer, head and neck cancer, colorectal cancer, pancreatic cancer, melanoma, mantle cell lymphoma (MCL), and multiple myeloma (S. Chen & L. Li, Degradation strategy of CCND1 in cancer cells and potential clinical application, Front. Oncol. (2022), 1-10.).

[0014] D-cyclins have long been identified as potential therapeutic targets, but have proven to be intractable for traditional small molecule drug discovery efforts due to the lack of actionable binding sites on the protein (E. A. Musgrove et al., Cyclin D as a therapeutic target in cancer, Nature (2011), 11:558-572.). Cyclin D1 was identified as the most prioritized cancer target by the Cancer Dependency Map (DepMap) project (F. M. Behan et al., Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature (2019), 568:511-516.).

[0015] Limited examples of targeted CDK4 degraders that can modulate CCND have recently been reported (International Publication No. WO 2020 / 247537; International Publication No. WO 2021 / 239117; Y. Xiong et al., Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets, J. Am. Chem. Soc. (2022), 144:22622-22632.).

[0016] Targeting protein degradation agents can allow for more flexible modulation of protein levels in vitro and in vivo compared to other techniques such as gene knockout or short hairpin RNA-mediated (shRNA) knockdown. Unlike gene knockout or shRNA knockdown, small molecule approaches further provide the opportunity to study dose and time dependence in disease models by modulating the route of administration, concentration, and frequency of administration of the corresponding heterobifunctional small molecule compound.

[0017] There remains a need to discover protein degradation agents that can modulate CCND, CDK4, and / or CDK6 activity, particularly degradation agents that utilize novel E3 ligases. Such degradation agents can be useful for treating disorders associated with CCND, CDK4, and / or CDK6 and can provide advantages in overcoming resistance or reducing toxicity associated with CDK4 / 6 inhibitors or cereblon or VHL-based degradation agents. SUMMARY

[0018] Described herein are monofunctional and heterobifunctional compounds comprising a DDB1 (DNA damage binding protein 1) E3 ligase binding moiety. The monofunctional compounds can be used as molecular glues or as synthetic intermediates for preparing heterobifunctional compounds. The heterobifunctional compounds comprising a DDB1 binding moiety conjugated to a protein binding moiety through a linker can be used for several purposes, including but not limited to as: 1) antiviral drugs; 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 glues (e.g., increasing protein-protein interactions between DDB1 and a second protein); or 5) targeted protein degradation agents. The molecular glue or targeted protein degradation function can be used to affect the activity or protein levels of a protein directly bound to the PBM (i.e., the target protein) and / or a related protein of interest (POI) that is not directly bound to the PBM.

[0019] Provided herein are heterobifunctional compounds of any one of Formulae (I)-(XII), and embodiments thereof, and pharmaceutically acceptable salts, pharmaceutical compositions, and uses thereof, as further described herein.

[0020] In one aspect, provided is a heterobifunctional compound of Formula (I):

[0021]

[0022] or a pharmaceutically acceptable salt thereof, wherein:

[0023] A is a protein binding moiety (PBM) capable of binding to CCND, CDK4, and / or CDK6;

[0024] L1 is a bond or a bivalent linker;

[0025] L 2 is a bond, -NH-, -N(C1-C3alkyl)-, -NHC(O)-, -N(C1-C3alkyl)C(O)-, -C(O)NH-,

[0026] -C(O)N(C1-C3alkyl)-, -O-, -C1-C4-alkylene-, -C2-C4-alkenylene-, or -C2-C4-alkynylene-;

[0027] Q is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 10 cycloalkyl, or 4-10 membered heterocyclyl;

[0028] each R 1 is independently R 1A , R 1B , R 1C , R 1D , or R 1E ;

[0029] each R 1A is independently H, C1-C6alkyl, C3-C6cycloalkyl, or C1-C6heteroalkyl, wherein each said C1-C6alkyl, C3-C6cycloalkyl, or C1-C6heteroalkyl is optionally substituted with one or more R 4A ;

[0030] each R 1B , R 1C , R 1D , and R 1E is independently H, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, OH, D, halo, CN, NO2, NR 5A R 5B , C(=O)R 5A , C(=O)OR 5A , OC(=O)R 5A , C(O)NR 5A R 5B , N(R 5A )C(O)R 5B , C3-C 10 cycloalkyl, C3-C 10 cycloalkoxy, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein each said C1-C6alkyl, C1-C6heteroalkyl, or C1-C6alkoxy is optionally substituted with one or more R 4B , and each said C3-C 10cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 4C replace;

[0031] R 2 It is an H or C1-C3 alkyl group;

[0032] Each R 3 They are all independent R 3A R 3B or R 3C ; or two Rs 3 They can form C3-C together with the atoms to which they are attached. 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 6A replace;

[0033] Each R 3A R 3B and R 3C All are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, D, halogenated, CN, NO2, NR 7A R 7B C(=O)R 7A C(=O)OR 7A OC(=O)R 7A C(O)NR 7A R 7B 、N(R 7A )C(O)R 7B C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 heteroalkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 6B Replace, and each of the C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 6C replace;

[0034] Each R 4A R4B and R 6B are each independently C1-C6alkoxy, oxo, OH, D, halo, CN, or NR 8A R 8B ;

[0035] each R 4C , R 6A , and R 6C are each independently C1-C4alkyl, C1-C6alkoxy, oxo, OH, D, halo, CN, or NR 9A R 9B ;

[0036] each R 5A , R 5B , R 7A , R 7B , R 8A , R 8B , R 9A , and R 9B are each independently H, C1-C6alkyl, C1-C6heteroalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein each said C1-C6alkyl or C1-C6heteroalkyl is optionally substituted with one or more R 10A , and each said C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 10B ; or

[0037] R 5A and R 5B , R 7A and R 7B , R 8A and R 8B , or R 9A and R 9B may be taken together with the N atom to which they are attached to form a 4-10 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, wherein each said 4-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with one or more R 10C ;

[0038] each R 10A is independently C1-C6alkoxy, oxo, OH, D, halo, CN, or NR 11A R 11B ;

[0039] each R 10B and R 10Ceach R is independently C1-C4alkyl, C1-C6alkoxy, oxo, OH, D, halo, CN, or NR 12A R 12B ;

[0040] each R 11A , R 11B , R 12A , and R 12B are independently H, C1-C4alkyl, or C3-C6cycloalkyl;

[0041] p is an integer from 0 to 4; and

[0042] q is an integer from 0 to 3;

[0043] provided that the compound of Formula (I) is not:

[0044] 2-(3-(2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetylamino)ethoxy)ethoxy)propionylamino)- N-(4,5-dimethylthiazol-2-yl)-6-methylnicotinamide; or

[0045] 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetylamino)heptyl)amino)-N-(4,5- dimethylthiazol-2-yl)-6-methylnicotinamide.

[0046] In one embodiment, the heterobifunctional compound of Formula (I) has the structure of Formula (II):

[0047]

[0048] or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment, the heterobifunctional compound of Formula (I) or (II) has the structure of Formula (III):

[0050]

[0051] or a pharmaceutically acceptable salt thereof.

[0052] In another embodiment, the heterobifunctional compound of Formula (I), (II), or (III) has the structure of Formula (IV):

[0053]

[0054] or a pharmaceutically acceptable salt thereof.

[0055] In other embodiments, provided herein are heterobifunctional compounds of any of the subformulae of Formula (V)-(XII) or a pharmaceutically acceptable salt thereof, as further described herein.

[0056] In another aspect, also provided herein are DDB1 binding compounds of Formula (XIII), and salts, compositions, and uses thereof, as further described.

[0057] In another aspect, also provided are pharmaceutical compositions and medicaments comprising a heterobifunctional compound or salt of any of Formulae (I)-(XII), alone or in combination with an additional therapeutic agent, such as an additional anti-cancer therapeutic agent.

[0058] In yet another aspect, also provided are methods for making the heterobifunctional compounds, salts, and compositions described above, and using the same, for example, in methods of degrading a protein of interest (POI), such as CCND or CDK4, or in methods for treating a disease or disorder associated with abnormal cell growth, such as cancer.

[0059] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety for the purpose of describing and disclosing, in their entirety, the specific purposes to which they are put in this specification. BRIEF DESCRIPTION OF DRAWINGS

[0060] Figure 1A Immunoblots showing CCND1, CCND3, and p-Rb proteins expressed by Calu-1 cells after 4 hours of treatment with a dose range of the CDK4 / 6 inhibitor palbociclib or the heterobifunctional compound CPD-10.

[0061] Figure 1B Immunoblots showing CCND1, CCND3, CDK4, FoxM1, Cyclin A2, and p-Rb proteins expressed by MCF7 cells under serum-starved conditions after 24 hours of treatment with a dose range of the CDK4 / 6 inhibitor palbociclib or the heterobifunctional compound CPD-10.

[0062] Figure 2A Immunoblots showing CCND1, CCND3, CDK4, p-Rb, FoxM1, and Cyclin A2 proteins expressed by T47D cells after 48 hours of treatment with a dose range of the heterobifunctional compound CPD-10 or its negative control compound CPD-143.

[0063] Figure 2B Antisurvival curves of Calu-1, MCF7, or T47D cells in the presence of CPD-10 or CPD-143 over 3-6 days.

[0064] Figure 3A The flow cytometry analysis of T47D cells stained with annexin V / 7-AAD after treatment with DMSO, palbociclib, or the bifunctional compound CPD-10 at specified concentrations for 6 days is shown.

[0065] Figure 3B The flow cytometry analysis of HCC1428 cells stained with annexin V / 7-AAD after treatment with DMSO, palbociclib, the isobifunctional compound CPD-10 or its control compound CPD-143 at specified concentrations for 6 days is shown.

[0066] Figure 4 The anti-survival curves of T47D parental or palbo-resistant cells were shown after 6 days in the presence of palbociclib or the bifunctional compounds CPD-10 or CPD-39.

[0067] Figure 5 The graph shows plasma concentrations of CPD-39 over time following administration via intravenous (iv) injection or oral (po) gavage. Detailed Implementation

[0068] This document provides heterobifunctional compounds of any of formulas (I)-(XII), pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and uses. Monofunctional compounds of formula (XIII), their salts thereof, compositions thereof, and uses are also provided. Various embodiments described herein include those listed in E1 to E85. Features specifically described in each embodiment may be combined with other specifically described features to provide further embodiments.

[0069] The invention can be more readily understood by referring to the following detailed description of aspects and embodiments of the invention, as well as the examples described herein.

[0070] Definitions

[0071] As used herein and in the appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural indicators. Thus, for example, unless otherwise stated, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or multiple cells), and so on.

[0072] As used herein, unless otherwise stated, “and / or” means “one or more” in the list of alternatives. For example, references to “CCND, CDK4 and / or CDK6” mean “one or more of CCND, CDK4 or CDK6”.

[0073] When a range is used herein to refer to physical properties such as molecular weight or chemical properties such as chemical formula, all combinations and sub-combinations of the range and specific embodiments thereof are intended to be included. The term “about” when referring to a range of numbers or values ​​means that the number or range mentioned is an approximation within experimental variability (or within statistical experimental error), and thus in some cases the number or range of values ​​will vary from ±1% to ±15% of the stated number or range of values, and preferably within ±10%.

[0074] The invention described herein can be suitably practiced in the absence of any element not expressly disclosed herein. Therefore, for example, any of the terms “comprising,” “substantially consisting of,” and “consisting of” in each context herein may be replaced by any of the other two terms. As used in this specification and the appended claims, unless stated otherwise, the following terms have the meanings described below.

[0075] "Amino" refers to an "unsubstituted amino" radical in the form of –NH2 or a "substituted amino" radical in the form of -NHR′ or -N(R′)2, as described herein and defined by the claims.

[0076] "Azide" or "azide" refers to the -N3 free radical.

[0077] "Cyano" refers to the -CN free radical.

[0078] "Halogen" or "halogenated" refers to bromine, chlorine, fluorine, or iodine substituents.

[0079] "Hydrazine" refers to the =N-NH2 free radical.

[0080] "Hydroxy group" refers to the -OH free radical.

[0081] "Imine" refers to the =NH free radical.

[0082] "Nitro" refers to the -NO2 free radical.

[0083] "O- radical" refers to the -O- free radical.

[0084] "Oxime" refers to the =N-OH free radical.

[0085] "Oxidation" refers to the =O free radical.

[0086] "Thio" refers to the =S free radical.

[0087] "Alkyl" refers to a straight-chain or branched hydrocarbon radical consisting only of carbon and hydrogen atoms, without any degree of unsaturation, and having a specified number of carbon atoms. In some embodiments, the alkyl group contains one to fifteen carbon atoms (e.g., C1-C1). 15alkyl). In certain embodiments, the alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, the alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, the alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl is selected from the group consisting of: methyl, ethyl, 1 -propyl (normal propyl), 1 -methylethyl (iso-propyl), 1 -butyl (normal butyl), 1 -methy lpropyl (sec -butyl), 2-methy lpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (normal pentyl). The alkyl is attached to the rest of the molecule by a single bond. 13 alkyl). In certain embodiments, the alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, the alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, the alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl is selected from the group consisting of: methyl, ethyl, 1 -propyl (normal propyl), 1 -methylethyl (iso-propyl), 1 -butyl (normal butyl), 1 -methy lpropyl (sec -butyl), 2-methy lpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (normal pentyl). The alkyl is attached to the rest of the molecule by a single bond. 15 alkyl). In certain embodiments, the alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, the alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, the alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl is selected from the group consisting of: methyl, ethyl, 1 -propyl (normal propyl), 1 -methylethyl (iso-propyl), 1 -butyl (normal butyl), 1 -methy lpropyl (sec -butyl), 2-methy lpropyl (iso-butyl), 1,1 -dimethylethyl (tert-butyl), 1 -pentyl (normal pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0088] Unless otherwise indicated, an alkyl group (including an alkenyl or alkynyl group) can be optionally substituted with one or more substituents, as further defined herein in the claims and disclosure. The total number of substituents on this alkyl moiety can equal, to the extent such substitution gives rise to chemically meaningful degrees, the total number of hydrogen atoms on this alkyl moiety. A substituted alkyl group typically contains 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, 1 to 4 optional substituents, or preferably 1 to 3 optional substituents. Unless otherwise indicated, the optional substituents are independently selected.

[0089] “Alkenyl” refers to an alkyl group as defined herein consisting of at least two carbon atoms and at least one carbon-carbon double bond. In certain embodiments, the alkenyl comprises two to fifteen carbon atoms (e.g., C2-C15 alkenyl). In certain embodiments, the alkenyl comprises two to thirteen carbon atoms (e.g., C2-C 15 alkenyl). In certain embodiments, the alkenyl comprises two to thirteen carbon atoms (e.g., C2-C 13Alkenyl group. In some embodiments, the alkenyl group comprises two to eight carbon atoms (e.g., C2-C8 alkenyl). In other embodiments, the alkenyl group comprises two to five carbon atoms (e.g., C2-C5 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (e.g., C2-C4 alkenyl). In other embodiments, the alkenyl group comprises two to three carbon atoms (e.g., C2-C3 alkenyl). Unless otherwise specified, the alkenyl group may optionally be substituted with one or more substituents as further defined in the claims and disclosure herein.

[0090] "Alkyne" refers to an alkyl group as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. In some embodiments, the alkynyl group contains two to fifteen carbon atoms (e.g., C2-C2). 15 (Alkyne group). In some embodiments, the alkynyl group contains two to thirteen carbon atoms (e.g., C2-C). 13 The alkynyl group comprises two to eight carbon atoms (e.g., C2-C8 alkynyl). In other embodiments, the alkynyl group comprises two to five carbon atoms (e.g., C2-C5 alkynyl). In other embodiments, the alkynyl group comprises two to four carbon atoms (e.g., C2-C4 alkynyl). In other embodiments, the alkynyl group comprises two to three carbon atoms (e.g., C2-C3 alkynyl). Unless otherwise stated, the alkynyl group may optionally be substituted with one or more substituents as further defined in the claims and disclosure herein.

[0091] Exemplary substituents suitable as optional substituents on the alkyl, alkenyl, or alkynyl moiety include, but are not limited to: halogenated (preferably F), cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, 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 -OC(O)-OR a -OR c -C(O)N(R a )2、-N(R a S(O) t R a -S(O) t ORa -S(O) t R a and -S(O) t N(R a )2 (where each t is 1 or 2), where each R a All are independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, carbocycloyl, carbocycloalkyl, heterocycloyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and R c It is a straight-chain or branched alkylene or alkenylene chain, wherein each of the above-described substituents is unsubstituted or optionally further substituted by a group suitable for the type of substituent described above. For example, the alkyl or alkylene portion (including the "alkyl" portion of cycloalkyl, carbocycloalkyl, or heterocycloalkyl groups, etc.) may optionally be further substituted by F, oxo, OH, alkoxy, amino, alkylamino, or dialkylamino; the cycloalkyl or heterocycloalkyl portion (including the "cyclic" portion of cycloalkyl, carbocycloalkyl, or heterocycloalkyl groups) may optionally be further substituted by alkyl, F, oxo, OH, alkoxy, amino, alkylamino, or dialkylamino; and the aryl or heteroaryl portion (including the "aromatic" portion of arylalkyl and heteroarylalkyl groups) may optionally be further substituted by halogen, OH, alkoxy, CN, amino, alkylamino, or dialkylamino.

[0092] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon group with a specified number of carbon atoms, which can link two other groups together. Sometimes it refers to the straight-chain group -(CH2). t - where t is 1-8, and preferably t is 1-4. Examples include, for example, methylene, ethylene, propylene, n-butylene, etc. Typically, the alkylene chain has one to twelve carbon atoms (C1-C2). 12"Alkylene" refers to a divalent radical derived from an alkyl group, as defined above. In some embodiments, the alkylene group contains one to eight carbon atoms (e.g., C1-C8 alkylene), one to five carbon atoms (e.g., C1-C5 alkylene), one to four carbon atoms (e.g., C1-C4 alkylene), one to three carbon atoms (e.g., C1-C3 alkylene), one to two carbon atoms (e.g., C1-C2 alkylene), or one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group contains five to eight carbon atoms (e.g., C5-C8 alkylene), two to five carbon atoms (e.g., C2-C5 alkylene), or three to five carbon atoms (e.g., C3-C5 alkylene). If specified, the alkylene group can also be substituted with other groups, and can include one or more unsaturations (i.e., alkenylene or alkynylene chains). The open valences of the alkylene group need not be at the terminal ends of the chain. Also included within the scope of the term "alkylene" are branched alkylene groups such as -CH(Me)-, -CH2CH(Me)-, and -C(Me)2- or cyclic groups such as cyclopropane-1,1-diyl and unsaturated groups such as ethylene (-CH=CH-) or propylene (-CH2-CH=CH-). Where an alkylene group is described as being optionally substituted, the substituents can include those typically found on alkyl groups as described herein and defined in the claims.

[0093] "Alkoxy" refers to a radical derived from an alcohol, as described above, by loss of a hydrogen atom from the carbon atom. Similarly, "thioalkoxy" refers to a radical derived from a thiol, as described above, by loss of a hydrogen atom from the carbon atom.

[0094] In some cases, substituted alkyl groups are specifically named by reference to the substituents. For example, "haloalkyl" refers to an alkyl group of the specified number of carbon atoms that is substituted with one or more halogens. Examples of haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl. "Fluoroalkyl" refers to an alkyl radical that is explicitly substituted with one or more fluorine radicals, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted, as defined above for alkyl groups.

[0095] "Alkoxyalkyl" refers to an alkyl group that is substituted with one or more alkoxy substituents, such as methoxymethyl (-CH2OMe) or 2-ethoxyethyl (-CH2CH2OEt).

[0096] "Aminoalkyl" refers to an alkyl group that is substituted with one or more substituted or unsubstituted amino substituents, such as aminomethyl (-CH2NH2), aminoethyl (-CH2CH2NH2), N,N-dimethylaminoethyl (-CH2CH2N(Me)2), or N-pyrrolidinylethyl (-CH2CH2-N-pyrrolidinyl).

[0097] "Hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl substituents, such as hydroxymethyl (-CH2OH) or 2-hydroxyethyl (-CH2CH2OH).

[0098] “Heteroalkyl,” “heteroalkenyl,” and “heteroyneyl” refer to substituted or unsubstituted alkyl, alkenyl, or ynyl groups in which one or more skeletal chain atoms are replaced by heteroatoms selected from O, N, S, P, or Si, or combinations thereof, wherein nitrogen, sulfur, and phosphorus heteroatoms may optionally be oxidized, and nitrogen heteroatoms may optionally be substituted or quaternized. Heteroalkyl groups include a specified number of chain atoms and one or more heteroatoms selected from -O-, -N(R")-, -S(O)-, and -S(O)2-, wherein R" is H or a C1-C4 alkyl group unless otherwise specified. If given, numerical ranges refer to the total chain length, including carbon atoms and chain heteroatoms. For example, 2- to 8-membered heteroalkyl groups have chain lengths of 2 to 8 atoms, including carbon atoms and chain heteroatoms. Such heteroalkyl chains may be referred to herein as “C2-C8 heteroalkyl.” Connection to the remainder of the molecule can be via heteroatoms or carbon atoms in the heteroalkyl, heteroalkenyl, or heteroyneyl chain. Unless otherwise stated as unsubstituted, heteroalkyl, heteroenyl, or heteroynyl groups may optionally be substituted by one or more substituents such as those suitable for the alkyl moiety as described herein. Divalent heteroalkyl, heteroenyl, and heteroynyl moieties may be referred to, respectively, as heteroalkylene, heteroenyl, or heteroynyl segments of specified chain lengths. It will be understood that the number and position of heteroatoms in saturated or unsaturated heteroalkyl chains are limited to the degree to which such compounds are chemically stable (i.e., excluding peroxide moieties, disulfide moieties, etc.).

[0099] "Aryl" or "aromatic" refers to a free radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from the ring carbon atom. The divalent aryl moiety can be called the aryl derivative moiety. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon. Typically, aryl groups contain six to twenty carbon atoms as ring members ("C6-C7"). 20 Aryl group, six to fourteen carbon atoms ("C6-C") 14 Aryl group, six to twelve carbon atoms ("C6-C") 12 "Aryl" or preferably six to ten carbon atoms ("C6-C") 10"aryl" or the prefix "ar" (such as in "arylalkyl" or "aralkyl") is intended to include aryl radicals optionally substituted with one or more substituents as defined in the claims and as further described below. "Heteroarylalkyl" or "heteroaralkyl" refers to an alkyl radical as defined herein, having at least one heteroaromatic substituent replacing a hydrogen on an alkyl radical. The heteroaromatic substituent is a heteroaromatic radical as defined herein. The alkyl portion of the heteroaralkyl radical is optionally substituted as described above for alkyl groups. The heteroaromatic portion of the heteroaralkyl radical is optionally substituted as described above for heteroaryl groups. The number of carbon atoms in the alkyl and heteroaromatic portions of the heteroaralkyl radical can be specified together or individually. For example, a benzyl group can be described as C7-heteroaralkyl or alternatively as C6-heteroaryl-C1-alkyl.

[0100] "Arylalkyl" or "aralkyl" refers to a radical of the formula -R c where R c is an alkyl chain as defined above, e.g., methylene, ethylene, etc. The alkyl chain portion of the aralkyl radical is optionally substituted as described above for alkyl chains. The aryl portion of the aralkyl radical is optionally substituted as described above for aryl groups. The number of carbon atoms in the alkyl and aryl portions of the aralkyl radical can be specified together or individually. For example, a benzyl group can be described as C7-arylalkyl or alternatively as C6-aryl-C1-alkyl.

[0101] "Carbocyclyl" or "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical composed only of carbon and hydrogen atoms, which can be a single ring or include fused, spiro, or bridged ring systems, having three to fifteen carbon atoms (e.g., "C3-C 15 cycloalkyl"). Such cycloalkyl ring systems can alternatively be referred to as 3-15 membered cycloalkyl groups. In some embodiments, the cycloalkyl ring comprises three to thirteen carbon atoms (e.g., "C3-C 13 cycloalkyl"). In some embodiments, the cycloalkyl ring comprises three to twelve carbon atoms (e.g., "C3-C 12 cycloalkyl"). In some embodiments, the cycloalkyl ring comprises three to ten carbon atoms (e.g., "C3-C 10In other embodiments, the cycloalkyl group can contain three to eight carbon atoms (e.g., “C3-C8 cycloalkyl”) or five to seven carbon atoms (e.g., “C5-C7 cycloalkyl”) or three to six carbon atoms (e.g., “C3-C6 cycloalkyl”). The cycloalkyl group can be attached to the rest of the molecule by a single bond or an exocyclic double bond. The carbocyclyl radical can be fully saturated (i.e., containing only C-C single bonds) or partially unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclyl radicals are also referred to as “cycloalkyl groups.” Partially unsaturated carbocyclyl rings can also be referred to as cycloalkenyl or cycloalkynyl moieties. A divalent cycloalkyl moiety can be referred to as a cycloalkylene moiety. Unless specifically indicated otherwise in the specification, the terms “carbocyclyl” and “cycloalkyl” are intended to include carbocyclyl radicals optionally substituted with one or more substituents as defined in the claims and as further described below.

[0102] Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, or cyclooctenyl. Examples of bridged cycloalkyl groups include, for example, adamantly (i.e., tricyclo[3.3.1.1]decyl), norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl (i.e., bicyclo[2.2.1]hept-2-enyl), or 7,7-dimethyl-bicyclo[2.2.1]heptyl. Examples of fused cycloalkyl groups include, for example, decalinyl, bicyclo[4.3.0]nonyl, bicyclo[3.3.0]octyl. Examples of spiro cycloalkyl groups include, for example, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[4.4]nonyl, spiro[4.5]decyl, or spiro[5.5]undecyl.

[0103] “Carbocyclylalkyl” or “cycloalkylalkyl” means a radical of the formula –R c a carbocyclyl radical, wherein R c is an alkylene chain as defined above. As defined above, the alkylene chain and the carbocyclyl radical are optionally substituted.

[0104] “Heterocyclyl” or “heterocycloalkyl” means a stable 3- to 20-membered non-aromatic ring radical, which contains from two to fourteen carbon atoms and one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur (i.e., N, O, and S(O) zone to six heteroatoms (preferably one to three heteroatoms). Such ring systems can be monocyclic or include fused, spirocyclic, or bridged ring systems. In some embodiments, the heterocyclyl ring system contains 3-20 ring atoms (including carbon and heteroatom ring atoms), referred to herein as 3-20 membered heterocyclyl. In some embodiments, the heterocyclyl ring system contains 3-14 ring atoms, i.e., 3-14 membered heterocyclyl. In some embodiments, the heterocyclyl ring system is 3-12 membered heterocyclyl, preferably containing 1-3 heteroatoms as described above. In some embodiments, the heterocyclyl ring system is 3-10 membered heterocyclyl, preferably containing 1-3 heteroatoms as described above. In some embodiments, the heterocyclyl ring system is 3-8 membered heterocyclyl, preferably containing 1-3 heteroatoms as described above. In some embodiments herein, the heterocyclyl ring system includes 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 4-13 membered heterocyclyl, or 4-10 membered heterocyclyl, wherein each such heterocyclyl preferably contains 1-3 heteroatoms. A divalent heterocycloalkyl moiety can be referred to as a “heterospirocyclyl” moiety. It will be understood that the number and location of heteroatoms in a heterocyclic ring is limited to the extent 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. A heterocyclyl group can be attached to the rest of the molecule through a C or N atom of the ring. Unless specifically set forth hereinabove, the term “heterocyclyl” is intended to include heterocyclyl radicals optionally substituted with one or more substituents as defined in the claims and as further described below.

[0105] Examples of heterocyclyl radicals include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, quinuclidinyl, trithianyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Spirocyclic heterocyclyl radicals include, for example, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2-azaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 2-azaspiro[4.4]nonyl, 2,7-diazaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 2,8-diazaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, or 3,9-diazaspiro[5.5]undecyl.

[0106] Unless otherwise indicated, a cycloalkyl and heterocyclyl moiety described herein as optionally substituted can be substituted with one or more independently selected substituents. The total number of substituents can equal the total number of hydrogen atoms on the cycloalkyl or heterocyclyl moiety to a reasonable extent of chemical sense. An optionally substituted cycloalkyl or heterocyclyl group typically contains 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, preferably 1 to 3 optional substituents or more preferably 1 to 2 optional substituents.

[0107] Exemplary groups suitable as substituents on a cycloalkyl or heterocyclyl moiety include: alkyl, fluoroalkyl alkenyl, alkynyl, halo (preferably F), cyano, nitro, oxo, thioxo, imino, hydroxyimino, trimethylsilanyl, R a , -R b -OR a , -R b -SR a , -R b -OC(O)-R a , -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 -N(R a )C(O)OR a , -R b -OC(O)N(R a )2, -R b -N(R a )C(O)R a , -R b -OC(O)-OR a , -R b -O-R c -C(O)N(R a )2, -R b -N(R a )S(O) t R a , -R b -S(O) t OR a , -R b -S(O) t R a , and -R b -S(O) t N(R a )2(wherein each Ra each R is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each R b each R is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted or optionally further substituted, unless otherwise indicated, as described for groups appropriate for the type of substituent.

[0108] “N-heterocyclyl” or “N-linked heterocyclyl” means a heterocyclyl radical containing at least one nitrogen, as defined above, and wherein 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-linked heterocyclyl radical is optionally substituted, as described above for heterocyclyl radicals. Examples of such N-linked heterocyclyl radicals include, but are not limited to: 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0109] “C-heterocyclyl” or “C-linked heterocyclyl” means a heterocyclyl radical containing at least one heteroatom, as defined above, and wherein 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-linked heterocyclyl radical is optionally substituted, as described above for heterocyclyl radicals. Examples of such C-linked heterocyclyl radicals include, but are not limited to: 2-morpholinyl, 2-piperidinyl or 3-piperidinyl or 4-piperidinyl, 2-piperazinyl, 2-pyrrolidinyl or 3-pyrrolidinyl, and the like.

[0110] "Heteroaryl" or "heteroaromatic" refers to a radical derived by the removal of a hydrogen atom from a monocyclic, fused-bicyclic, or polycyclic hydrocarbon ring system, wherein at least one of the ring carbon atoms has been replaced with N, O, or S, and wherein at least one of the rings in the ring system is completely unsaturated, i.e., it contains a cyclically delocalized (4n+2) p-electron system according to Hückel theory. The inclusion of heteroatoms allows for aromaticity in 5- and 6-membered rings. Typically, heteroaryl groups contain from 5 to 20 ring atoms ("5-20 membered heteroaryl"), sometimes 5 to 14 ring atoms ("5-14 membered heteroaryl"), or 5 to 12 ring atoms ("5-12 membered heteroaryl"), preferably 5 to 10 ring atoms ("5-10 membered heteroaryl"), in each case including carbon ring atoms and hetero ring atoms. A heteroaryl ring is attached to the base molecule through a ring atom of the heteroaromatic ring, such that aromaticity is maintained. Thus, a 6-membered heteroaryl ring can be attached to the base molecule through a ring C atom, while a 5-membered heteroaryl ring can be attached to the base molecule through a ring C or N atom. A divalent heteroaryl moiety can be referred to as a heteroarylene moiety. Unless specifically set forth herein, the term "heteroaryl" or the prefix "heteroar" (such as in "heteroaralkyl") is intended to include heteroaryl radicals optionally substituted with one or more substituents as defined in the claims and further described below. Similar to arylalkyl moieties, the term "heteroarylalkyl" or "heteroaralkyl" refers to a radical of the formula -R c - a radical of heteroaryl.

[0111] Examples of heteroaryl rings include, but are not limited to: pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole (including 1,2,3-triazole and 1,3,4-triazole), oxadiazole (including 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole), thiadiazole (including 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole), tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, benzotriazole, pyrrolopyridine (including pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[3,2-c]pyridine), imidazopyridine (including imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine), pyrazolopyridine (including pyrazolo[4,3-d]pyridine, pyrazolo[4,3-c]pyridine, pyrazolo[3,4-c]pyridine, pyrazolo[3,4-b]pyridine), isoindole, indazole, purine, indolizine, imidazopyridine (including imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine), pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-c]pyrimidine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, naphthridine (including 1,6-naphthridine, 1,7-naphthridine, 1,8-naphthridine, 1,5-naphthridine, 2,6-naphthridine, 2,7-naphthridine), pyrido-pyrimidine (including pyrido[3,2-d]pyrimidine, pyrido[4,3-d]pyrimidine, pyrido[3,4-d]pyrimidine, pyrido[2,3-d]pyrimidine), pyrido-pyrazine (including pyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine), pyrimido-pyrimidine (including pyrimido[5,4-d]pyrimidine, pyrimido[4,5-d]pyrimidine), pyrazino[2,3-b]pyrazine, and carbazole. In preferred embodiments, the 5- or 6-membered heteroaryl group is selected from: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl rings.

[0112] Unless otherwise indicated, aryl and heteroaryl moieties described herein as optionally substituted can be substituted with one or more substituents, which are independently selected. The total number of substituents on an aryl or heteroaryl moiety can equal the total number of hydrogens on such a moiety that it is chemically reasonable for such a moiety to have, and which maintains the degree of aromaticity. An optionally substituted aryl or heteroaryl group typically contains 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, preferably 1 to 3 optional substituents, or more preferably 1 to 2 optional substituents.

[0113] Exemplary groups suitable as substituents on the aryl or heteroaryl moiety include: alkyl, fluoroalkyl alkenyl, alkynyl, halo, cyano, nitro, trimethylsilanyl, R a , -R b -OR a , -R b -SR a , -R b -OC(O)-R a , -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 -N(R a )C(O)OR a , -R b -OC(O)N(R a )2, -R b -N(R a )C(O)R a , -R b -OC(O)-OR a , -R b -O-R c -C(O)N(R a )2, -R b -N(R a )S(O) t R a , -R b -S(O) t OR a , -R b -S(O) t R a , and -R b -S(O) t N(R a )2(wherein each t is 1 or 2), wherein each R a is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each R b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and each of the above substituents is unsubstituted or optionally further substituted, unless otherwise indicated, as described for groups suitable for substituents of that type.

[0114] "N-heteroaryl" or "N-linked heteroaryl" means a heteroaryl radical, as defined above, containing at least one nitrogen, and wherein the point of attachment of the heteroaryl radical to the rest of the molecule is through a N atom in the heteroaryl radical. The N-linked heteroaryl radical is optionally substituted, as described above for heteroaryl radicals.

[0115] "C-heteroaryl" or "C-linked heteroaryl" means a heteroaryl radical, as defined above, and wherein 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-linked heteroaryl radical is optionally substituted, as described above for heteroaryl radicals.

[0116] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes situations where the event or circumstance occurs and situations where it does not.

[0117] The terms "optionally substituted" and "substituted or unsubstituted" can be used interchangeably to mean that the group being described can have no non-hydrogen substituents (i.e., unsubstituted) or that the group can have one or more non-hydrogen substituents (i.e., substituted). Unless otherwise indicated, the total number of substituents that can be present, equaling the number of H atoms present in the unsubstituted form of the group being described, can be present. In cases where an optional substituent is attached by a double bond, such as an oxo (=0) substituent, the group takes up two available valences, so the total number of other substituents included is reduced by two. In cases where optional substituents are independently selected from a list of alternatives, the groups are independently selected and can be the same or different. Throughout this disclosure, it will be understood that the number and nature of optional substituents will be limited to the extent that such substitution results in a chemically sensible molecule.

[0118] As used herein, the term "reactive functional group" refers to an atom or group of atoms that is intended or can reasonably be expected to undergo a chemical reaction. Examples of reactive functional groups include, but are not limited to: a primary or secondary amine, protected or unprotected; a carboxylic acid, carboxylic ester, or activated derivative thereof (e.g., acid halide, anhydride, Weinreb amide, activated ester, etc.); halo, hydroxyl, formyl, oxo (=0), sulfonate (-OSO2R°, where R° is alkyl, haloalkyl, or aryl, e.g., mesylate, triflate, or tosylate), boronic acid, boronate; azide; an alkyl moiety substituted with halo, hydroxyl, oxo, sulfonate, boronic acid, boronate, carboxylic acid, carboxylic ester, alkoxy, amide, ketone, etc.; aldehyde, ketone, amide, nitrile, imine, or acetal; aryl or heteroaryl group substituted with halo, hydroxyl, sulfonate, boronic acid, or boronate; a, b-unsaturated amide, a, b-unsaturated ketone, a, b-unsaturated acid, or a, b-unsaturated ester; a-halo amide, a-halo ketone, a-halo acid, or a-halo ester; sulfonic acid or sulfonyl halide; protected or unprotected thiol, sulfide, or disulfide; alkene or alkyne moiety; epoxide, aziridine, etc. Suitable protecting groups for protected amines include carbamates (e.g., Boc, Cbz, Fmoc, or Alloc), silyl protecting groups (e.g., trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS)), benzyl protecting groups (e.g., benzyl (Bn) or p-methoxybenzyl (PMB)), and other suitable protecting groups known in the art. P. G. M. Wuts, Greene’s Protective Groups in Organic Synthesis, Wiley, 5th edition.

[0119] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers and can occur as enantiomers, diastereomers, racemates, or other stereoisomeric forms or mixtures thereof, in some embodiments, which are defined in terms of absolute stereochemistry as (R)- or (S)-. The present disclosure is intended to include all stereoisomeric forms of the compounds disclosed herein, unless indicated otherwise. Bonds to asymmetric centers of compounds can be depicted using a solid (—), a wedged solid or a dashed wedge To depict the structure, solid lines are used to represent the bonds with the asymmetry center. Using solid lines to depict the bonds with the asymmetry center indicates that the stereochemistry is undetermined, and that all possible stereoisomers at that stereocenter (e.g., specific isomers, racemic mixtures, etc.) are included. Using wedge-shaped solid lines or wedge-shaped dashed lines to depict the bonds with the asymmetry center indicates that only the stereoisomers shown are included. Where defined, the absolute configuration can also be indicated by (R)- or (S)-. In compounds containing more than one asymmetry center, the use of both solid lines and wedge-shaped solid lines or wedge-shaped dashed lines at different asymmetry centers indicates that the structure at the stereocenter depicted using solid lines is undetermined.

[0120] The compounds disclosed herein also include geometric isomers, trans-restricted isomers, other conformational isomers, and / or tautomers. When the compounds described herein contain an alkenyl group, this disclosure is intended to include E and Z geometric isomers of the alkene double bond (e.g., cis or trans), unless otherwise stated. Positional isomers (e.g., structural isomers, such as ortho, meta, and para isomers surrounding the benzene ring) may also be included if the drawn structures are indicated by variable attachment points.

[0121] A "tautomer" is a molecule in which it is possible for a proton to transfer from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist as tautomers. Where tautomerism is possible, a chemical equilibrium of tautomers will exist. The proportion of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Examples of tautomeric equilibria include:

[0122]

[0123] Unless otherwise stated, the structures described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, and are otherwise identical to those shown in one of the provided formulas, except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found naturally. For example, except that one or more hydrogen atoms are replaced by deuterium ( 2 H) or tritium ( 3 H) Replacement or carbon atom is 13 C- or 14 Compounds having this structure, other than C-enriched carbon substitutions, are included within the scope of this disclosure.

[0124] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds can be labeled with isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, phosphorus, sulfur, chlorine, bromine, or iodine. It is also contemplated to use... 2 H, 3 H, 11C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 18 O、 14 F, 15 F, 16 F, 17 F, 18 F, 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br、 125 Isotopic substitution of I. All isotopic variants of the compounds of this invention, whether radioactive or not, are covered within the scope of this invention. In some embodiments, the compounds herein include 2 H, 3 H, 11 C 13 C and / or 14 The isotopic form enriched by C.

[0125] Certain isotope-labeled compounds of the present invention, for example, those containing radioactive isotopes such as 3 H and 14 Those of type C can be used for drug and / or substrate tissue distribution determination. Tritized (i.e....) 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability.

[0126] Using heavier isotopes such as deuterium (i.e. 2 H) substitution can also provide certain therapeutic advantages such as greater metabolic stability, increased in vivo half-life, increased duration of action, or reduced dose requirements. In some embodiments, the compound is deuterated at at least one position. In some embodiments, some or all of the compounds disclosed herein are... 1 H atoms are 2 H atom substitution.

[0127] Isotopically-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples below, by substituting an isotopically-labeled reagent for a non-isotopically labeled reagent. Methods for synthesis of deuterium-containing compounds are known and include, by way of non-limiting example, the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997.

[0128] Unless otherwise indicated, all references to compounds herein include references to salts (including pharmaceutically acceptable salts), solvates (including hydrates), and complexes thereof, as well as solvates and complexes of salts thereof, and isotopically-labeled versions of the same.

[0129] In certain embodiments, a compound or salt described herein as “substantially pure” means that it contains less than about 5%, preferably less than about 1%, and / or more preferably less than about 0.1% of other small organic molecules such as unreacted intermediates or synthetic byproducts produced, for example, in one or more steps of a synthetic process.

[0130] The compounds described herein can exist in the form of salts. The term “salt” refers to inorganic and organic salts of the compounds herein. Such salts can be prepared in situ during the isolation and purification of the compounds or by separately treating the compounds with a suitable organic or inorganic acid or base and isolating the salt thus formed.

[0131] A “pharmaceutically acceptable salt” is a salt that retains the biological effectiveness and properties of the free base compound suitable for administration to a subject. Reference to “pharmaceutically acceptable salts” of the compounds described herein is intended to encompass any pharmaceutically suitable salt form. Preferred pharmaceutically acceptable salts include pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Non-pharmaceutically acceptable salts, including salts of chiral acids, can also be useful in synthesis, isolation, purification, chiral resolution, and the like.

[0132] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with such organic acids as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and

[0133] "Pharmaceutically acceptable base addition salt" refers to those salts of the free acids which are biologically effective and nontoxic in biological systems and otherwise are not undesirable. These salts are prepared from addition of inorganic or organic bases to the free acid. In some embodiments, the pharmaceutically acceptable base addition salts are 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 salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins, for example, 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-methylglucosamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like. See Berge et al., supra.

[0134] Salts can be prepared according to methods known in the art, for example, by mixing together solutions of a base or acid, respectively, and the desired acid or base. The resulting salt form can be isolated by precipitation and filtration or can be recovered by evaporation of the solvent. Compounds having basic functionality present in free base form can be converted to acid addition salts by treatment with a stoichiometric excess of the appropriate acid. Such acid addition salts can be reconverted to the corresponding free base by treatment with a stoichiometric excess of a suitable base such as potassium carbonate or sodium hydroxide, usually in the presence of an aqueous solvent at temperatures between about 0 °C and 100 °C. The free base form can be isolated by conventional methods such as extraction into an organic solvent. Acid addition salts can be converted to each other by making use of the different solubilities of the salts, volatility of the acids, or the acidic or basic nature, or by treatment with an appropriately loaded ion exchange resin. For example, the interconversion can be effected by reaction of a salt with a stoichiometric slight excess of an acid whose pK is lower than that of the acid component of the starting salt. Such interconversions are usually carried out at temperatures between about 0 °C and the boiling point of the solvent used as the medium for the process. Similar exchanges are possible for base addition salts, usually by way of an intermediate free base form.

[0135] The compounds and salts of any of formulas (I)-(XIII) may exist in unsolvated or solvated forms. A “solvate” is a molecular complex comprising a compound or salt and one or more solvent molecules. Preferably, a solvate comprises one or more pharmaceutically acceptable solvents such as water or ethanol. The term “hydrate” is used when the solvent is water. Hydrates can be classified as site-isolated hydrates, channel hydrates, or metal ion coordination hydrates. When solvent or water molecules are tightly bound, the complex can have a well-defined stoichiometry independent of humidity. When solvent or water molecules are weakly bound, the solvent or water content can be non-stoichiometric and dependent on humidity or dry conditions.

[0136] This document also includes multicomponent complexes (in addition to salts and solvates) in which a compound of any of formulas (I)-(XII) and at least one other component are present in stoichiometric or non-stoichiometric amounts. Examples of such complexes include cage-like structures (i.e., drug-host inclusion complexes) and cocrystallizations, which are typically crystalline complexes in which the constituent components are bound together by non-covalent interactions.

[0137] A "prodrug" is a masking compound that acts as a drug precursor, which may itself have little or no pharmacological activity and releases the active drug in vivo through chemical or physiological processes (e.g., due to exposure to physiological pH or through enzymatic action) after administration. See, for example, 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series (T. Higuchi and W. Stella); 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E.B. Roche, American Pharmaceutical Association); "Design of Prodrugs", by H. Bundgaard (Elsevier, 1985). Compounds or salts of any of formulas (I)-(XII) may be administered as prodrugs.

[0138] Heterobifunctional compounds

[0139] Provided herein are heterobifunctional compounds of any of Formulae (I)-(XII) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and salts. The heterobifunctional compounds described herein comprise a DNA damage binding protein 1 (DDB1) binding moiety, a bivalent linker, and a protein binding moiety (PBM). 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 PBM is capable of binding to CCND, CDK4, and / or CDK6. In certain preferred embodiments, the PBM is capable of binding to CDK4 and / or CDK6. Such compounds or salts can be used for several purposes, including modulating the protein level or activity of CCND, CDK4, and / or CDK6.

[0140] Embodiments E1-E49 recite compounds of Formulae (I)-(XII) and pharmaceutically acceptable salts thereof, and pharmaceutical compositions of such compounds and salts.

[0141] E1. A heterobifunctional compound of Formula (I):

[0142]

[0143] or a pharmaceutically acceptable salt thereof, as described in the Summary.

[0144] E2. The heterobifunctional compound of Embodiment E1, having the structure of Formula (II):

[0145]

[0146] or a pharmaceutically acceptable salt thereof.

[0147] E3. The heterobifunctional compound of Embodiment E1 or E2, having the structure of Formula (III):

[0148]

[0149] or a pharmaceutically acceptable salt thereof.

[0150] E4. The heterobifunctional compound of any one of Embodiments E1-E3, having the structure of Formula (IV):

[0151]

[0152] or a pharmaceutically acceptable salt thereof.

[0153] E5. The heterobifunctional compound of any one of Embodiments E1-E4, or a pharmaceutically acceptable salt thereof, wherein Q is selected from:

[0154]

[0155] * denotes the point of attachment; and

[0156] R 1 and p are as defined in formula (I).

[0157] E6. The heterobifunctional compound or pharmaceutically acceptable salt thereof according to embodiment E5, wherein Q is selected from:

[0158]

[0159] wherein:

[0160] * denotes the point of attachment; and

[0161] R 1B , R 1C , R 1D , and R 1E are as defined in formula (I).

[0162] E7. The heterobifunctional compound or pharmaceutically acceptable salt thereof according to any one of embodiments E1-E4, wherein Q is selected from:

[0163]

[0164] wherein:

[0165] * denotes the point of attachment; and

[0166] R 1A , R 1B , R 1C , and R 1D are as defined in formula (I).

[0167] E8. The heterobifunctional compound or pharmaceutically acceptable salt thereof according to embodiment E7, wherein Q is selected from:

[0168]

[0169] wherein:

[0170] * denotes the point of attachment; and

[0171] R 1A , R 1B , R 1C , R 1D , and R 1E are as defined in formula (I).

[0172] E9. The heterobifunctional compound according to embodiment E3, having the structure of formula (V):

[0173]

[0174] Or its pharmaceutically acceptable salt, wherein:

[0175] R 1 R 3 A, L 1 L 2 p and q are defined as in equation (I); and

[0176] Q is a C6 aryl or a 6-membered heteroaryl.

[0177] E10. The heterobifunctional compound according to embodiment E9, having a structure of formula (VA), (VB), (VC), or (VD):

[0178] Or its pharmaceutically acceptable salt, wherein:

[0179] R 1 R 2 R 3 A, L 1 L 2 p, q, R 1B R 1C R 1D and R 1E As defined in equation (I);

[0180] X 3 Is it N or CR? 1B ;

[0181] X 4 Is it N or CR? 1C ;

[0182] X 5 Is it N or CR? 1D ;and

[0183] X 6 Is it N or CR? 1E .

[0184] E11. The heterobifunctional compound according to embodiment E9 or E10 has the following structure:

[0185]

[0186] Or its pharmaceutically acceptable salt, wherein:

[0187] R 1 R 2 R 3 A, L 1 L 2 p and q are defined as in equation (I).

[0188] E12. The heterobifunctional compound according to embodiment E3 has the structure of formula (VI):

[0189]

[0190] Or its pharmaceutically acceptable salt, wherein:

[0191] R 1 R 3 A, L 1 L 2 p and q are defined as in equation (I); and

[0192] Q is a 5-membered heteroaryl group.

[0193] E13. The heterobifunctional compound according to embodiment E12 has the following structure:

[0194]

[0195] Or its pharmaceutically acceptable salt, wherein:

[0196] R 1 R 3 A, L 1 L 2 p, q and R 1A As defined in equation (I);

[0197] X 1 Is it O, S, or NR? 1A ;and

[0198] X 2 Is it O, S, or NR? 1A .

[0199] E14. The heterobifunctional compound according to embodiment E13 has the following structure:

[0200]

[0201]

[0202]

[0203]

[0204] Or its pharmaceutically acceptable salt, wherein:

[0205] R 1 R 3 A, L 1 L 2 p, q and R1A as defined in formula (I).

[0206] E15. The heterobifunctional compound according to embodiment E4, having the structure of formula (VII):

[0207]

[0208] or a pharmaceutically acceptable salt thereof, wherein:

[0209] R 1 , R 3A , A, L 1 , L 2 , and p are as defined in formula (I); and

[0210] Q is C6 aryl or 6-membered heteroaryl.

[0211] E16. The heterobifunctional compound according to embodiment E15, having the structure of formula (VII-A), (VII-B), (VII-C), or (VII-D):

[0212] or a pharmaceutically acceptable salt thereof, wherein:

[0213] R 1 , R 3A , A, L 1 , L 2 , p, R 1B , R 1C , R 1D , and R 1E are as defined in formula (I);

[0214] X 3 is N or CR 1B ;

[0215] X 4 is N or CR 1C ;

[0216] X 5 is N or CR 1D ; and

[0217] X 6 is N or CR 1E .

[0218] E17. The heterobifunctional compound according to embodiment E15 or E16, having the structure:

[0219]

[0220] or a pharmaceutically acceptable salt thereof, wherein:

[0221] R 1 R 3A A, L 1 L 2 p is defined as in equation (I).

[0222] E18. The heterobifunctional compound according to embodiments E4, E15, E16 or E17, having a structure selected from the following formula (IX):

[0223] Or its pharmaceutically acceptable salt, wherein:

[0224] R 1A R 1B R 1C R 3A A, L 1 and L 2 As defined in equation (I).

[0225] E19. The heterobifunctional compound according to embodiment E4 has the structure of formula (VIII):

[0226]

[0227] Or its pharmaceutically acceptable salt, wherein:

[0228] R 1 R 3A A, L 1 L 2 and p are as defined in equation (I); and

[0229] Q is a 5-membered heteroaryl group.

[0230] E20. The heterobifunctional compound according to embodiment E19 has the following structure:

[0231]

[0232] Or its pharmaceutically acceptable salt, wherein:

[0233] R 1 R 3A A, L 1 L 2 p and R 1A As defined in equation (I);

[0234] X 1 Is it O, S, or NR? 1A ;and

[0235] X 2 Is it O, S, or NR? 1A .

[0236] E21. The heterobifunctional compound according to embodiment E19 or E20 has the following structure:

[0237]

[0238]

[0239]

[0240] Or its pharmaceutically acceptable salt, wherein:

[0241] R 1 R 3A A, L 1 L 2 p and R 1A As defined in equation (I).

[0242] E22. The heterobifunctional compound according to embodiments E4, E19, E20 or E21 has the following structure: Or its pharmaceutically acceptable salt, wherein:

[0243] R 1A R 1B R 1C R 3A A, L 1 and L 2 As defined in equation (I).

[0244] E23. The heterobifunctional compound according to any one of embodiments E1 to E22, wherein A is a PBM having the structure of formula (A):

[0245] Or its pharmaceutically acceptable salt, wherein:

[0246] X A 1 X A 2 Y A 1 and Y A 2 Each is CR independently A 4 Or N;

[0247] R A 1 It is NR A 5 R A 6 、N(R A5 )C(=O)R A 6 Optional substitution of C6-C 12 Aryl or optionally substituted 5-13 heteroaryl groups;

[0248] R A 2 It is hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 heteroalkyl, C3-C8 cycloalkyl, or 3-8 membered heterocyclic group; or

[0249] R A 1 and R A 2 Together with the atoms to which they are attached, they can optionally form optionally substituted C3-C8 cycloalkyl groups, 3-8 membered heterocyclic groups, C6-C... 12 Aryl or 5-13 heteroaryl groups;

[0250] L 3 It is selected from -R A 3A _R A 3B - a divalent group, wherein R A 3A and R A 3B Each is an independent key, -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 - C1-C8 alkylene, C2-C8 alkenylene, C2-C8 ynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene or 5-13 heteroarylene, provided that the two -O- and / or -S- are not adjacent;

[0251] Each R A 4 All are independently selected from: 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, 3-8 membered heterocyclic, C6-C 12 Aryl or 5-13 heteroaryl groups;

[0252] R A 5 and R A 6 Independently selected from: hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or

[0253] R A 5 and R A 6 These, together with the atoms to which they are attached, optionally form 3-20 membered heterocyclic base rings; and

[0254] R A 7 R A 8 R A 9 and R A 10 Each is independently selected from: hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or R A 8 and R A 9 Together with the atoms to which they are attached, they can optionally form 3-20 member heterocyclic base rings.

[0255] E24. The heterobifunctional compound according to embodiment E23, wherein A is a PBM of formula (A) having a structure of formula (A1), (A2), or (A3):

[0256] Or its pharmaceutically acceptable salt, wherein:

[0257] Y A 3 It is CR A 19 Or N;

[0258] R A 11 R A 14 and R A 18 Each group is 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 3-8 membered heterocyclic, C6-C 12 Aryl or 5-13 heteroaryl groups;

[0259] R A 12 and R A 15 Each independently selected from R A 20 COR A 20 CO2R A 20 or CONR A 20 R A 21 , where R A 20 and R A 21 Independently selected from: hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or 3-8 membered heterocyclic or R A 20 and R A 21 Together with the atoms to which they are attached, they can optionally form 3-20 membered heterocyclic base rings;

[0260] R A 13 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 heteroalkyl, C3-C8 cycloalkyl or 3-8 membered heterocyclic groups;

[0261] R A 16 and R A17 Each is 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, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or

[0262] R A 16 and R A 17 Together with the atoms to which they are attached, they optionally form C3-C8 cycloalkyl groups or 3-8 membered heterocyclic groups; and

[0263] R A 19 Independently selected from: hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or 3-8 membered heterocyclic groups; and

[0264] m A It is 0, 1, or 2.

[0265] E25. The heterobifunctional compound according to embodiment E23, wherein A is a PBM of formula (A) having the structure of formula (A4):

[0266] Or its pharmaceutically acceptable salt, wherein:

[0267] X A 3 It is CR A 25 Or N;

[0268] R A 22 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 heterocyclic, C6-C 12 aryl or 3-13 heteroaryl; and

[0269] R A 23 R A 24 and R A 25Each is independently selected from: hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C2-C8 heterocyclic.

[0270] E26. The heterobifunctional compound according to any one of embodiments E1 to E23, wherein A is a PBM of formula (A) having the structure of any one of formulas (A5), (A6), (A7), (A8), or (A9):

[0271]

[0272]

[0273] E27. The heterobifunctional compound according to embodiment E4 has the structure of formula (XI):

[0274]

[0275] Or its pharmaceutically acceptable salt, wherein:

[0276] R 1 R 3A L 1 Q and p are defined as in equation (I);

[0277] X A 1 X A 2 Y A 1 and Y A 2 Each is CR independently A 4 Or N;

[0278] R A 1 It is NR A 5 R A 6 、N(R A 5 )C(=O)R A 6 Optional substitution of C6-C 12 Aryl or optionally substituted 5-13 heteroaryl groups;

[0279] R A 2It is hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 heteroalkyl, C3-C8 cycloalkyl, or 3-8 membered heterocyclic group; or

[0280] R A 1 and R A 2 Together with the atoms to which they are attached, they can optionally form optionally substituted C3-C8 cycloalkyl groups, 3-8 membered heterocyclic groups, C6-C... 12 Aryl or 5-13 heteroaryl groups;

[0281] L 3 It is selected from -R A 3A_ R A 3B - a divalent group, wherein R A 3A and R A 3B Each is an independent key, -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 - C1-C8 alkylene, C2-C8 alkenylene, C2-C8 ynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene or 5-13 heteroarylene, provided that the two -O- and / or -S- are not adjacent;

[0282] Each R A 4 All are independently selected from: 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)RA 10 C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 Aryl or 5-13 heteroaryl groups;

[0283] R A 5 and R A 6 Independently selected from: hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or

[0284] R A 5 and R A 6 These, together with the atoms to which they are attached, optionally form 3-20 membered heterocyclic base rings; and

[0285] R A 7 R A 8 R A 9 and R A 10 Each is independently selected from: hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or

[0286] R A 8 and R A 9 Together with the atoms to which they are attached, they can optionally form 3-20 member heterocyclic base rings.

[0287] E28. The heterobifunctional compound according to embodiment E27, having a structure of formula (XI-A), (XI-B), (XI-C), or (XI-D):

[0288]

[0289] Or its pharmaceutically acceptable salt, wherein:

[0290] R 1A R 1B and R 1C As defined in equation (I).

[0291] E29. The heterobifunctional compound according to embodiment E4 has the structure of formula (XII):

[0292]

[0293] Or its pharmaceutically acceptable salt, wherein:

[0294] R 1 R 3A L 1 L 2 Q and p are defined as in equation (I).

[0295] E30. The heterobifunctional compound according to embodiment E29, having a structure of formula (XII-A), (XII-B), (XII-C), or (XII-D):

[0296] Or its pharmaceutically acceptable salt, wherein:

[0297] R 1A R 1B R 1C R 3A L 1 and L 2 As defined in equation (I).

[0298] E31. The heterobifunctional compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E1 to E30, wherein L 1 It is a keyed or type (L-1) binary connector:

[0299]

[0300] in:

[0301] Each A L and B L They are all independently selected from the following divalent parts: bond, R L a R L a -R L b R L a C(O)R L b R L a C(O)OR L b R L aOC(O)R L b 、R L a C(O)N(R L 1 )R L b 、R L a N(R L 1 )C(O)R L b 、R L a C(S)N(R L 1 )R L b 、R L a N(R L 1 )C(S)R L b 、R L a OR L b 、R L a SR L b 、R L a SOR L <CO00712>、R L a SO2R L b 、R L a SO2N(R L 1 )R L b 、R L a N(R L 1 )SO2R L b 、R L a N(R L 1 )R L b )]和R L a N(R L 1 )C(O)N(R L 2 )R L b ;

[0302] Each R L a and R L b All are independently selected from: key, R L r (C1-C8 alkylene)-R L r R L r -(C1-C8 alkylene), (C1-C8 alkylene)-R L r -(C1-C8 alkylene), C1-C8 alkylene, C2-C8 alkenyl, C2-C8 yntynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl, and C3-C8 heteroyntynyl, wherein each of the C1-C8 alkylene, C2-C8 alkenyl, C2-C8 yntynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl, or C3-C8 heteroyntynyl moieties is optionally surrounded by one or more R L c replace;

[0303] Each R L r All are independently selected from: C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene and 5-13 heteroarylene, wherein each of the C3-C 12 Cycloalkylene or 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. L d Replace, and each of the C6-C 12 Arene or 5-13 heteroarylene groups are optionally surrounded by one or more R groups. L e replace;

[0304] Each R L 1 and R L 2 All are independently selected from: H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic, C6-C 12 Aryl and 5-13 heteroaryl groups, wherein each of the C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl groups is optionally surrounded by one or more R groups. L f Replace, each of the C3-C 12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally surrounded by one or more R groups. L gReplace, and each of the C6-C 12 Aryl or 5-13 heteroaryl groups are optionally surrounded by one or more R groups. L h Replace; or

[0305] 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 They optionally form C3-C together with the atoms to which they are attached. 12 Carbocyclic or 3-12 membered heterocyclic groups;

[0306] Each R L c and R L f All are independently selected from: F, OH, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl) and N(C1-C4 alkyl)(C3-C6 cycloalkyl);

[0307] Each R L d and R L g All are independently selected from: F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl), and N(C1-C4 alkyl)(C3-C6 cycloalkyl); and

[0308] Each R L e and R L hAll are independently selected from: halogen, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, CN, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl) and N(C1-C4 alkyl)(C3-C6 cycloalkyl); or

[0309] Two Rs L c R L d R L e R L f R L g and R L h They optionally form C3-C together with the atoms to which they are attached. 12 Carbon cyclic group or 3-12 membered heterocyclic group.

[0310] E32. The heterobifunctional compound or salt according to embodiment E31, wherein A L It is selected from the following divalent part: R L a R L a -R L b R L a C(O)R L b R L a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L b R L a OR L b and R L a N(R L 1 )R L b .

[0311] E33. The heterobifunctional compound or salt according to embodiment E31 or E32, wherein:

[0312] AL It is R L a C(O)NHR L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group;

[0313] A L It is R L a C(O)NHR L b R L a It is (C1-C4 alkylene)-R L r And R L b It is a C1-C4 alkylene group;

[0314] A L It is R L a C(O)NHR L b R L a It is a C1-C4 alkylene group, and R L b It is R L r -(C1-C4 alkylene);

[0315] A L It is R L a C(O)NHR L b R L a It is a key, and R L b It is (C1-C4 alkylene)-R L r -(C1-C4 alkylene);

[0316] A L It is R L a C(O)NHR L b R L a It is a C1-C4 alkylene group, and R L b It is a key;

[0317] A L It is R La C(O)NHR L b R L a It is a key, and R L b It is a C1-C4 alkylene group;

[0318] A L It is R L a C(O)NHR L b R L a It is a key, and R L b It is a key;

[0319] A L It is R L a N(R L 1 )C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group;

[0320] A L It is R L a N(R L 1 )C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a key;

[0321] A L It is R L a N(R L 1 )C(O)R L b R L a It is a key, and R L b It is a C1-C4 alkylene group;

[0322] A L It is R L a N(R L 1 )C(O)R Lb R L a It is a key, and R L b It is a key;

[0323] A L It is R L a NHC(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group;

[0324] A L It is R L a C(O)R L b R L a It is (C1-C4 alkylene)-R L r And R L b It is a key;

[0325] A L It is R L a C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is R L r -(C1-C4 alkylene);

[0326] A L It is R L a C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group;

[0327] A L It is R L a C(O)R L b R L a It is a C1-C4 alkylene group, and R L bIt is a key;

[0328] A L It is R L a C(O)R L b R L a It is a key, and R L b It is a C1-C4 alkylene group;

[0329] A L It is R L a C(O)R L b R L a It is a key, and R L b It is a key;

[0330] A L It is R L a -R L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group;

[0331] A L It is R L a -R L b R L a It is (C1-C4 alkylene)-R L r And R L b It is a C1-C4 alkylene group;

[0332] A L It is R L a NHR L b R L a It is a C1-C8 alkylene group, and R L b It is a key;

[0333] A L It is R L a NHR L b R L aIt is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene; or

[0334] A L It is R L a NHR L b R L a It is a key, and R L b It is a C1-C8 alkylene group.

[0335] E34. A heterobifunctional compound or salt according to any one of embodiments E31 to E33, wherein B L It is selected from the following divalent parts: bond, R L a R L a -R L b R L a C(O)R L b R L a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L b R L a OR L b and R L a N(R L 1 )R L b .

[0336] E35. The heterobifunctional compound or salt according to embodiment E34, wherein B L It is selected from key, R L a R L a OR L b and R L a N(R L 1 )R Lb The divalent part.

[0337] E36. The heterobifunctional compound or salt according to embodiment E35, wherein B L It is R L a OR L b R L a It is a key, and R L b It is R L r (C1-C8 alkylene)-R L r or R L r -(C1-C8 alkylene).

[0338] E37. The heterobifunctional compound or salt according to embodiment E35, wherein B L It is R L a N(R L 1 )R L b R L a It is a key, and R L b It is R L r (C1-C8 alkylene)-R L r or R L r -(C1-C8 alkylene).

[0339] E38. The heterobifunctional compound or salt according to embodiment E35, wherein B L It is R L a , where R L a It is R L r (C1-C8 alkylene)-R L r R L r -(C1-C8 alkylene) or (C1-C8 alkylene)-R L r -(C1-C8 alkylene).

[0340] E39. The heterobifunctional compound or salt according to embodiment E38, wherein B L It is R La , where R L a It is R L r (C1-C4 alkylene)-R L r R L r -(C1-C4 alkylene) or (C1-C4 alkylene)-R L r -(C1-C4 alkylene).

[0341] E40. A heterobifunctional compound or salt according to any one of embodiments E31 to E39, wherein A L Or B L At least one R in L r Part of it is C3-C 12 Cycloalkylene or 3-12-membered heterocyclic alkylene groups, each optionally surrounded by one or more R groups. L d replace.

[0342] E41. A heterobifunctional compound or salt according to any one of embodiments E31 to E39, wherein A L Or B L At least one R in L r Part of it is C6-C 12 arylene or 5-13 heteroarylene, each optionally bounded by one or more R L e replace.

[0343] E42. The heterobifunctional compound or salt according to any one of embodiments E31 to E41, wherein L 1 Includes one or more R selected from Equations (L-2), (L-3), (L-4), (L-5), and (L-6). L r part:

[0344] in:

[0345] X R 'and Y R 'Independently selected from N and CR R b ;

[0346] A R 1 B R 1 C R 1 and DR 1 Each occurrence is independently selected from: bond, O, CO, SO, SO2, C(O)NR R b S(O)2NR R b NR R b and CR R b R R c ;

[0347] A R 2 B R 2 C R 2 D R 2 and E R 2 Each occurrence is independently selected from N and CR. R b ;

[0348] A R 3 Each time it appears, it is independently selected from N and C, and B R 3 C R 3 D R 3 and E R 3 Each occurrence is independently selected from N, O, S, NR. R b and CR R b ;

[0349] R R b and R R cEach time it appears, it is independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino and optionally substituted C1-C8 alkylamino, optionally substituted 3-12-membered carbocyclic, optionally substituted 3-12-membered cycloalkoxy, optionally substituted 3-12-membered carbocyclic amino, optionally substituted 4-12-membered heterocyclic, optionally substituted C6-C 12 aryl and optionally substituted 5-13 heteroaryl groups; or

[0350] Two Rs R b and R R c They optionally form C3-C together with the atoms to which they are attached. 12 Carbocyclic or 3-12 membered heterocyclic groups; and

[0351] m R 1 n R 1 o R 1 and p R 1 Selected independently from 0, 1, 2, 3, 4 and 5.

[0352] E43. The heterobifunctional compound or salt according to embodiment E42, wherein R L r Selected from:

[0353]

[0354] E44. The heterobifunctional compound or salt according to embodiment E43, wherein R L r Selected from:

[0355]

[0356] E45. A heterobifunctional compound or salt according to any one of embodiments E31 to E35, wherein B L It is a key.

[0357] E46. A heterobifunctional compound or salt according to any one of embodiments E31 to E35, wherein B L It is RL r .

[0358] E47. The heterobifunctional compound or a pharmaceutically acceptable salt thereof according to any one of embodiments E1 to E30, wherein L 1 It is a bivalent connector selected from the following:

[0359]

[0360]

[0361] Where # is related to L 2 The attachment point is A, and * is the attachment point of A.

[0362] E48. The heterobifunctional compound or a pharmaceutically acceptable salt thereof according to embodiment E47, wherein L 1 It is a bivalent connector selected from the following:

[0363]

[0364] Where # is related to L 2 The attachment point is A, and * is the attachment point of A.

[0365] E49. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in any one of embodiments E1 to E48, and at least one pharmaceutically acceptable excipient.

[0366] In any of the compounds of formulas (I)-(IV), A is a PBM capable of binding to CCND, CDK4, and / or CDK6. In some embodiments, A is a PBM capable of binding to CDK4 and / or CDK6. In some embodiments, A is a PBM capable of binding to CDK4. In some embodiments, A is a PBM capable of binding to CDK6. In common embodiments, A is a PBM capable of binding to both CDK4 and CDK6. In some embodiments of any of formulas (I)-(IV), A is a PBM of any of formulas (A), (A1), (A2), (A3), or (A4), as further described herein. In some embodiments, A is a PBM of any of formulas (A5), (A6), (A7), (A8), or (A9), as described herein. In some preferred embodiments, A is a PBM of formula (A5).

[0367] In any of the compounds of formulas (I)-(IV), L 1 It is a key or a divalent connector. In some implementations, L 1 It is a key or type (L) bivalent connector, as further described herein. In some preferred embodiments, L1 It is a keyed or type (L-1) bivalent connector, as further described herein. In some embodiments, L 1 It is a key or type (J) bivalent connector, as further described herein.

[0368] In any of the compounds of formulas (I)-(IV), L 2 It is a bond, -NH-, -N(C1-C3 alkyl)-, -NHC(O)-, -N(C1-C3 alkyl)C(O)-, -C(O)NH-, -C(O)N(C1-C3 alkyl)-, -O-, -C1-C4-alkylene-, -C2-C4-alkenyl-, or -C2-C4-ynylene-. In some embodiments, L 2 It is -NH-, -N(C1-C3 alkyl)-, -NHC(O)-, or -N(C1-C3 alkyl)C(O)-. In some such embodiments, L 2 It is -NH- or -N(C1-C3 alkyl)-. In a preferred embodiment, L 2 It is -NH-. In some implementations, L 2 It is -N(C1-C3 alkyl)-. In other embodiments, L 2 It is -C(O)NH- or -C(O)N(C1-C3 alkyl)-. In some embodiments, L 2 It is a bond, -C1-C4-alkylene-, -C2-C4-alkenyl-, or -C2-C4-ynylene-. In some embodiments, L 2 It is a bond or -C1-C4-alkylene-. In some such embodiments, L 2 It is a key. In other such implementations, L 2 It is -C1-C4-alkylene-.

[0369] In any of the compounds of formulas (I)-(IV), Q is C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic groups. In some embodiments, Q is C6-C. 10Aryl or 5-10-membered heteroaryl. In some embodiments, Q is a C6-aryl (i.e., phenyl) or a 5-6-membered heteroaryl. In some embodiments, Q is phenyl. In some embodiments, Q is a 5-6-membered heteroaryl. In some preferred embodiments, Q is a 5-6-membered heteroaryl selected from pyridine, pyridazine, imidazole, isoxazole, oxazole, and pyrazole. In some preferred embodiments, Q is selected from phenyl, pyridine, pyridazine, imidazole, isoxazole, oxazole, and pyrazole. In some embodiments, Q is a 6-membered heteroaryl. In some such embodiments, Q is a 6-membered heteroaryl selected from pyridine, pyridazine, pyrimidine, and pyrazine. In some preferred embodiments, Q is pyridine or pyridazine. In some preferred embodiments, Q is pyridin-2-yl or pyridazin-3-yl. In some embodiments, Q is a 5-membered heteroaryl. In some such embodiments, Q is a 5-membered heteroaryl group selected from pyrrole, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, and thiadiazole. In some preferred embodiments, Q is imidazole, isoxazole, or pyrazole. In some such embodiments, Q is imidazole. In some such embodiments, Q is isoxazole. In some such embodiments, Q is oxazole. In some such embodiments, Q is pyrazole.

[0370] In any of the compounds of formulas (I)-(IV), Q is optionally replaced by p substituents R. 1 Replace, where p is an integer from 0 to 4, and each R 1 They are all independent R 1A R 1B R 1C R 1D or R 1E In some implementations, p is an integer from 1 to 3. In common implementations, p is an integer from 1 to 2. In some implementations, p is 1. In some implementations, p is 2.

[0371] In a common implementation of any of equations (I)-(IV), each R 1A All are optional substituents attached to the nitrogen atom of ring Q, and each R 1B R 1C R 1D or R 1E These are all optional substituents attached to the carbon atom of ring Q.

[0372] In any of the compounds of formulas (I)-(IV), each R 1A Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl, wherein each of the C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl is optionally surrounded by one or more R 4A Instead, as further described. In other embodiments, R1A Each optionally substituted portion is unsubstituted. In some such implementations, each R 1A Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl. In some embodiments, each R 1A Each is independently H, C1-C6 alkyl, or C3-C6 cycloalkyl. In some preferred embodiments, each R 1A All are independently H or C1-C4 alkyl groups. In some such embodiments, each R 1A Each is independently H, CH3, CH2CH3, CH2CH2CH3, or CH(CH3)2. In some such embodiments, each R 1A Each is independently H, CH3, or CH2CH3. In some preferred embodiments, each R 1A All are independently C3-C6 cycloalkyl groups. In some such embodiments, each R 1A Each is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some such embodiments, each R 1A They are either cyclopropyl or cyclobutyl.

[0373] In any of the compounds of formulas (I)-(IV), in the presence of each R 4A All are independently C1-C6 alkoxy, oxo, OH, D, halogen (preferably F), CN, or NR. 8A R 8B In some implementations, when R 4A It is NR 8A R 8B At that time, each R 8A and R 8B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 8A and R 8B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings. In some such embodiments, each R... 8A and R 8B Each is independently H or C1-C4 alkyl. In other embodiments, each NR 8A R 8B Each is independently NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2. In some preferred embodiments, each R 4A They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2.

[0374] In any of the compounds of formulas (I)-(IV), each R 1B R1C R 1D and R 1E All of these can be independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, D, halogenated, CN, NO2, NR 5A R 5B C(=O)R 5A C(=O)OR 5A OC(=O)R 5A C(O)NR 5A R 5B 、N(R 5A )C(O)R 5B C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 heteroalkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 4B Replace, and each of the C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 4C Replacement, as further described.

[0375] In some implementations, each R 1B R 1C R 1D and R 1E All are independently H, C1-C6 alkyl, C1-C6 alkoxy, halogenated, CN, NR 5A R 5B C3-C 10 cycloalkyl or C3-C 10 Cycloalkoxy groups, wherein each of the C1-C6 alkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 4B Replace, and each of the C3-C 10 cycloalkyl or C3-C 10 Cycloalkoxy groups are optionally surrounded by one or more R groups. 4C Instead, as further described. In some implementations, R 1B R 1C R 1D and R 1E Each optionally substituted portion is unsubstituted. In some preferred embodiments, each R 1B R 1C R 1D and R 1EAll are independently H, C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 5A R 5B C3-C6 cycloalkyl or C3-C 10 Cycloalkoxy group.

[0376] In some implementations, when R 1B R 1C R 1D or R 1E It is NR 5A R 5B At that time, each R 5A and R 5B Each is independently H, C1-C6 alkyl, or C3-C 10 cycloalkyl or R 5A and R 5B Together with the N atoms to which they are attached, they form 4-10 member heterocyclic base rings. In some preferred embodiments, each R 5A and R 5B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 5A and R 5B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings.

[0377] In some implementations, each R 1B R 1C R 1D and R 1E They are all independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, F, Cl, CN, NH2, NHCH3, N(CH3)2, N-pyrrolidinyl or cyclopropyl.

[0378] In some implementations of any of equations (I)-(IV), where applicable, each R 4B All are independently C1-C6 alkoxy, oxo, OH, D, halogen (preferably F), CN, or NR. 8A R 8B And each R 4C Each of these is independently a C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halogen (preferably F), CN, or NR. 9A R 9B In some such implementations, each R 8A R 8B R 9A and R 9B All are independently H or C1-C6 alkyl groups. In some such embodiments, each R 8A R 8B R9A and R 9B Each is independently H or C1-C4 alkyl. In other embodiments, each NR 8A R 8B and NR 9A R 9B All are independently NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2. In some preferred embodiments of any of formulas (I)-(IV), where present, each R 4B All are independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl), or N (C1-C4-alkyl)2. In some preferred embodiments of any of formulas (I)-(IV), where present, each R 4C Each is independently a C1-C4 alkyl, C1-C4 alkoxy, OH, D, F, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2. In some such embodiments, each R 4B Each is independently a C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2, and each R 4C They are all independently C1-C4 alkyl, C1-C4 alkoxy, OH, D, F, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2.

[0379] In some implementations of any of equations (I)-(IV), R 1B R 1C R 1D and R 1E At least one of them is NR 5A R 5B , where each R 5A and R 5B Each is independently H, C1-C6 alkyl, or C3-C 10 cycloalkyl or R 5A and R 5B Together with the attached N atoms, they form 4-10 membered heterocyclic rings; preferably C3-C6 cycloalkyl or R 5A and R 5B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic rings (e.g., N-linked pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl moieties).

[0380] In some preferred embodiments, each R 1A Each is independently H, C1-C4 alkyl, or C3-C6 cycloalkyl, and each R 1B R 1C R 1D and R1E All are independently H, C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 5A R 5B Or C3-C6 cycloalkyl. In such embodiments, each R 1A Each is independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl, and each R 1B R 1C R 1D and R 1E They are all independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, F, Cl, NH2, NHCH3, N(CH3)2, N-pyrrolidinyl or cyclopropyl.

[0381] In any of the compounds of formulas (I)-(IV), R 2 It is an H or C1-C3 alkyl group. In a preferred embodiment, R 2 It is H.

[0382] In compounds of any of formulas (I)-(III), the core pyridine ring is optionally replaced by q substituents R. 3 Replace, where q is an integer from 0 to 3, and each R 3 They are all independent R 3A R 3B or R 3C ; or two Rs 3 They can form fused C3-C atoms together with the atoms to which they are attached. 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl or 5-10 heteroaryl groups, each optionally bounded by one or more R groups. 6A Replacement. In some implementations, q is an integer from 1 to 3. In some implementations, q is an integer from 1 to 2. In some implementations, q is 1. In some implementations, q is 2.

[0383] In the compound of formula (IV), the core pyridine ring is R-shaped on the carbon atom shown. 3A replace.

[0384] In any of the compounds of formulas (I)-(IV), each R 3A R 3B and R 3C All are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, halogenated, CN, NO2, NR 7A R 7B C(=O)R 7A C(=O)OR7A OC(=O)R 7A C(O)NR 7A R 7B 、N(R 7A )C(O)R 7B C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 heteroalkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 6B Replace, and each of the C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 6C Instead, as further described. In some implementations, each R 3A R 3B and R 3C All are independently C1-C6 alkyl, C1-C6 alkoxy, halogenated, CN, NR 7A R 7B C3-C 10 cycloalkyl or C3-C 10 Cycloalkoxy groups, wherein each of the C1-C6 alkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 6B Replace, and each of the C3-C 10 cycloalkyl or C3-C 10 Cycloalkoxy groups are optionally surrounded by one or more R groups. 6C Instead, as further described. In some implementations, R 3A R 3B and R 3C Each optionally substituted portion is unsubstituted. In some such implementations, each R 3A R 3B and R 3C All are independently C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 7A R 7B C3-C6 cycloalkyl or C3-C 10 Cycloalkoxy group.

[0385] In some implementations of any of equations (I)-(IV), R 3A R 3B or R 3C At least one of them is NR 7A R 7BIn some such implementations, when R 3A R 3B or R 3C It is NR 7A R 7B At that time, each R 7A and R 7B Each is independently H, C1-C6 alkyl, or C3-C 10 cycloalkyl or R 7A and R 7B Together with the N atoms to which they are attached, they form 4-10 membered heterocyclic base rings. In some such embodiments, each R... 7A and R 7B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 7A and R 7B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings.

[0386] In some preferred embodiments, each R 3A R 3B and R 3C All are independently H, C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 7A R 7B C3-C6 cycloalkyl or C3-C 10 Cycloalkoxy. In some such embodiments, each R 3A R 3B and R 3C They are all independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, F, Cl, CN, NH2, NHCH3, NHCH(CH3)2, NH(c-butyl), NH(tert-butyl), N(CH3)2, N-pyrrolidinyl or cyclopropyl.

[0387] In some preferred embodiments of formula (IV), R 3A It is NR 7A R 7B In some such implementations, R 3A It is NH2, NHCH3, NHCD3, NHCH(CH3)2, NH(c-butyl), NH(tert-butyl), N(CH3)2 or N-pyrroloalkyl.

[0388] In any of the compounds of formulas (I)-(III), in the presence of each R 6A Each is independently a C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halogen, CN, or NR. 9A R 9BIn any of the compounds of formulas (I)-(IV), in the presence of any one of them, each R 6B They are all independently C1-C6 alkoxy, oxo, OH, D, halogenated, CN, or NR. 9A R 9B Preferably, each R 6B All are independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl), or N (C1-C4-alkyl)2. In compounds of any of formulas (I)-(IV), each R, in the presence of any of them, 6C Each is independently a C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halogen, CN, or NR. 9A R 9B Preferably, each R 6C All are independently C1-C4 alkyl, C1-C4 alkoxy, OH, D, F, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2. In some embodiments, when R 6A R 6B or R 6C Any one of them is NR 9A R 9B At that time, each R 9A and R 9B Each is independently H, C1-C6 alkyl, or C3-C 10 cycloalkyl or R 9A and R 9B Together with the N atoms to which they are attached, they form 4-10 membered heterocyclic base rings. In some such embodiments, each R... 9A and R 9B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 9A and R 9B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings.

[0389] In any of the compounds of formulas (I)-(IV), in the presence of each R 5A R 5B R 7A R 7B R 8A R 8B R 9A and R 9B All are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl or C1-C6 heteroalkyl groups is optionally surrounded by one or more R groups. 10AReplace, and each of the C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 10B Replace; or R 5A and R 5B R 7A and R 7B R 8A and R 8B or R 9A and R 9B They can form 4-10 membered heterocyclic rings or 5-10 membered heteroaryl rings together with the N atoms to which they are attached, wherein each of the 4-10 membered heterocyclic or 5-10 membered heteroaryl groups is optionally surrounded by one or more R atoms. 10C replace.

[0390] In some such implementations, where applicable, each R 10A They are all independently C1-C6 alkoxy, oxo, OH, D, halogenated, CN, or NR. 11A R 11B Preferably, each R 10A All are independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl), or N (C1-C4-alkyl)2. In some embodiments, each R, when present, 10B and R 10C Each is independently a C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halogen, CN, or NR. 12A R 12B Preferably, each R 10B and R 10C All are independently C1-C4 alkyl, C1-C4 alkoxy, F, Cl, CN, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2. In some embodiments, where present, each R 11A R 11B R 12A and R 12B They are all independently H or C1-C4 alkyl groups.

[0391] In some implementations of any of equations (I)-(IV), where applicable, each R 5A R 5B R 7A R 7B R 8A R 8B R 9A and R 9B Each is independently H, C1-C6 alkyl, or C3-C 10cycloalkyl; or R 5A and R 5B R 7A and R 7B R 8A and R 8B or R 9A and R 9B They can form 4-10 membered heterocyclic groups together with the N atoms to which they are attached. In some such embodiments, each R 5A R 5B R 7A R 7B R 8A R 8B R 9A and R 9B All are independently H, C1-C4 alkyl or C3-C6 cycloalkyl; or R 5A and R 5B R 7A and R 7B R 8A and R 8B or R 9A and R 9B They can form 4-6 membered heterocyclic groups together with the N atoms to which they are attached.

[0392] In some preferred embodiments of any of equations (I)-(IV), Q is selected from:

[0393]

[0394] in:

[0395] * indicates an attachment point; and

[0396] R 1A R 1B R 1C R 1D and R 1E As defined in equation (I).

[0397] In some such implementations of any of equations (I)-(IV), Q is selected from:

[0398]

[0399] In some such implementations of any of equations (I)-(IV), Q is selected from:

[0400]

[0401] Embodiments of any of formulas (I)-(IV) described herein may also be applied to compounds of any of formulas (V)-(XII) to the extent that such embodiments are not incompatible.

[0402] In some embodiments, the heterobifunctional compound of formula (III) has the structure of formula (V) or a pharmaceutically acceptable salt thereof, as described above. In some such embodiments, the compound of formula (V) has the structure of formula (VA), (VB), (VC), or (VD).

[0403] In some such embodiments, the compound of formula (V) has the structure of formula (VA), wherein: X 3 Is it N or CR? 1B ;X 4 Is it N or CR? 1C And X 6 Is it N or CR? 1E In some such implementations, X 3 It is N; X 4 It is CR 1C And X 6 It is CR 1E In some such implementations, X 3 It is CR 1B ;X 4 It is CR 1C And X 6 It is CR 1E In some of the above implementation schemes, R 1E It is H.

[0404] In some such embodiments, the compound of formula (V) has the structure of formula (VB), wherein: X 5 Is it N or CR? 1D And X 6 Is it N or CR? 1E In some such implementations, X 5 It is CR 1D And X 6 It is CR 1E In some such implementations, X 5 It is N; and X 6 It is CR 1E In some such implementations, X 5 It is CR 1D And X 6 It is N. In some of the above implementations, R 1D It is H. In some of the above implementations, R 1E It is H.

[0405] In some such embodiments, the compound of formula (V) has the structure of formula (VC), wherein: X 5 Is it N or CR? 1D In some such implementations, X5 It is N. In some such implementations, X 5 It is CR 1D .

[0406] In some such embodiments, the compound of formula (V) has the structure of formula (VD).

[0407] In some embodiments, the compound of formula (V) has the structure of any one of formulas (V-a1) to (V-c2). In some such embodiments, the compound of formula (V) has the structure of formula (V-a1) or (V-a2).

[0408] In some embodiments, the heterobifunctional compound of formula (III) has the structure of formula (VI) or a pharmaceutically acceptable salt thereof, as described above.

[0409] In some such embodiments, the heterobifunctional compound of formula (VI) has a structure of any one of (VI-A) to (VI-N). In some such embodiments, the heterobifunctional compound of formula (VI) has a structure of any one of (VI-a1) to (VI-n3).

[0410] In some embodiments, the heterobifunctional compound of formula (IV) has the structure of formula (VII) or a pharmaceutically acceptable salt thereof, as described above.

[0411] In some such embodiments, the compound of formula (VII) has the structure of formula (VII-A), (VII-B), (VII-C) or (VII-D).

[0412] In some such embodiments, the compound of formula (VII) has the structure of formula (VII-A), wherein: X 3 Is it N or CR? 1B ;X 4 Is it N or CR? 1C And X 6 Is it N or CR? 1E In some such implementations, X 3 It is N; X 4 It is CR 1C And X 6 It is CR 1E , where R 1E It is H. In some such implementations, X 3 It is CR 1B ;X 4 It is CR 1C And X 6 It is CR 1E , where R 1E It is H.

[0413] In some such embodiments, the compound of formula (VII) has the structure of formula (VII-B), wherein: X 5 Is it N or CR? 1D And X 6 Is it N or CR? 1E In some such implementations, X 5 It is CR 1D And X 6 It is CR 1E In some such implementations, X 5 It is N; and X 6 It is CR 1E In some such implementations, X 5 It is CR 1D And X 6 It is N.

[0414] In some such embodiments, the compound of formula (VII) has the structure of formula (VII-C), wherein: X 5 Is it N or CR? 1D In some such implementations, X 5 It is N. In some such implementations, X 5 It is CR 1D .

[0415] In some such embodiments, the compound of formula (VII) has the structure of formula (VII-D).

[0416] In some embodiments, the compound of formula (VII) has the structure of any one of formulas (VII-a1) to (VII-c2). In some such embodiments, the heterobifunctional compound of formula (VII) has the structure of formula (VII-a1) or (VII-a2).

[0417] In some embodiments, the heterobifunctional compound of formula (IV) has the structure of formula (VIII) or a pharmaceutically acceptable salt thereof, as described above.

[0418] In some such embodiments, the compound of formula (VIII) has the structure of any one of formulas (VIII-A) to (VIII-N). In some such embodiments, the compound of formula (VIII) has the structure of any one of formulas (VIII-a1) to (VIII-n3).

[0419] In a preferred embodiment of the compound of any of formulas (I)-(VIII), R 2 It is H.

[0420] In some embodiments, the heterobifunctional compound of formula (IV) has the structure of formula (IX) or a pharmaceutically acceptable salt thereof, as described above.

[0421] In some such embodiments, the compound of formula (IX) has the structure of any one of formulas (IX-A) to (IX-N).

[0422] In some embodiments, the heterobifunctional compound of formula (IV) has a structure of formula (X) selected from any of formulas (XA) to (XL) or a pharmaceutically acceptable salt thereof, as described above.

[0423] In some embodiments of any of formulas (I)-(X), A is a PBM of any of formulas (A), (A1), (A2), (A3), or (A4), as described herein. In some such embodiments, A is a PBM of any of formulas (A5), (A6), (A7), (A8), or (A9), as described herein. In some preferred embodiments, A is a PBM of formula (A5).

[0424] In some embodiments, the heterobifunctional compound of formula (IV) has the structure of formula (XI) or a pharmaceutically acceptable salt thereof, as described above. In some such embodiments, the compound of formula (XI) has the structure of formula (XI-A), (XI0B), (XI-C), or (XI-D).

[0425] In some embodiments, the heterobifunctional compound of formula (IV) has the structure of formula (XII) or a pharmaceutically acceptable salt thereof, as described above. In some such embodiments, the compound of formula (XII) has the structure of formula (XII-A), (XII-B), (XII-C), or (XII-D).

[0426] Some preferred embodiments of the compounds or salts of any of formulas (I)-(XII) have, to the extent that such embodiments are not incompatible, any combination of one, two, three, four, five, or more than five of the following options:

[0427] A is a PBM that can be combined with CDK4 and / or CDK6;

[0428] A is a PBM with the structure of formula (A);

[0429] A is a PBM with a structure of (A1), (A2), (A3), or (A4);

[0430] A is a PBM with the structure of formula (A5), (A6), (A7), (A8), or (A9);

[0431] A is a PBM with the structure of formula (A5);

[0432] L 1 It is a keyed or type (L-1) bivalent connector;

[0433] L 1 It is a keyed or type (L-1) bivalent connector, where A L It is selected from the following divalent part: R L a R L a -R L b R L a C(O)R L b R L a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L b R L a OR L b and R L a N(R L 1 )R L b ;

[0434] L 1 It is a keyed or type (L-1) bivalent connector, where A L It is selected from the following divalent part: R L a C(O)R L b R L a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L b and R L a N(R L 1 )RL b ;

[0435] L 1 It is a keyed or type (L-1) bivalent connector, where B L It is selected from the following divalent parts: bond, R L a R L a -R L b R L a C(O)R L b R L a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L b R L a OR L b and R L a N(R L 1 )R L b ;

[0436] L 1 It is a keyed or type (L-1) bivalent connector, where B L It is selected from the following divalent parts: bond, R L a R L a -R L b R L a OR L b and R L a N(R L 1 )R L b ;

[0437] L 1 It is a keyed or type (L-1) bivalent connector, where B L It is selected from key and R L a The divalent part in, where RL a It is R L r ;

[0438] L 1 Includes one or more R selected from Equations (L-2), (L-3), (L-4), (L-5), and (L-6). L r part;

[0439] R L r Selected from:

[0440]

[0441] L 1 It is a key or type (J) divalent connector;

[0442] L 2 It is -NH-;

[0443] Q is a 5-6 quinone heteroaryl group;

[0444] Q is a 5-6 membered heteroaryl group selected from pyridine, pyridazine, imidazole, isoxazole, oxazole and pyrazole;

[0445] Q is pyridine or pyridazine;

[0446] Q is either pyridin-2-yl or pyridazin-3-yl;

[0447] Q is imidazole, isoxazole, oxazole, or pyrazole;

[0448] Q stands for imidazole;

[0449] Q is isoxazole;

[0450] Q is oxazole;

[0451] Q is pyrazole;

[0452] Q is selected from:

[0453]

[0454] Where * indicates an attachment point;

[0455] Q is selected from:

[0456] Where * indicates an attachment point;

[0457] Q is selected from:

[0458]

[0459] Where * indicates an attachment point;

[0460] Each R 1A They are all independently H, C1-C4 alkyl, or C3-C6 cycloalkyl;

[0461] Each R 1A Each is independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl; each R 1A They are all independently H or C1-C4 alkyl groups;

[0462] Each R 1A They are all independently H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0463] Each R 1B R 1C R 1D and R 1E All are independently H, C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 5A R 5B C3-C6 cycloalkyl or C1-C4 cycloalkoxy;

[0464] Each R 1B R 1C R 1D and R 1E They are all independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, F, Cl, NH2, NHCH3, N(CH3)2, N-pyrrolidinyl or cyclopropyl;

[0465] R 1B R 1C R 1D and R 1E At least one of them is NR 5A R 5B , where each R 5A and R 5B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 5A and R 5B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0466] R 2 It is H;

[0467] Each R 3A R 3B and R 3C All are independently H, C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 7A R 7B Or C3-C6 cycloalkyl;

[0468] Each R 3A R 3B and R 3C They are all independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, F, Cl, CN, NH2, NHCH3, NHCD3, NHCH(CH3)2, NH(c-butyl), NH(tert-butyl), N(CH3)2, N-pyrrolidinyl or cyclopropyl;

[0469] R 3A R 3B and R 3C At least one of them is NR 7A R 7B ;

[0470] R 3A It is NR 7A R 7B ;

[0471] Each R 4A They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2;

[0472] Each R 4B They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2;

[0473] Each R 4C They are all independently C1-C4 alkyl, C1-C4 alkoxy, OH, D, F, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2;

[0474] Each R 5A and R 5B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 5A and R 5B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0475] Each R 6B They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2;

[0476] Each R 6C They are all independently C1-C4 alkyl, C1-C4 alkoxy, OH, D, F, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2;

[0477] Each R 7A and R 7B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 7A and R 7B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0478] Each R 8A and R 8B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 8A and R 8B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0479] Each R 9A and R 9B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 9A and R 9B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0480] Each R 10A They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2;

[0481] Each R 10B and R 10C They are all independently C1-C4 alkyl, C1-C4 alkoxy, F, Cl, CN, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2;

[0482] Each R 11A R 11B R 12A and R 12B They are all independently H, C1-C4 alkyl, or C3-C6 cycloalkyl;

[0483] Each R 11A R 11B R 12A and R 12B They are all independently H or C1-C4 alkyl groups;

[0484] p is an integer from 1 to 3;

[0485] p is an integer from 1 to 2;

[0486] q is an integer from 1 to 2; and

[0487] q is 1.

[0488] Representative examples of heterobifunctional compounds of formula (I)-(XII) are shown in Tables 4A and 4B.

[0489] DDB1 binding moiety

[0490] This document further describes monofunctional compounds comprising the DDB1 E3 ligase-binding moiety. In some embodiments, such compounds may consist of the DDB1-binding moiety. In some embodiments, such compounds may consist substantially of the DDB1-binding moiety (e.g., a DDB1-binding moiety modified with a linker portion, optionally including reactive functional groups, but lacking a PBM). Monofunctional compounds can be used for various purposes, such as as molecular colloids or as synthetic intermediates for the preparation of heterobifunctional compounds, as further described herein.

[0491] The listed embodiments E50 to E61 relate to monofunctional compounds of formula (XIII) and their salts, as well as compositions of such compounds and salts.

[0492] E50. A compound of formula (XIII):

[0493]

[0494] Or its salt, wherein:

[0495] Z 1 It is L 1 -Z 2 or L 1 -G;

[0496] L 1 It is a key or a divalent connector;

[0497] Z 2 It is H, D, halogenated, C1-C4 alkyl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic group, wherein each of the C1-C4 alkyl group, C3 ... 10 Cycloalkyl or 4-10-membered heterocyclic groups are optionally substituted with halogen, OH, oxo, C1-C4 alkoxy, NH2, NH(C1-C4-alkyl), or N(C1-C4-alkyl)2;

[0498] G is a reactive functional group;

[0499] L 2 It is a bond, -NH-, -N(C1-C3 alkyl)-, -NHC(O)-, -N(C1-C3 alkyl)C(O)-, -C(O)NH-,

[0500] -C(O)N(C1-C3 alkyl)-, -O-, -C1-C4-alkylene-, -C2-C4-alkenyl- or -C2-C4-ynylene-;

[0501] Q is C6-C 10 Aryl, 5-10 heteroaryl, C3-C 10 Cycloalkyl or 4-10 membered heterocyclic groups;

[0502] Each R 1 They are all independent R 1A R 1B R 1C R 1D or R 1E ;

[0503] Each R 1A Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl, wherein each of the C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl is optionally surrounded by one or more R 4A replace;

[0504] Each R 1B R 1C R 1D and R 1E All of these can be independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, D, halogenated, CN, NO2, NR 5A R 5B C(=O)R 5A C(=O)OR 5A OC(=O)R 5A C(O)NR 5A R 5B 、N(R 5A )C(O)R 5B C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 heteroalkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 4B Replace, and each of the C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 4C replace;

[0505] R 2 It is an H or C1-C3 alkyl group;

[0506] Each R 3 They are all independent R 3A R 3B or R3C ; or two Rs 3 They can form C3-C together with the atoms to which they are attached. 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 6A replace;

[0507] Each R 3A R 3B and R 3C All are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, D, halogenated, CN, NO2, NR 7A R 7B C(=O)R 7A C(=O)OR 7A OC(=O)R 7A C(O)NR 7A R 7B 、N(R 7A )C(O)R 7B C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 heteroalkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 6B Replace, and each of the C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 6C replace;

[0508] Each R 4A R 4B and R 6B They are all independently C1-C6 alkoxy, oxo, OH, D, halogenated, CN, or NR. 8A R 8B ;

[0509] Each R 4C R 6A and R 6C Each is independently a C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halogen, CN, or NR. 9A R 9B ;

[0510] Each R 5A R 5B R 7A R 7B R 8A R 8B R 9A and R 9B All are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl or C1-C6 heteroalkyl groups is optionally surrounded by one or more R groups. 10A Replace, and each of the C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 10B Replace; or

[0511] R 5A and R 5B R 7A and R 7B R 8A and R 8B or R 9A and R 9B They can form 4-10 membered heterocyclic rings or 5-10 membered heteroaryl rings together with the N atoms to which they are attached, wherein each of the 4-10 membered heterocyclic or 5-10 membered heteroaryl groups is optionally surrounded by one or more R atoms. 10C replace;

[0512] Each R 10A They are all independently C1-C6 alkoxy, oxo, OH, D, halogenated, CN, or NR. 11A R 11B ;

[0513] Each R 10B and R 10C Each is independently a C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halogen, CN, or NR. 12A R 12B ;

[0514] Each R 11A R 11B R 12A and R 12B They are all independently H, C1-C4 alkyl, or C3-C6 cycloalkyl;

[0515] p is an integer from 0 to 4; and

[0516] q is an integer from 0 to 3;

[0517] The prerequisite is that the compound of formula (XIII) is not:

[0518] 2-Amino-N-(4,5-dimethylthiazolyl-2-yl)-6-methylnicotinamide;

[0519] (2-(2-(3-((3-((4,5-dimethylthiazo-2-yl)carbamoyl)-6-methylpyridin-2-yl)amino)-3-oxopropoxy)ethoxy)ethyl)tert-butyl carbamate;

[0520] 2-(3-(2-(2-aminoethoxy)ethoxy)propionylamino)-N-(4,5-dimethylthiazolyl-2-yl)-6-methylnicotinamide;

[0521] (7-((6-chloro-3-((4,5-dimethylthiazo-2-yl)carbamoyl)-pyridin-2-yl)amino)heptyl)tert-butyl carbamate;

[0522] (7-((3-((4,5-dimethylthiazo-2-yl)carbamoyl)-6-methylpyridin-2-yl)amino)heptyl)tert-butyl carbamate; or

[0523] 2-((7-aminoheptyl)amino)-N-(4,5-dimethylthiazolyl-2-yl)-6-methylnicotinamide.

[0524] E51. The compound according to embodiment E50 has a structure of formula (XIII-A), (XIII-B), (XIII-C), or (XIII-D):

[0525] Or its salt.

[0526] E52. The compound or salt according to embodiment E50 or E51, wherein Q is a phenyl or a 5-6 heteroaryl group.

[0527] E53. The compound or salt according to embodiment E52, wherein Q is selected from pyridine, pyridazine, imidazole, isoxazole, oxazole and pyrazole.

[0528] E54. The compound or salt according to embodiment E53, wherein Q is selected from:

[0529]

[0530] Where * represents an attachment point.

[0531] E55. The compound or salt according to embodiment E54, wherein:

[0532] Each R1A All are independently H, C1-C4 alkyl, or C3-C6 cycloalkyl; and

[0533] Each R 1B R 1C R 1D and R 1E All are independently H, C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 5A R 5B C3-C6 cycloalkyl or C3-C6 cycloalkoxy.

[0534] E56. A compound or salt according to any one of embodiments E50 to E55, Z 1 It is L 1 -G.

[0535] E57. A compound or salt according to any one of embodiments E50 to E56, wherein G is selected from protected or unprotected primary or secondary amines, carboxylic acids, carboxylic esters, halogenated, hydroxylated, C1-C4 alkoxy, C1-C4 haloalkoxy, formyl, C1-C4 alkyl sulfonate, C1-C4 haloalkyl sulfonate, C6-C 10 Aryl sulfonates, boric acids, borate esters and azides.

[0536] E58. A compound or salt according to any one of embodiments E50 to E57, wherein G is halogenated, OH, OR d NH2, NH (C1-C4-alkyl), NH-CO2R d N3, CO2H, CO2R d or OSO2R d , where each R d All are independently C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, or optionally substituted C7-C 14 Arylalkyl or optionally substituted C6-C 13 Aryl.

[0537] E59. A compound or salt according to any one of embodiments E50 to E55, wherein Z 1 It is L 1 -Z 2 .

[0538] E60. The compound or salt according to embodiment E59, wherein Z 2 It is H, D, or halogenated.

[0539] E61. The compound or salt according to embodiment E59, wherein Z 2 It is a C1-C4 alkyl, C3-C 10Cycloalkyl or 4-10 membered heterocyclic group, wherein each of the C1-C4 alkyl group, C3 ... 10 Cycloalkyl or 4-10-membered heterocyclic groups are optionally substituted with halogen, OH, oxo, C1-C4 alkoxy, NH2, NH(C1-C4-alkyl), or N(C1-C4-alkyl)2.

[0540] Embodiments of compounds of any of formulas (I)-(XII) described herein, with respect to Q, R 1 R 2 R 3 R 3A L 1 L 2 p and q may also be applied to compounds or salts of formula (XIII), (XIII-A), (XIII-B), (XIII-C) or (XIII-D) to the extent that they are not incompatible with such embodiments.

[0541] In some implementations of formula (XIII), L 1 It is a key. In some implementations of formula (XIII), L 1 It is a bivalent connector of formula (L), as described herein. In some preferred embodiments of formula (XIII), L 1 It is a bivalent connector of formula (L-1), as described herein. In some embodiments of formula (XIII), L 1 It is a bivalent connector of formula (J), as described in this article.

[0542] In some embodiments of formula (XIII), (XIII-A), (XIII-B), (XIII-C), or (XIII-D), G is selected from: protected or unprotected primary or secondary amines, carboxylic acids, carboxylic acid esters (e.g., C1-C4 alkyl, C2-C4 alkenyl, benzyl, or PMB esters), halogenated, hydroxylated, C1-C4 alkoxy, C1-C4 haloalkoxy, formyl, C1-C4 alkyl sulfonate (e.g., methanesulfonate), C1-C4 haloalkyl sulfonate (e.g., trifluoromethanesulfonate), C6-C 10 Aryl sulfonates (e.g., toluenesulfonates), boric acids, borate esters, and azides. In some embodiments, G is a urethane-protected primary amine (e.g., NH-Boc, NH-Cbz, NH-Fmoc, or NH-Alloc), an unprotected primary amine, a carboxylic acid, a halogenated or hydroxyl moiety.

[0543] Some preferred embodiments of formulas (XIII), (XIII-A), (XIII-B), (XIII-C), or (XIII-D) have, to the extent that such embodiments are not incompatible, any combination of one, two, three, four, five, or more than five of the following options:

[0544] L 1 It is a keyed or type (L-1) bivalent connector;

[0545] L 1 It is a keyed or type (L-1) bivalent connector, where A L It is selected from the following divalent part: R L a R L a -R L b R L a C(O)R L b R L a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L b R L a OR L b and R L a N(R L 1 )R L b ;

[0546] L 1 It is a keyed or type (L-1) bivalent connector, where B L It is selected from the following divalent parts: bond, R L a R L a -R L b R L a C(O)R L b R L a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L bR L a OR L b and R L a N(R L 1 )R L b ;

[0547] L 1 It is a key or type (J) divalent connector;

[0548] L 2 It is -NH-;

[0549] G represents halogenated, OH, or OR. d NH2, NH (C1-C4-alkyl), NH-CO2R d N3, CO2H, CO2R d or OSO2R d , where each R d All are independently C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkenyl, or optionally substituted C7-C 14 Arylalkyl or optionally substituted C6-C 13 Aryl;

[0550] Q is a 5-6 quinone heteroaryl group;

[0551] Q is a 5-6 membered heteroaryl group selected from pyridine, pyridazine, imidazole, isoxazole, oxazole and pyrazole;

[0552] Q is pyridine or pyridazine;

[0553] Q is either pyridin-2-yl or pyridazin-3-yl;

[0554] Q is imidazole, isoxazole, oxazole, or pyrazole;

[0555] Q stands for imidazole;

[0556] Q is isoxazole;

[0557] Q is oxazole;

[0558] Q is pyrazole;

[0559] Q is selected from:

[0560]

[0561] Where * indicates an attachment point;

[0562] Q is selected from:

[0563] Where * indicates an attachment point;

[0564] Q is selected from:

[0565] Where * indicates an attachment point;

[0566] Each R 1A They are all independently H, C1-C4 alkyl, or C3-C6 cycloalkyl;

[0567] Each R 1A Each is independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, or cyclobutyl;

[0568] Each R 1A They are all independently H or C1-C4 alkyl groups;

[0569] Each R 1A They are all independently H, CH3, CH2CH3, CH2CH2CH3 or CH(CH3)2;

[0570] Each R 1B R 1C R 1D and R 1E All are independently H, C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 5A R 5B C3-C6 cycloalkyl or C3-C6 cycloalkoxy;

[0571] Each R 1B R 1C R 1D and R 1E They are all independently H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, F, Cl, NH2, NHCH3, N(CH3)2, N-pyrrolidinyl or cyclopropyl;

[0572] R 1B R 1C R 1D and R 1E At least one of them is NR 5A R 5B , where each R 5A and R 5B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 5A and R 5B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0573] R 2 It is H;

[0574] Each R3A R 3B and R 3C All are independently H, C1-C4 alkyl, C1-C4 alkoxy, halogenated, CN, NR 7A R 7B Or C3-C6 cycloalkyl;

[0575] Each R 3A R 3B and R 3C They are all independently CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, F, Cl, CN, NH2, NHCH3, NHCD3, NHCH(CH3)2, NH(c-butyl), NH(tert-butyl), N(CH3)2, N-pyrrolidinyl or cyclopropyl;

[0576] R 3A R 3B and R 3C At least one of them is NR 7A R 7B ;

[0577] R 3A It is NR 7A R 7B ;

[0578] Each R 4A They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2;

[0579] Each R 4B They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2;

[0580] Each R 4C They are all independently C1-C4 alkyl, C1-C4 alkoxy, OH, D, F, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2;

[0581] Each R 5A and R 5B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 5A and R 5B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0582] Each R 6B They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2;

[0583] Each R 6C They are all independently C1-C4 alkyl, C1-C4 alkoxy, OH, D, F, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2;

[0584] Each R 7A and R 7B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 7A and R 7B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0585] Each R 8A and R 8B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 8A and R 8B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0586] Each R 9A and R 9B Each is independently H, C1-C4 alkyl or C3-C6 cycloalkyl or R 9A and R 9B Together with the N atoms to which they are attached, they form 4-6 membered heterocyclic base rings;

[0587] Each R 10A They are all independently C1-C4 alkoxy, OH, D, F, NH2, NH (C1-C4-alkyl) or N (C1-C4-alkyl)2;

[0588] Each R 10B and R 10C They are all independently C1-C4 alkyl, C1-C4 alkoxy, F, Cl, CN, NH2, NH(C1-C4-alkyl) or N(C1-C4-alkyl)2;

[0589] Each R 11A R 11B R 12A and R 12B They are all independently H, C1-C4 alkyl, or C3-C6 cycloalkyl;

[0590] Each R 11A R 11B R 12A and R 12B They are all independently H or C1-C4 alkyl groups;

[0591] p is an integer from 1 to 3;

[0592] p is an integer from 1 to 2;

[0593] q is an integer from 1 to 2; and

[0594] q is 1.

[0595] Representative compounds of formula (XIII) are shown in Tables 1A and 1B.

[0596] Linker

[0597] This document describes compounds comprising a divalent connector. In some embodiments, compounds of any of formulas (I)-(XIII) are provided, comprising a DDB1 binding moiety and a connector moiety L. 1 The connector portion can be a key or a divalent connector. In some embodiments of any of formulas (I)-(XII), L 1 Covalently attached to the PBM. In some embodiments of any of formulas (I)-(XIII), L 1 Through L 2 And it is covalently attached to the DDB1 binding portion. In some embodiments of any of equations (I)-(XII), L 1 Through L 2 It is covalently attached to both PBM and DDB1.

[0598] In some implementations of any of equations (I)-(XIII), L 1 This is a type (L) bivalent connector:

[0599] in:

[0600] Each A L W L 1 W L 2 and B L They are all independently selected from the following divalent parts: bond, R L a R L a -R L b R L a C(O)R L b R L a C(O)OR L b R L a OC(O)R L b R L aC(O)N(R L 1 )R L b 、R L a N(R L 1 )C(O)R L b 、R L a C(S)N(R L 1 )R L b 、R L a N(R L 1 ]​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​L b All are independently selected from: key, R L r (C1-C8 alkylene)-R L r R L r -(C1-C8 alkylene), (C1-C8 alkylene)-R L r -(C1-C8 alkylene), C1-C8 alkylene, C2-C8 alkenyl, C2-C8 ynynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl, and C3-C8 heteroynynyl, wherein each of the C1-C8 alkylene, C2-C8 alkenyl, C2-C8 ynynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl, or C3-C8 heteroynynyl is optionally surrounded by one or more R L c replace;

[0602] Each R L r All are independently selected from: C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene and 5-13 heteroarylene, wherein each of the C3-C 12 Cycloalkylene or 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. L d Replace, and each of the C6-C 12 Arene or 5-13 heteroarylene groups are optionally surrounded by one or more R groups. L e replace;

[0603] Each R L 1 and R L 2 All are independently selected from: H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic, C6-C 12 Aryl and 5-13 heteroaryl groups, wherein each of the C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl groups is optionally surrounded by one or more R groups. L f Replace, each of the C3-C 12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally surrounded by one or more R groups. L g Replace, and each of the C6-C 12 Aryl or 5-13 heteroaryl groups are optionally surrounded by one or more R groups. Lh Replace; or

[0604] 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 They optionally form C3-C together with the atoms to which they are attached. 12 Carbocyclic or 3-12 membered heterocyclic groups;

[0605] Each R L c and R L f All are independently selected from: F, OH, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl) and N(C1-C4 alkyl)(C3-C6 cycloalkyl);

[0606] Each R L d and R L g All are independently selected from: F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl) and N(C1-C4 alkyl)(C3-C6 cycloalkyl);

[0607] Each R L e and R L hAll are independently selected from: halogen, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, CN, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl) and N(C1-C4 alkyl)(C3-C6 cycloalkyl); or

[0608] R L c R L d R L e R L f R L g and R L h The two atoms in the mixture, together with the atoms to which they are attached, optionally form C3-C. 12 Carbocyclic or 3-12 membered heterocyclic groups; and

[0609] m L It is an integer selected from 0 to 15.

[0610] In some implementations of formula (L), m L It is 0, and W L 1 and W L 2 Empty.

[0611] In some implementations of formula (L), m L It is 0, and the divalent connector has the structure of formula (L-1), where A L and B L As defined in equation (L).

[0612] In some implementations of any of equations (I)-(XIII), L 1 The connector is of type (L-1):

[0613] in:

[0614] Each A L and B L They are all independently selected from the following divalent parts: bond, R L a R L a -R L b R L a C(O)R L b RL a C(O)OR L b 、R L a OC(O)R L b 、R L a C(O)N(R L 1 )R L b 、R L a N(R L 1 )C(O)R L b 、R L a C(S)N(R L 1 )R L b 、R L a N(R L 1 )C(S)R L b 、R L a OR L b 、R L a SR L b 、R L a SOR L b 、R L [[ID=W67]] a SO2R L b 、R L a SO2N(R L 1 )R L b 、R L a N(R L 1 )SO2R L b 、R L a N(R L 1 )R L b 和R L a N(R It should be noted that some of the chemical expressions might be more accurately understood and translated in the context of a comprehensive chemical knowledge system. This translation attempts to maintain the original text structure and chemical notations as precisely as possible.L 1 )C(O)N(R L 2 )R L b ;

[0615] Each R L a and R L b All are independently selected from: key, R L r (C1-C8 alkylene)-R L r R L r -(C1-C8 alkylene), (C1-C8 alkylene)-R L r -(C1-C8 alkylene), C1-C8 alkylene, C2-C8 alkenyl, C2-C8 ynynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl, and C3-C8 heteroynynyl, wherein each of the C1-C8 alkylene, C2-C8 alkenyl, C2-C8 ynynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl, or C3-C8 heteroynynyl moieties is optionally surrounded by one or more R L c replace;

[0616] Each R L r All are independently selected from: C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene and 5-13 heteroarylene, wherein each of the C3-C 12 Cycloalkylene or 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. L d Replace, and each of the C6-C 12 Arene or 5-13 heteroarylene groups are optionally surrounded by one or more R groups. L e replace;

[0617] Each R L 1 and R L 2 All are independently selected from: H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic, C6-C 12 Aryl and 5-13 heteroaryl groups, wherein each of the C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl groups is optionally surrounded by one or more R groups. Lf Replace, each of the C3-C 12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally surrounded by one or more R groups. L g Replace, and each of the C6-C 12 Aryl or 5-13 heteroaryl groups are optionally surrounded by one or more R groups. L h Replace; or

[0618] 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 They optionally form C3-C together with the atoms to which they are attached. 12 Carbocyclic or 3-12 membered heterocyclic groups;

[0619] Each R L c and R L f All are independently selected from: F, OH, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl) and N(C1-C4 alkyl)(C3-C6 cycloalkyl);

[0620] Each R L d and R L g All are independently selected from: F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl), and N(C1-C4 alkyl)(C3-C6 cycloalkyl); and

[0621] Each R Le and R L h All are independently selected from: halogen, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, CN, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl) and N(C1-C4 alkyl)(C3-C6 cycloalkyl); or

[0622] Two Rs L c R L d R L e R L f R L g and R L h They optionally form C3-C together with the atoms to which they are attached. 12 Carbon cyclic group or 3-12 membered heterocyclic group.

[0623] In some embodiments of formula (L) or formula (L-1), A L It is a key. In some embodiments of formula (L) or formula (L-1), A L It is R L a And R L a It is a C1-C8 alkylene group. In some embodiments of formula (L) or formula (L-1), A L It is R L a N(R L 1 )C(O)R L b R L a It is a C1-C8 alkylene group, and R L b It is a C1-C8 alkylene group. In some embodiments of formula (L) or formula (L-1), A L It is R L a N(R L 1 )C(O)R L b R L a It is a C1-C8 alkylene group, and R L b It is a key. In some embodiments of formula (L) or formula (L-1), AL It is R L a -N(R L 1 )C(O)R L b R L a It is a key, and R L b It is a C1-C8 alkylene group. In some embodiments of formula (L) or formula (L-1), A L It is R L a N(R L 1 )C(O)R L b R L a It is a key, and R L b It is a key. In some embodiments of formula (L) or formula (L-1), A L It is R L a C(O)N(R L 1 )R L b R L a It is a C1-C8 alkylene group, and R L b It is a C1-C8 alkylene group. In some embodiments of formula (L) or formula (L-1), A L It is R L a C(O)N(R L 1 )R L b R L a It is a C1-C8 alkylene group, and R L b It is a key. In some embodiments of formula (L) or formula (L-1), A L It is R L a C(O)N(R L 1 )R L b R L a It is a key, and R L b It is a C1-C8 alkylene group. In some embodiments of formula (L) or formula (L-1), A L It is R La C(O)N(R L 1 )R L b R L a It is a key, and R L b It is a key. In some embodiments of formula (L) or formula (L-1), A L It is R L a C(O)R L b R L a It is a key, and R L b It is a C1-C8 alkylene group. In some embodiments of formula (L) or formula (L-1), A L It is R L a C(O)R L b R L a It is a C1-C8 alkylene group, and R L b It is a key. In some embodiments of formula (L) or formula (L-1), A L It is R L a C(O)R L b R L a It is a key, and R L b It is the key. In any of the above implementations, B L It is selected from the following divalent parts: bond; R L a , where R L a It is R L r or R L r -(C1-C8 alkylene); R L a OR L b , where R L a It is a key and R L b It is R L r R L r -(C1-C8 alkylene) or (C1-C8 alkylene)-R Lr ; and R L a N(R L 1 )R L b , where R L a It is a key and R L b It is R L r ; where each R L r Some of them are optional replacements of C3-C 12 Cycloalkylene or 3-12 membered heterocyclic alkylene groups.

[0624] In some implementations of formula (L) or formula (L-1), the two R L c The groups, together with the atoms to which they are attached, may optionally form C3-C6 carbon cyclic groups or 3-6 membered heterocyclic groups.

[0625] In some implementations of any of equations (I)-(XIII), L 1 It is a binary connector of type (L) or type (L-1), wherein:

[0626] A L It is selected from the following divalent parts:

[0627] 1)R L a C(O)N(R L 1 )R L b ,in:

[0628] (a)R L a It is a C1-C8 alkylene group, and R L b It is a C1-C8 alkylene group;

[0629] (b)R L a It is a C1-C8 alkylene group, and R L b It is a key;

[0630] (c)R L a It is a key, and R L b It is a C1-C8 alkylene group;

[0631] (d)R L a It is a key, and RL b It is a key;

[0632] (e)R L a It is (C1-C8 alkylene)-R L r And R L b It is a C1-C8 alkylene group;

[0633] (f)R L a It is a C1-C8 alkylene group, and R L b It is R L r -(C1-C8 alkylene);

[0634] (g)R L a It is a C1-C8 alkylene group, and R L b It is (C1-C8 alkylene)-R L r -(C1-C8 alkylene);

[0635] (h)R L a It is a C1-C8 alkylene group, and R L b It is (C1-C8 alkylene)-R L r ;

[0636] (i)R L a It is a C1-C8 alkylene group, and R L b It is R L r ;

[0637] (j)R L a It is a key, and R L b It is (C1-C8 alkylene)-R L r -(C1-C8 alkylene);

[0638] (k)R L a It is a key, and R L b It is R L r -(C1-C8 alkylene);

[0639] (l)RL a It is a key, and R L b It is (C1-C8 alkylene)-R L r ;or

[0640] (m)R L a It is a key, and R L b It is R L r ;

[0641] 2)R L a N(R L 1 )C(O)R L b ,in:

[0642] (a)R L a It is a C1-C8 alkylene group, and R L b It is a C1-C8 alkylene group;

[0643] (b)R L a It is a C1-C8 alkylene group, and R L b It is a key;

[0644] (c)R L a It is a key, and R L b It is a C1-C8 alkylene group;

[0645] (d)R L a It is a key, and R L b It is a key;

[0646] (e)R L a It is (C1-C8 alkylene)-R L r And R L b It is a C1-C8 alkylene group;

[0647] (f)R L a It is a C1-C8 alkylene group, and R L b It is R L r -(C1-C8 alkylene);

[0648] (g)R L a It is a C1-C8 alkylene group, and R L b It is (C1-C8 alkylene)-R L r -(C1-C8 alkylene);

[0649] (h)R L a It is a C1-C8 alkylene group, and R L b It is (C1-C8 alkylene)-R L r ;

[0650] (i)R L a It is a C1-C8 alkylene group, and R L b It is R L r ;

[0651] (j)R L a It is a key, and R L b It is (C1-C8 alkylene)-R L r -(C1-C8 alkylene);

[0652] (k)R L a It is a key, and R L b It is R L r -(C1-C8 alkylene);

[0653] (l)R L a It is a key, and R L b It is (C1-C8 alkylene)-R L r ;or

[0654] (m)R L a It is a key, and R L b It is R L r ;

[0655] 3)R L a C(O)R L b,in:

[0656] (a)R L a It is a C1-C8 alkylene group, and R L b It is a C1-C8 alkylene group;

[0657] (b)R L a It is a C1-C8 alkylene group, and R L b It is a key;

[0658] (c)R L a It is a key, and R L b It is a C1-C8 alkylene group;

[0659] (d)R L a It is a key, and R L b It is a key;

[0660] (e)R L a It is (C1-C8 alkylene)-R L r And R L b It is a C1-C8 alkylene group;

[0661] (f)R L a It is a C1-C8 alkylene group, and R L b It is (C1-C8 alkylene)-R L r -(C1-C8 alkylene);

[0662] (g)R L a It is a C1-C8 alkylene group, and R L b It is (C1-C8 alkylene)-R L r ;

[0663] (h)R L a It is a C1-C8 alkylene group, and R L b It is R L r ;

[0664] (i)R L aIt is a C1-C8 alkylene group, and R L b It is R L r -(C1-C8 alkylene);

[0665] (j)R L a It is a key, and R L b It is (C1-C8 alkylene)-R L r -(C1-C8 alkylene);

[0666] (k)R L a It is a key, and R L b It is R L r -(C1-C8 alkylene);

[0667] (l)R L a It is a key, and R L b It is (C1-C8 alkylene)-R L r ;or

[0668] (m)R L a It is a key, and R L b It is R L r ;

[0669] 4)R L a N(R L 1 )R L b ,in:

[0670] (a)R L a It is a C1-C8 alkylene group, and R L b It is a C1-C8 alkylene group;

[0671] (b)R L a It is a C1-C8 alkylene group, and R L b It is a key;

[0672] (c)R L a It is a key, and R L bIt is a C1-C8 alkylene group;

[0673] (d)R L a It is a key, and R L b It is a key;

[0674] (e)R L a It is (C1-C8 alkylene)-R L r And R L b It is a C1-C8 alkylene group;

[0675] (f)R L a It is a C1-C8 alkylene group, and R L b It is (C1-C8 alkylene)-R L r -(C1-C8 alkylene);

[0676] (g)R L a It is a C1-C8 alkylene group, and R L b It is (C1-C8 alkylene)-R L r ;

[0677] (h)R L a It is a C1-C8 alkylene group, and R L b It is R L r ;

[0678] (i)R L a It is a C1-C8 alkylene group, and R L b It is R L r -(C1-C8 alkylene);

[0679] (j)R L a It is a key, and R L b It is (C1-C8 alkylene)-R L r -(C1-C8 alkylene);

[0680] (k)R L a It is a key, and R L bIt is R L r -(C1-C8 alkylene);

[0681] (l)R L a It is a key, and R L b It is (C1-C8 alkylene)-R L r ;or

[0682] (m)R L a It is a key, and R L b It is R L r ;and

[0683] 5)R L a -R L b ,in:

[0684] (a)R L a It is a C1-C8 alkylene group, and R L b It is a key;

[0685] (b)R L a It is (C1-C8 alkylene)-R L r And R L b It is a C1-C8 alkylene group;

[0686] (c)R L a It is (C1-C8 alkylene)-R L r And R L b It is a key; or

[0687] (d)R L a It is R L r -(C1-C8 alkylene), and R L b It is a key;

[0688] Each R L r Most are C3-C 12 Cycloalkylene or 3-12-membered heterocyclic alkylene groups;

[0689] Each C1-C8 alkylene moiety is optionally surrounded by one or more R L c Replace; and

[0690] Each C3-C 12 Cycloalkylene or 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. L d replace.

[0691] In some implementations of any of equations (I)-(XIII), the two R L c The groups, together with the atoms to which they are attached, may optionally form C3-C6 carbon cyclic groups or 3-6 membered heterocyclic groups.

[0692] In some implementations of any of equations (I)-(XIII), L 1 It is a binary connector of type (L) or type (L-1), wherein:

[0693] A L It is R L a C(O)N(R L 1 )R L b ,and:

[0694] (a)R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group;

[0695] (b)R L a It is a C1-C4 alkylene group, and R L b It is a key;

[0696] (c)R L a It is a key, and R L b It is a C1-C4 alkylene group;

[0697] (c)R L a It is a key, and R L b It is a key;

[0698] (d)R L a It is (C1-C4 alkylene)-R L r And R Lb It is a C1-C4 alkylene group;

[0699] (e)R L a It is a C1-C4 alkylene group, and R L b It is R L r -(C1-C4 alkylene); or

[0700] (f)R L a It is a key, and R L b It is (C1-C4 alkylene)-R L r -(C1-C4 alkylene);

[0701] In some implementations of any of equations (I)-(XIII), L 1 It is a binary connector of type (L) or type (L-1), wherein:

[0702] A L It is R L a C(O)R L b ,and:

[0703] (a)R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group;

[0704] (b)R L a It is a C1-C4 alkylene group, and R L b It is a key;

[0705] (c)R L a It is a key, and R L b It is a C1-C4 alkylene group;

[0706] (d)R L a It is a key, and R L b It is a key;

[0707] (e)R L a It is (C1-C4 alkylene)-R L r And R L bIt is a C1-C4 alkylene group;

[0708] (f)R L a It is a C1-C4 alkylene group, and R L b It is R L r -(C1-C4 alkylene); or

[0709] (g)R L a It is a key, and R L b It is (C1-C4 alkylene)-R L r -(C1-C4 alkylene);

[0710] In some preferred embodiments, A L It is R L a C(O)N(R L 1 )R L b ,and:

[0711] (a)R L a It is a C1-C2 alkylene group, and R L b It is a C1-C2 alkylene group;

[0712] (b)R L a It is a C1-C2 alkylene group, and R L b It is a key;

[0713] (c)R L a It is a key, and R L b It is a C1-C2 alkylene group;

[0714] (d)R L a It is a key, and R L b It is a key;

[0715] (e)R L a It is (C1-C2 alkylene)-R L r And R L b It is a C1-C2 alkylene group;

[0716] (f)R La It is a C1-C2 alkylene group, and R L b It is R L r -(C1-C2 alkylene); or

[0717] (g)R L a It is a key, and R L b It is (C1-C2 alkylene)-R L r -(C1-C2 alkylene).

[0718] In some preferred embodiments, A L It is R L a C(O)R L b ,and:

[0719] (a)R L a It is a C1-C2 alkylene group, and R L b It is a C1-C2 alkylene group;

[0720] (b)R L a It is a C1-C2 alkylene group, and R L b It is a key;

[0721] (c)R L a It is a key, and R L b It is a C1-C2 alkylene group;

[0722] (d)R L a It is a key, and R L b It is a key;

[0723] (e)R L a It is (C1-C2 alkylene)-R L r And R L b It is a C1-C2 alkylene group;

[0724] (f)R L a It is a C1-C2 alkylene group, and R L b It is R L r-(C1-C2 alkylene); or

[0725] (g)R L a It is a key, and R L b It is (C1-C2 alkylene)-R L r -(C1-C2 alkylene).

[0726] In any of the above preferred embodiments, R L 1 It is H.

[0727] In some formulas (L) or (L-1), A L In any of the preferred embodiments of the above implementation schemes, B L It is selected from the following divalent parts:

[0728] 1) Key;

[0729] 2)R L a , where R L a It is R L r or R L r -(C1-C8 alkylene);

[0730] 3)R L a OR L b , where R L a It is a key, R L b It is R L r R L r -(C1-C8 alkylene) or (C1-C8 alkylene)-R L r ;and

[0731] 4)R L a N(R L 1 )R L b , where R L a It is a key, and R L b It is R L r ;

[0732] Each RL r Some are arbitrarily assigned to one or more Rs L d Replacement C3-C 12 Cycloalkylene or 3-12-membered heterocyclic alkylene groups or optionally one or more R groups L e The substituted 5-13 heteroarylene groups; and

[0733] Each C1-C8 alkylene moiety is optionally surrounded by one or more R L c replace.

[0734] In L 1 In some embodiments of the (L) or (L-1) type connector, A L W L 1 W L 2 and B L One or more of them are R each time they appear. L a , where R L a It is an optional replacement of R L r (C1-C8 alkylene)-R L r R L r -(C1-C8 alkylene) or (C1-C8 alkylene)-R L r -(C1-C8 alkylene), and each R L r All are independently selected from the arbitrarily substituted C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 Aromatic and 5-13 heteroarylene compounds.

[0735] In L 1 In some embodiments of the (L) or (L-1) type connector, A L W L 1 W L 2 and B L One or more of them are R each time they appear. L a -R L b , where each R L a and R L bAll are independently selected from: key, R L r (C1-C8 alkylene)-R L r R L r -(C1-C8 alkylene), (C1-C8 alkylene)-R L r -(C1-C8 alkylene), C1-C8 alkylene, C2-C8 alkenyl, C2-C8 ynynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl and C3-C8 heteroynynyl, each optionally substituted as described herein.

[0736] In L 1 In some embodiments of the (L) or (L-1) type connector, A L W L 1 W L 2 and B L One or more of them are R each time they appear. L a -R L b , where R L a and R L b One of them is an optionally substituted C1-C8 alkylene, C2-C8 alkenylene, C2-C8 ynynylene, C2-C8 heteroalkylene, C3-C8 heteroalkenylene, or C3-C8 heteroynylene, and R L a and R L b The other one is R L r , where R L r Independently selected from: optional substituted C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 Aromatic and 5-13 heteroarylene compounds.

[0737] In L 1 In some embodiments of the (L) or (L-1) type connector, A L W L 1 W L 2 and B L One or more of them are R each time they appear. L a , where R L aIt is optionally substituted with C1-C8 alkylene, C2-C8 alkenylene, C2-C8 ynynylene, C2-C8 heteroalkylene, C3-C8 heteroalkenylene, or C3-C8 heteroynylene.

[0738] In L 1 In some embodiments of the (L) or (L-1) type connector, A L W L 1 W L 2 and B L One or more of them are R each time they appear. L a , where R L a It is R L r And R L r It is an optional substitution of C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene and 5-13 heteroarylene compounds. In some such embodiments, R L r It is an optional substitution of C3-C 12 Cycloalkylene. In some such embodiments, R L r It is an optionally substituted 3-12 member heterocyclic subgroup. In some such embodiments, R L r It is an optional substitution of C6-C 12 Aromatic or 5-13 heteroarylene.

[0739] In L 1 In some embodiments of the (L) or (L-1) type connector, A L W L 1 W L 2 and B L Each time it appears, it is independently an optionally substituted C1-C8 alkylene group. In some embodiments, A L W L 1 W L 2 and B L Each time it appears, it is an optionally substituted C2-C8 alkenyl group. In some embodiments, A L W L 1 W L 2 and B LEach time it appears, it is an optionally substituted C2-C8 ynylene group. In some embodiments, A L W L 1 W L 2 and B L Each time it appears, it is an optionally substituted C2-C8 heteroalkylene group. In some embodiments, A L W L 1 W L 2 and B L Each time it appears, it is an optionally substituted C3-C8 heteroene group. In some embodiments, A L W L 1 W L 2 and B L Each time it appears, it is an optional substituted C3-C8 heteroynyl group.

[0740] In L 1 In some implementations of the type (L) connector, m L It is 0, and W L 1 and W L 2 It is empty (i.e., the connector has the structure of (L-1)).

[0741] In L 1 In some implementations of type (L) or (L-1) connectors, each R L a and R L b All are independently selected from: key, R L r (C1-C8 alkylene)-R L r R L r -(C1-C8 alkylene), (C1-C8 alkylene)-R L r -(C1-C8 alkylene), C1-C8 alkylene, C2-C8 alkenyl, C2-C8 ynynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl, and C3-C8 heteroynynyl, wherein each of the C1-C8 alkylene, C2-C8 alkenyl, C2-C8 ynynyl, C2-C8 heteroalkylene, C3-C8 heteroalkenyl, or C3-C8 heteroynynyl is optionally surrounded by one or more R L c Replacement. In such implementations, each R L rAll are independently selected from: C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene and 5-13 heteroarylene, wherein each of the C3-C 12 Cycloalkylene or 3-12-membered heterocyclic groups are optionally surrounded by one or more R groups. L d Replace, and each of the C6-C 12 Arene or 5-13 heteroarylene groups are optionally surrounded by one or more R groups. L e Replacement. In some such implementations, R L a and R L b One or both are R L r , where R L r It is an optional substitution of C3-C 10 Cycloalkylene, 3-10 membered heterocyclic cycloidene, C6-C 12 Aromatic or 5-13 heteroarylene.

[0742] In some implementation schemes, A L It is selected from the following divalent part: R L a R L a -R L b R L a C(O)R L b R L a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L b R L a OR L b and R L a N(R L 1 )R L b .

[0743] In some such implementations: A L It is RL a C(O)NHR L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group; A L It is R L a C(O)NHR L b R L a It is (C1-C4 alkylene)-R L r And R L b It is a C1-C4 alkylene group; A L It is R L a C(O)NHR L b R L a It is a C1-C4 alkylene group, and R L b It is R L r -(C1-C4 alkylene); A L It is R L a C(O)NHR L b R L a It is a key, and R L b It is (C1-C4 alkylene)-R L r -(C1-C4 alkylene); A L It is R L a C(O)NHR L b R L a It is a C1-C4 alkylene group, and R L b It is a key; A L It is R L a C(O)NHR L b R L a It is a key, and R L b It is a C1-C4 alkylene group; A L It is R La C(O)NHR L b R L a It is a key, and R L b It is a key; A L It is R L a N(R L 1 )C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group; A L It is R L a N(R L 1 )C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a key; A L It is R L a N(R L 1 )C(O)R L b R L a It is a key, and R L b It is a C1-C4 alkylene group; A L It is R L a N(R L 1 )C(O)R L b R L a It is a key, and R L b It is a key; A L It is R L a NHC(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group; A L It is R L a C(O)RL b R L a It is (C1-C4 alkylene)-R L r And R L b It is a key; A L It is R L a C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is R L r -(C1-C4 alkylene); A L It is R L a C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene group; A L It is R L a C(O)R L b R L a It is a C1-C4 alkylene group, and R L b It is a key; A L It is R L a C(O)R L b R L a It is a key, and R L b It is a C1-C4 alkylene group; A L It is R L a C(O)R L b R L a It is a key, and R L b It is a key; A L It is R L a -R L b R L a It is a C1-C4 alkylene group, and R Lb It is a C1-C4 alkylene group; A L It is R L a -R L b R L a It is (C1-C4 alkylene)-R L r And R L b It is a C1-C4 alkylene group; A L It is R L a NHR L b R L a It is a C1-C8 alkylene group, and R L b It is a key; A L It is R L a NHR L b R L a It is a C1-C4 alkylene group, and R L b It is a C1-C4 alkylene; or A L It is R L a NHR L b R L a It is a key, and R L b It is a C1-C8 alkylene group. In A L In some implementation schemes, each R L r Most are C3-C 12 Cycloalkylene or 3-12-membered heterocyclic alkylene groups, each optionally surrounded by one or more R groups. L d Replace. In A L In other such implementations, each R L r Most are C6-C 12 arylene or 5-13 heteroarylene, each optionally bounded by one or more R L e replace.

[0744] In some implementation schemes, A LIt is a bond, -C(=O)-, -C(=O)NH-, -NH-, -NH-C(=O)-, -O-, -(C1-C8 alkylene)-C(=O)NH-, -(C1-C8 alkylene)-C(=O)-, -(C1-C8 alkylene)NH-, -(C1-C8 alkylene)-NH-C(=O)-, -(C1-C8 alkylene)-O-, -C1-C8 alkylene-, -C2-C8 alkenyl-, or -C2-C8 alkynyl-. In some embodiments, A L It is a bond, -(C1-C8 alkylene)-C(=O)NH-, -(C1-C8 alkylene)-C(=O)-, -(C1-C8 alkylene)NH-, -(C1-C8 alkylene)-NH-C(=O)-, -(C1-C8 alkylene)-O-, or -C1-C8 alkylene-. L It is a key. In some implementations, A L It is -C(=O)-. In some implementations, A L It is -C(=O)NH-. In some implementations, A L It is -NH-. In some implementations, A L It is -NH-C(=O)-. In some implementations, A L Yes -O-. In some implementations, A L It is -(C1-C8 alkylene)-C(=O)NH-. In some embodiments, A L It is -(C1-C8 alkylene)-C(=O)-. In some embodiments, A L It is -(C1-C8 alkylene)NH-. In some embodiments, A L It is -(C1-C8 alkylene)-NH-C(=O)-. In some embodiments, A L It is -(C1-C8 alkylene)-O-. In some embodiments, A L It is a C1-C8 alkylene group. In some embodiments, A L It is a -C2-C8 alkenyl group. In some embodiments, A L It is -C2-C8 ynyl-.

[0745] In some implementation schemes, B L It is selected from the following divalent parts: bond, R L a R L a -R L b R L a C(O)R L b RL a C(O)N(R L 1 )R L b R L a N(R L 1 )C(O)R L b R L a OR L b and R L a N(R L 1 )R L b In some implementations, B L It is selected from key, R L a R L a OR L b and R L a N(R L 1 )R L b The divalent portion. In some implementations, B L It is selected from key, R L a R L a OR L b and R L a N(R L 1 )R L b The divalent part, where R L a It is R L r or R L r -(C1-C4 alkylene).

[0746] In some implementation schemes, B L It is R L a OR L b R L a It is a key, and R L b It is R Lr (C1-C8 alkylene)-R L r or R L r -(C1-C8 alkylene). In some embodiments, B L It is R L a N(R L 1 )R L b R L a It is a key, and R L b It is R L r (C1-C8 alkylene)-R L r or R L r -(C1-C8 alkylene). In some embodiments, B L It is a key. In other implementations, B L It is R L a , where R L a It is R L r (C1-C8 alkylene)-R L r R L r -(C1-C8 alkylene) or (C1-C8 alkylene)-R L r -(C1-C8 alkylene). In some such embodiments, B L It is R L a , where R L a It is R L r (C1-C4 alkylene)-R L r R L r -(C1-C4 alkylene) or (C1-C4 alkylene)-R L r -(C1-C4 alkylene).

[0747] In B L In some implementation schemes, each R L r Most are C3-C 12 Cycloalkylene or 3-12-membered heterocyclic alkylene groups, each optionally surrounded by one or more R groups.L d Replace. In B L In some implementation schemes, each R L r Most are C6-C 12 arylene or 5-13 heteroarylene, each optionally bounded by one or more R L e replace.

[0748] In some implementation schemes, B L It is a bond, -C(=O)-, -C(=O)NH-, -NH-, -NH-C(=O)-, -O-, -C1-C8 alkylene-, -C2-C8 alkenylene-, -C2-C8 alkynylene-, -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)-. In some embodiments, B L It 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)-. In some embodiments, B L It is a key. In some implementations, B L It is -C(=O)-. In some implementations, B L It is -C(=O)NH-. In some implementations, B L It is -NH-. In some implementations, B L It is -NH-C(=O)-. In some implementations, B L Yes -O-. In some implementations, B L It is a C1-C8 alkylene group. In some embodiments, B L It is -C2-C8 alkenyl-. In some embodiments, B L It is -C2-C8 ynylene-. In some embodiments, B L It is -NH-(C1-C8 alkylene)-. In some embodiments, B L It is -O-(C1-C8 alkylene)-. In some embodiments, B L It is -C(=O)-(C1-C8 alkylene)-. In some embodiments, B L It is -C(=O)NH-(C1-C8 alkylene)-. In some embodiments, B LIt is -NH-C(=O)-(C1-C8 alkylene)-.

[0749] In some implementations, where applicable, each W L 1 They are all independent R L r Or C1-C3 alkylene; and each W L 2 Each is independently a bond, O, or NH. In some such implementations, each W L 1 They are all independent R L r ; and each W L 2 Each is independently a bond, O, or NH. In some such implementations, each W L 1 Each is independently a C1-, C2-, or C3-alkylene group; and each W L 2 Each is independently a bond, O, or NH. In some such implementations, each W L 1 Each is independently a C1-, C2-, or C3-alkylene group; and each W L 2 Each is independently either O or NH. In other such implementations, each W L 1 Each is independently a C1-, C2-, or C3-alkylene group; and each W L 2 Each is independently O. In other implementations, each W L 1 Each is independently a C1-, C2-, or C3-alkylene group; and each W L 2 They are all NH independently.

[0750] In some implementations, where applicable, each W L 1 Each is independently a bond, O or NH; and each W L 2 They are all independent R L r Or C1-C3 alkylene. In some such embodiments, each W L 1 Each is independently a bond, O or NH; and each W L 2 They are all independent R L r In some such implementations, each W L1 Each is independently a bond, O or NH; and each W L 2 Each is independently a C1-, C2-, or C3-alkylene group. In other such embodiments, each W L 1 Each is independently a key or an O; and each W L 2 Each is independently a C1-, C2-, or C3-alkylene group. In some such embodiments, each W L 1 Each is independently O; and each W L 2 Each is independently a C1-, C2-, or C3-alkylene group. In some such embodiments, each W L 1 Each is independently NH; and each W L 2 They are all independently C1-, C2-, or C3-alkylene groups.

[0751] In some implementations, where present, each -W L 1 -W L 2 - Each is independently -CH2CH2O- or -CH2-. In some implementations, each -W L 1 -W L 2 - Each is independently -CH2CH2O-. In some implementations, each -W L 1 -W L 2 - They are all independently -CH2-.

[0752] In some implementation schemes, A L Or B L At least one R in L r Part of it is C3-C 12 Cycloalkylene or 3-12-membered heterocyclic alkylene groups, each optionally surrounded by one or more R groups. L d Replacement. In other implementations, A L Or B L At least one R in L r Part of it is C6-C 12 arylene or 5-13 heteroarylene, each optionally bounded by one or more R L e replace.

[0753] In some implementations, each R L r Each part is independently selected from C3-C 10 Cycloalkylene or 3-12-membered heterocyclic alkylene groups, each optionally surrounded by one or more R groups. L d Replacement. In some implementations, each R L r Each part is independently selected from C6-C 12 arylene or 5-13 heteroarylene, each optionally bounded by one or more R L e replace.

[0754] In some implementations, each R L r Some of them are optional replacements of C3-C 12 Cycloalkylene. In some embodiments, each R L r The components are mostly substituted 3-12-membered heterocyclic subgroups. In some embodiments, each R L r Some of them are optional replacements of C6-C 12 Aromatic compounds. In some implementations, each R... L r Most of them are 5-13 heteroaryl compounds with optional substitution.

[0755] In some implementations, m L It is an integer selected from 0-15, 1-14, 1-13, 1-12, 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, or 1-2. In some implementations, m L It is an integer selected from 0 to 13. In some implementations, m L It is an integer selected from 0 to 12. In some implementations, m L It is an integer selected from 0 to 11. In some implementations, m L It is an integer selected from 0 to 10. In some implementations, m L It is an integer selected from 0 to 9. In some implementations, m L It is an integer selected from 0 to 8. In some implementations, m L It is an integer selected from 0 to 7. In some implementations, m L It is an integer selected from 0 to 6. In some implementations, m L It is an integer selected from 0 to 5. In some implementations, m L It is an integer selected from 0 to 4. In some implementations, m LIt is an integer selected from 0 to 3. In some implementations, m L It is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.

[0756] In some implementations of any of equations (I)-(XIII), when L 1 When the connector is of formula (L), the connector comprises one or more optionally substituted polyethylene glycol (PEG) units. In some embodiments, the PEG is optionally substituted, and the length is 1-5, 2-7, 2-10, 2-20, 5-25, or 4-30 -(O-CH2CH2)- units. In some embodiments, L 1 It contains optionally substituted alkylene groups. In some embodiments, L 1 It is a straight-chain alkylene group. In some embodiments, L 1 C2-C with optional substitution 30 C2-C 25 C3-C 25 C4-C 10 C6-C 12 C6-C 18 Or C4-C 20 Alkyl unit. In some embodiments, L 1 It contains optionally substituted carbon rings. In some embodiments, L 1 It contains optionally substituted heterocyclic rings. In some embodiments, L 1 C6-C with optional substitution 12 Aryl ring. In some embodiments, L 1 It contains optionally substituted 5-13 membered heteroaryl rings. In some embodiments, L 1 It contains one or more ethers. In some embodiments, L 1 Contains 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 Alkyl ether unit. In some embodiments, L 1 It contains one or more amines. In some embodiments, L 1 Contains one or more C2-C 30 C2-C 25 C3-C 25 C4-C 10 C6-C 12 C6-C 18 Or C4-C20 Alkylamino unit. In some embodiments, L 1 It contains 1-5, 2-7, 2-10, 2-20, 5-25, or 4-30 -(NH-CH2CH2)- units with optional substitution. In some embodiments, L 1 It contains one or more amides. In some embodiments, L 1 It contains one or more sulfonamides. In some embodiments, L 1 It contains one or more carbamates. In some embodiments, L 1 It contains one or more carbonates.

[0757] In some implementations of any of equations (I)-(XIII), L 1 It contains at least one ring portion R L r A connector of type (L) or (L-1), wherein R L r It can be monocyclic, fused, or spirocyclic C3-C. 12 Cycloalkylene or 3-12 membered heterocyclic or monocyclic or fused C6-C 12 arylene or 5-13 heteroarylene, each optionally substituted as described. In other embodiments of any of formulas (I)-(XIII), L 1 It is a connector of formula (J) containing at least one ring portion, -Ar"- or -Cy"-, as described herein. Examples suitable for including the ring portion in a connector of formula (L), (L-1) or (J) include portions of formula (L-2), formula (L-3), formula (L-4), formula (L-5) and formula (L-6), and embodiments thereof described herein.

[0758] In some implementations of any of equations (I)-(XIII), L 1 It includes one or more rings selected from formulas (L-2), (L-3), (L-4), (L-5), and (L-6):

[0759] in:

[0760] X R 'and Y R 'Independently selected from N and CR R b ;

[0761] A R 1 B R 1 C R 1 and D R1 Each time it appears, it is independently selected from bond, O, CO, SO, SO2, C(O)NR. R b S(O)2NR R b NR R b and CR R b R R c ;

[0762] A R 2 B R 2 C R 2 D R 2 and E R 2 Each occurrence is independently selected from N and CR. R b ;

[0763] A R 3 Each time it appears, it is independently selected from N and C, and B R 3 C R 3 D R 3 and E R 3 Each occurrence is independently selected from N, O, S, NR. R b and CR R b ;

[0764] R R b and R R cEach time it appears, it is independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 heteroalkyl, optionally substituted C2-C8 heteroalkenyl, optionally substituted C2-C8 heteroalkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino and optionally substituted C1-C8 alkylamino, optionally substituted 3-12-membered carbocyclic, optionally substituted 3-12-membered cycloalkoxy, optionally substituted 3-12-membered carbocyclic amino, optionally substituted 4-12-membered heterocyclic, optionally substituted C6-C 12 aryl and optionally substituted 5-13 heteroaryl groups; or

[0765] Two Rs R b and R R c They optionally form C3-C together with the atoms to which they are attached. 12 Carbocyclic or 3-12 membered heterocyclic groups; and

[0766] m R 1 n R 1 o R 1 and p R 1 Selected independently from 0, 1, 2, 3, 4 and 5.

[0767] In some embodiments of any of formulas (I)-(XIII), connector L 1 It contains one or more rings selected from the following:

[0768]

[0769] In some such implementations, connector L 1 It contains one or more rings selected from the following:

[0770]

[0771] In some such implementations, connector L 1 It contains one or more rings selected from the following:

[0772]

[0773] In some such implementations, connector L1 It contains one or more rings selected from the following:

[0774]

[0775] In some such implementations, connector L 1 It contains one or more rings selected from the following:

[0776]

[0777] When connector L 1 When it contains one or more rings as described above, such a ring can be used as R. L r Part of it is contained in the compound, wherein L 1 A divalent linker of formula (L) or (L-1). Alternatively, such a ring can be included in the compound as an -Ar"- or -Cy"- part, where L 1 The bivalent connector of formula (J).

[0778] In some implementations, L 1 It is a connector of type (L) or (L-1), containing one or more R selected from type (L-2), type (L-3), type (L-4), type (L-5) and type (L-6). L r Partial. In other implementations, L 1 It is a connector of formula (J) containing one or more -Ar"- or -Cy"- portions selected from formulas (L-2), (L-3), (L-4), (L-5) and (L-6).

[0779] In some implementations, L 1 Selected from: -(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 9; p2 is an integer selected from 0 to 15; and p3 is an integer selected from 0 to 9.

[0780] In some implementations, connector L 1 It is -(CH2) 0-3 -(C3-C 12 (cycloalkyl)-(CH2) 0-4 -、-(CH2) 0-3 -(3-12 membered heterocyclic group)-(CH2) 0-4 -、-(CH2) 0-3 -(C6-C 12 (aryl)-(CH2) 0-4 -、-(CH2) 0-3 -(5-13 heteroaryl)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)-(CH2) 0-3 -(C3-C 12 (cycloalkyl)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)-(CH2) 0-3 -(3-12 membered heterocyclic group)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)-(CH2) 0-3 -(C6-C 12 (aryl)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)-(CH2) 0-3 -(5-13 heteroaryl)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)NH-(CH2) 0-3 -(C3-C 12 (cycloalkyl)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)NH-(CH2) 0-3 -(3-12 membered heterocyclic group)-(CH2) 0-4 -、-(CH2) 0-3-C(=O)NH-(CH2) 0-3 -(C6-C 12 (aryl)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)NH-(CH2) 0-3 -(5-13 heteroaryl)-(CH2) 0-4 -、-(CH2) 0-3 -NHC(=O)-(CH2) 0-3 -(C3-C 12 (cycloalkyl)-(CH2) 0-4 -、-(CH2) 0-3 -NHC(=O)-(CH2) 0-3 -(3-12 membered heterocyclic group)-(CH2) 0-4 -、-(CH2) 0-3 -NHC(=O)-(CH2) 0-3 -(C6-C 12 (aryl)-(CH2) 0-4 -or-(CH2) 0-3 -NHC(=O)-(CH2) 0-3 -(5-13 heteroaryl)-(CH2) 0-4 -

[0781] In some implementations, connector L 1 It is -(CH2) 0-3 -(C3-C 12 (cycloalkyl)-(CH2) 0-4 -、-(CH2) 0-3 -(3-12 membered heterocyclic group)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)-(CH2) 0-3 -(C3-C 12 (cycloalkyl)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)-(CH2) 0-3 -(3-12 membered heterocyclic group)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)NH-(CH2) 0-3 -(C3-C 12 (cycloalkyl)-(CH2) 0-4 -、-(CH2) 0-3 -C(=O)NH-(CH2) 0-3 -(3-12 membered heterocyclic group)-(CH2) 0-4 -、-(CH2) 0-3-NHC(=O)-(CH2) 0-3 -(C3-C 12 (cycloalkyl)-(CH2) 0-4 -or-(CH2) 0-3 -NHC(=O)-(CH2) 0-3 -(3-12 membered heterocyclic group)-(CH2) 0-4 -

[0782] In some implementations, connector L 1 It 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 -(alkenyl)-(CH2) 0-3 -、-C(=O)-(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、-C(=O)-(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 -、-C(=O)-(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -、(CH2) 0-3 -(alkenyl)-(CH2) 0-3 -、-(CH2) 0-3 -(ethynyl)-(CH2) 0-3 -、-(CH2) 0-3 -(3-8 membered carbon cycloyl)-(CH2) 0-3 -or-(CH2) 0-3 -(3-8 membered heterocyclic carbonyl group)-(CH2) 0-3 -

[0783] In some implementations of any of equations (I)-(XIII), L 1 It is a divalent connector of type (J):

[0784] in:

[0785] x is an integer from 1 to 30;

[0786] Each unit -(J)- is independently selected from: bond, -N(R) 13 )-、-(C(R 14 )2) 1-3 -、-O-、-C(O-、-C(=N(R) 13 ))-、-C(S)-、-C(R 14 )=C(R 14 -, -C≡C-, -S-, -S(O)-, -S(O)2-, -Ar"- and -Cy"-, provided that two -O- and / or -S- are not adjacent;

[0787] Each -Ar"- is independently C6-C 10 arylene or 5-10 heteroarylene groups, each optionally bounded by one or more R groups. 15 replace;

[0788] Each -Cy"- is independently a monocyclic, fused, or spirocyclic C3-C 12 Cycloalkylene or 3-12-membered heterocyclic alkylene groups, each optionally surrounded by one or more R groups. 16 replace;

[0789] Each R 13 Each is independently selected from H, D, C1-C6 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic groups, wherein each of the C1-C6 alkyl groups is optionally separated by one or more R groups. 17A Substitution, and each of the C3-C6 cycloalkyl and 3-6-membered heterocyclic groups is optionally replaced by one or more R 17B replace;

[0790] Each R 14 Each is independently selected from: H, D, F, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, C1-C6 alkylamino, C3-C6 cycloalkylamino, and 3-6 membered heterocyclic groups, wherein each of the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, and (C1-C6 alkyl)2amino groups is optionally separated by one or more R groups. 18A Substitution, and each of the C3-C6 cycloalkyl and 3-6-membered heterocyclic groups is optionally replaced by one or more R 18B Replace; or two Rs 14 Together with the atoms to which they are attached, they can optionally form C3-C6 carbon cyclic groups or 3-6 membered heterocyclic groups;

[0791] Each R 15Each of the following is independently selected from: H, D, F, CN, OH, NH2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, C1-C6 alkylamino, (C1-C6 alkyl)2amino, C3-C6 cycloalkylamino, and oxo, wherein each of the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, and (C1-C6 alkyl)2amino is optionally converted by one or more R 19A Substitution, and each of the C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C3-C6 cycloalkylamino and 3-6 membered heterocyclic groups is optionally replaced by one or more R 19B replace;

[0792] Each R 17A R 18A and R 19A All are independently selected from: D, F, OH, C1-C4 alkoxy, oxo, NH2, NH (C1-C4 alkyl), and N (C1-C4 alkyl)2; and

[0793] Each R 16 R 17B R 18B and R 19B All are independently selected from: D, F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, oxo, NH2, NH(C1-C4 alkyl) and N(C1-C4 alkyl)2.

[0794] In some embodiments of formula (J), x is an integer from 1 to 20. In some embodiments of formula (J), x is an integer from 1 to 15. In some embodiments of formula (J), x is an integer from 1 to 10. In some embodiments of formula (J), x is an integer from 1 to 5.

[0795] In some implementations, where x is an integer from 1 to 10, equation (J) can be expressed as:

[0796]

[0797] Each of the units J1, J2, J3, J4, J5, J6, J7, J8, J9 and J 10 Both are independent as defined for –(J)-.

[0798] In some implementations, where x is an integer from 1 to 5, equation (J) can be expressed as:

[0799]

[0800] Each of the units J1, J2, J3, J4 and J5 is independent as defined for –(J)-.

[0801] In some implementations, where x is an integer from 1 to 3, equation (J) can be expressed as:

[0802]

[0803] Each of the units J1, J2, and J3 is independent as defined for –(J)-.

[0804] Similar representations can be used for other integer ranges of x in equation (J).

[0805] In some embodiments of formula (J), one or more groups –(J)- are sequentially arranged in a pattern comprising repeating polyethylene glycol (PEG) units containing -(CH2-CH2-O). In some embodiments of formula (J), one or more groups –(J)- are sequentially arranged in a pattern comprising -C(O)-N(R)-. 13 - or -C(O)-N(R) 13 )-(C(R 14 )2) 1-3 The pattern of repeating formamide units (J). In some embodiments of formula (J), -(J) x One or more –(J)- are sequentially arranged into alternating polyethylene glycol (PEG) units containing -(CH2-CH2-O)- and units containing -C(O)-N(R)-. 13 The pattern of the formamide unit )-.

[0806] In some preferred embodiments of any of equations (I)-(XIII), L 1 It is a bivalent connector of type (L-1), where A L and B L As defined in Table 3.

[0807] Table 3. Exemplary connectors of formula (L-1)

[0808]

[0809]

[0810]

[0811]

[0812] In some implementations of any of equations (I)-(XIII), L 1 It is a bivalent connector selected from the following:

[0813]

[0814]

[0815]

[0816]

[0817]

[0818] In any of the equations (I)-(XII), # represents L. 2 The attachment point, and * is the attachment point with A; or in equation (XIII), # is the attachment point with L. 2 The attachment point, and * is with Z 2 Or the attachment point of G.

[0819] In some implementations of any of equations (I)-(XIII), L 1 It is a bivalent connector selected from the following:

[0820]

[0821] In any of the equations (I)-(XII), # represents L. 2 The attachment point, and * is the attachment point with A; or in equation (XIII), # is the attachment point with L. 2 The attachment point, and * is with Z 2 Or the attachment point of G.

[0822] Some exemplary DDB1 binding compounds and intermediates have the structures shown in Tables 1A and 1B.

[0823] Table 1A. Representative DDB1-binding compounds and intermediates

[0824]

[0825]

[0826]

[0827]

[0828] Table 1B. Representative DDB1-binding compounds and intermediates

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836] Target protein binding site

[0837] In some embodiments, compounds comprising a protein-binding moiety (PBM) that binds to a target protein are disclosed herein. The compounds may include heterobifunctional molecules comprising a protein-binding moiety.

[0838] In some embodiments, this document discloses that the target protein is cyclin-dependent kinase 4 (CDK4) and / or cyclin-dependent kinase 6 (CDK6). In some embodiments, the target protein is CDK4. In some embodiments, the target protein is CDK6.

[0839] In some implementations, A is a PBM combined with CDK4 and / or CDK6. In some such implementations, A is a PBM combined with CDK4. In some such implementations, A is a PBM combined with CDK6. In some such implementations, A is a PBM combined with both CDK4 and CDK6.

[0840] In some implementations, A is a PBM having the structure of formula (A):

[0841]

[0842] in:

[0843] X A 1 X A 2 Y A 1 and Y A 2 Each is CR independently A 4 Or N;

[0844] R A 1 It is NR A 5 R A 6 、N(R A 5 )C(=O)R A 6 Optional substitution of C6-C 12 Aryl or optionally substituted 5-13 heteroaryl groups;

[0845] R A 2 It is hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 heteroalkyl, C3-C8 cycloalkyl, or 3-8 membered heterocyclic group; or

[0846] R A 1 and R A 2 Together with the atoms to which they are attached, they can optionally form optionally substituted C3-C8 cycloalkyl groups, 3-8 membered heterocyclic groups, C6-C... 12 Aryl or 5-13 heteroaryl groups;

[0847] L 3 It is selected from -R A 3A_ R A 3B - a divalent group, wherein R A 3A and R A 3B Each is an independent key, -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 - C1-C8 alkylene, C2-C8 alkenylene, C2-C8 ynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 12 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene or 5-13 heteroarylene, provided that the two -O- and / or -S- are not adjacent;

[0848] Each R A 4 All are independently selected from: 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, 3-8 membered heterocyclic, C6-C 12 Aryl or 5-13 heteroaryl groups;

[0849] R A 5 and R A 6 Independently selected from: hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or

[0850] R A 5 and R A 6 These, together with the atoms to which they are attached, optionally form 3-20 membered heterocyclic base rings; and

[0851] R A 7 R A 8 R A 9 and R A 10 Each is independently selected from: hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or

[0852] R A 8 and R A 9 Together with the atoms to which they are attached, they can optionally form 3-20 member heterocyclic base rings.

[0853] In some implementation schemes, R A 1 and R A 2 Together with the atoms to which they are attached, they form optionally substituted 3-8 membered heterocyclic groups or 5-13 membered heteroaryl groups.

[0854] In some implementations, A is a PBM of formula (A) having the structure of formula (A1), (A2), or (A3):

[0855] in:

[0856] Y A 3 It is CR A 19 Or N;

[0857] R A 11 R A 14 and R A 18 Each group is 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 3-8 membered heterocyclic, C6-C 12 Aryl or 5-13 heteroaryl groups;

[0858] R A 12 and R A 15 Each independently selected from R A 20 COR A 20 CO2R A 20 or CONR A 20 R A 21 , where R A 20 and R A 21 Independently selected from: hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or 3-8 membered heterocyclic or R A 20 and R A 21 Together with the atoms to which they are attached, they can optionally form 3-20 membered heterocyclic base rings;

[0859] R A 13 Selected from: hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 heteroalkyl, C3-C8 cycloalkyl or 3-8 membered heterocyclic groups;

[0860] R A 16 and R A17 Each is 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, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or

[0861] R A 16 and R A 17 Together with the atoms to which they are attached, they optionally form C3-C8 cycloalkyl groups or 3-8 membered heterocyclic groups; and

[0862] R A 19 Independently selected from: hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or 3-8 membered heterocyclic groups; and

[0863] m A It is 0, 1, or 2.

[0864] In some implementations, the PBM of formula (A) has the structure of formula (A1).

[0865] In some implementations, the PBM of formula (A) has the structure of formula (A2).

[0866] In some implementations, the PBM of formula (A) has the structure of formula (A3).

[0867] In some implementations, m A It is 1.

[0868] In some implementation schemes, R A 1 It is an optional substitution of C6-C 12 Aryl or optionally substituted 3-13 heteroaryl groups.

[0869] In some implementations, the PBM of formula (A) has the structure of formula (A4):

[0870] in:

[0871] X A 3 It is CR A 25 Or N;

[0872] RA 22 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 heterocyclic, C6-C 12 aryl or 3-13 heteroaryl; and

[0873] R A 23 R A 24 and R A 25 Each is independently selected from: hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C2-C8 heterocyclic.

[0874] In some implementation schemes, X A 1 X A 2 and X A 3 Each is N. In some implementations, X A 1 It is N. In some implementations, X A 2 It is N. In some implementations, X A 3 It is N.

[0875] In some implementation schemes, X A 1 It is CR A 4 In some implementations, X A 2 It is CR A 4 In some implementations, X A 3 It is CR A 4 In some implementations, X A 1 It is CH. In some implementations, X A 2 It is CH. In some implementations, X A 3 It is CH.

[0876] In some implementation schemes, YA 1 Y A 2 and Y A 3 Each is N. In some implementations, Y A 1 It is N. In some implementations, Y A 2 It is N. In some implementations, Y A 3 It is N.

[0877] In some implementation schemes, Y A 1 It is CR A 4 In some implementation schemes, Y A 2 It is CR A 4 In some implementation schemes, Y A 3 It is CR A 4 In some implementation schemes, Y A 1 Y A 2 and Y A 3 Each is CH.

[0878] In some implementation schemes, R A 2 R A 4 R A 13 R A 19 R A 23 and R A 24 Each is independently selected from hydrogen, halogen, C1-C3 alkyl, or C3-C6 cycloalkyl. In some embodiments, R A 2 R A 4 R A 13 R A 19 R A 23 and R A 24 Each is independently selected from: hydrogen, F, Cl, CH3, CH2CH3, CH(CH3)2, CF3, CHF2, cyclopropyl or cyclobutyl.

[0879] In some implementation schemes, R A 11 and R A 14 Each is independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclic groups. In some embodiments, R A 11 and R A 14 Each is independently selected from C1-C8 alkyl or C3-C8 cycloalkyl. In some embodiments, R A 11 and R A 14 Each is independently selected from C1-C8 alkyl groups. In some embodiments, R A 11 and R A 14 Each is independently selected from C3-C8 cycloalkyl groups.

[0880] In some implementation schemes, R A 12 and R A 15 Each independently selected from R A 20 COR A 20 or CONR A 20 R A 21 , where R A 20 and R A 21 Each is independently selected from C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclic groups. In some embodiments, R A 12 and R A 15 Each independently selected from COR A 20 or CONR A 20 R A 21 , where R A 20 and R A 21 Each is independently selected from C1-C8 alkyl groups.

[0881] In some implementation schemes, R A 16 and R A 17Each is independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclic groups. In some embodiments, R A 16 and R A 17 Each is independently selected from C1-C8 alkyl groups. In some embodiments, R A 16 and R A 17 Each is independently selected from C3-C8 cycloalkyl groups. In some embodiments, R A 16 and R A 17 Each is independently selected from C2-C8 heterocyclic groups.

[0882] In some implementation schemes, R A 16 and R A 17 These atoms, together with the atoms they are attached to, optionally form 3-6 membered cycloalkyl or 3-6 membered heterocyclic rings. In some embodiments, R A 16 and R A 17 These atoms, together with the atoms they are attached to, optionally form 3-6 membered cycloalkyl groups. In some embodiments, R A 16 and R A 17 These, along with the atoms they are attached to, optionally form 3-6 membered heterocyclic base rings. In some embodiments, R A 18 and R A 22 Each is independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, or C2-C8 heterocyclic groups. In some embodiments, R A 18 and R A 22 Each is independently selected from: H, CH3, CH2CH3, CH(CH3)2, CF3, CHF2, cyclopropyl or cyclobutyl.

[0883] In some implementations, L 3 It is selected from -R A 3A -R A 3B - a divalent group, wherein R A 3A and R A 3B Each is an independent key, -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 - C1-C8 alkylene, C2-C8 alkenylene, C2-C8 ynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 arylene or 5-13 heteroarylene, provided that the two -O- and / or -S- are not adjacent. In some such embodiments, R A 3A and R A 3B Each is an independent key, -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 -. In some such implementations, R A 3A and R A 3B Each of the following is independently C1-C8 alkylene, C2-C8 alkenylene, C2-C8 ynynylene, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 Aromatic or 5-13 heteroarylene.

[0884] In some implementation schemes, R A 3A Selected from: key, -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 -; and R A 3BSelected from: C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkyneide, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 Aromatic or 5-13 heteroarylene.

[0885] In some implementation schemes, R A 3B Selected from: key, -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 -; and R A 3A Selected from: C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkyneide, C1-C8 heteroalkylene, C2-C8 heteroalkenylene, C1-C8 haloalkylene, C3-C 13 Cycloalkylene, 3-12 membered heterocyclic cycloidene, C6-C 12 Aromatic or 5-13 heteroarylene.

[0886] In some implementations, L 3 It is a bond, C1-C3 alkylene, C3-C8 cycloalkylene, C2-C8 heteroalkylene, 3-8-membered heterocyclic group, -(C1-C3 alkylene)-(C3-C8 cycloalkylene)-, -(C1-C3 alkylene)-(3-8-membered heterocyclic group)-, or -(C1-C3 alkylene)-(C2-C8 heteroalkylene). In some embodiments, L 3 It is a bond, C1-C3 alkylene, C3-C 12 Cycloalkylene, C2-C8 heteroalkylene, 3-12 membered heterocycloalkylene, -(C1-C3 alkylene)-(C3-C 12 Cycloalkylene)-, -(C1-C3 alkylene)-(3-12 heterocycloalkylene)- or -(C1-C3 alkylene)-(C2-C8 heteroalkylene).

[0887] In some implementations, L 3 It is a key. In some implementations, L 3 It is a C1-C3 alkylene group. In some embodiments, L 3 It is a C3-C8 cycloalkylene group. In some embodiments, L 3It is a C2-C8 heteroalkylene group. In some embodiments, L 3 It is a 3-8 member heterocyclic subgroup. In some implementations, L 3 It is -(C1-C3 alkylene)-(C3-C8 cycloalkylene)-. In some embodiments, L 3 It is -(C1-C3 alkylene)-(3-8 membered heterocyclic)-. In some embodiments, L 3 It is -(C1-C3 alkylene)-(C2-C8 heteroalkylene). In some embodiments, L 3 It is C3-C 12 Cycloalkylene. In some embodiments, L 3 It is a 3-12 member heterocyclic subgroup. In some implementations, L 3 It is -(C1-C3 alkylene)-(C3-C 12 Cycloalkylene)-. In some embodiments, L 3 It is -(C1-C3 alkylene)-(3-12 heterocyclic)-.

[0888] In some implementations, L 3 Yes -R A 3A_ R A 3B -, where R A 3A It is a bond or a C1-C8 alkylene group, and R A 3B It is a 3-12 member heterocyclic subcycloid or C3-C 13 Cycloalkylene. In some such embodiments, R A 3A It is a key, and R A 3B It is a 3-12 member heterocyclic subgroup. In some such embodiments, R A 3A It is a key, and R A 3B It is C3-C 13 Cycloalkylene. In some such embodiments, R A 3A It is a C1-C8 alkylene group, and R A 3B It is a 3-12 member heterocyclic subcycloid or C3-C 13 Cycloalkylene. In some such embodiments, R A 3A It is a C1-C8 alkylene group, and R A 3B It is a 3-12 member heterocyclic subgroup. In some such embodiments, R A 3AIt is a C1-C8 alkylene group, and R A 3B It is C3-C 13 Cycloalkylene.

[0889] In some implementations, L 3 Yes -R A 3A -R A 3B -, where R A 3A It is a 3-12 member heterocyclic subcycloid or C3-C 13 Cycloalkylene, and R A 3B It is a 3-12 member heterocyclic subcycloid or C3-C 13 Cycloalkylene. In some such embodiments, R A 3A It is a 3-12 member heterocyclic subcyclodextrin, and R A 3B It is a 3-12 member heterocyclic subgroup. In some such embodiments, R A 3A It is a 3-12 member heterocyclic subcyclodextrin, and R A 3B It is C3-C 13 Cycloalkylene.

[0890] In some implementations, L 3 Yes -R A 3A -R A 3B -, where R A 3A It is a 3-12 member heterocyclic subcycloid or C3-C 13 Cycloalkylene, and R A 3B Yes -NR A 7 -. In some such implementations, R A 3A It is a 3-12 member heterocyclic subcyclodextrin, and R A 3B Yes -NR A 7 -. In some such implementations, R A 3A It is C3-C 13 Cycloalkylene, and R A 3B Yes -NR A 7 -

[0891] In some implementations, L 3 Selected from:

[0892]

[0893]

[0894] In some implementations, L 3 It is a key.

[0895]

[0896] In some implementations, L 3 yes In some implementations, L 3 yes In some implementations, L 3 yes In some implementations, L 3 yes In some implementations, L 3 yes In some implementations, L 3 yes

[0897] In some preferred embodiments, A is a PBM of formula (A) having the structure of formula (A5), (A6), (A7), (A8), or (A9):

[0898]

[0899] In a particularly preferred embodiment, A is a PBM having the structure of formula (A5).

[0900] In some implementations, A is a PBM having the structure of formula (A6).

[0901] In some implementations, A is a PBM having the structure of formula (A7).

[0902] In some implementations, A is a PBM having the structure of formula (A8).

[0903] In some implementations, A is a PBM having the structure of formula (A9).

[0904] In some embodiments, the protein of interest (POI) is CCND. In some embodiments, the protein of interest is CCND1. In some embodiments, the protein of interest is CCND2. In some embodiments, the protein of interest is CCND3.

[0905] Exemplary protein-binding portions are shown in Table 2.

[0906] Table 2

[0907]

[0908]

[0909]

[0910]

[0911]

[0912] Heterofunctional compounds

[0913] In some embodiments, the compounds include heterobifunctional compounds of any of formulas (I)-(XII). Exemplary heterobifunctional compounds of formulas (I)-(XII) are shown in Tables 4A and 4B.

[0914] Table 4A. Representative heterobifunctional compounds.

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941] Table 4B. Other representative isobifunctional compounds.

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981] The listed embodiments F1 to F679 relate to the compounds exemplified in Tables 4A and 4B or their pharmaceutically acceptable salts, and pharmaceutical compositions of such compounds or salts.

[0982] F1. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)propyl)amino)-N-(4,5-dimethylthiazolyl-2-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[0983] F2. A heterobifunctional compound 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(6-methoxypyridazin-3-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[0984] F3. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(4,5-dimethylthiazolyl-2-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[0985] F4. A heterobifunctional compound 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(4,5-dimethylthiazolyl-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[0986] F5. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[0987] F6. A heterobifunctional compound 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(6-cyclopropyl-5-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[0988] F7. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-cyclopropyl-5-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[0989] F8. A heterobifunctional compound 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[0990] F9. A heterobifunctional compound 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(6-cyclopropyl-5-methylpyridin-2-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[0991] F10. A heterobifunctional compound 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[0992] F11. A heterobifunctional compound 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(6-methoxypyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[0993] F12. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-fluorobenzamide or a pharmaceutically acceptable salt thereof.

[0994] F13. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

[0995] F14. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionylamino)pentyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[0996] F15. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-isopropylpyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[0997] F16. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[0998] F17. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-(methylamino)-N-(6-(pyrrolidine-1-yl)pyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[0999] F18. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1000] F19. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-(methylamino)-N-(6-(trifluoromethyl)pyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1001] F20. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(5-chloropyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1002] F21. A heterobifunctional compound 2-((5-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)amino)pentyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1003] F22. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)hexyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1004] F23. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)(methyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1005] F24. A heterobifunctional compound 2-((1-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)-1H-pyrazol-4-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1006] F25. A heterobifunctional compound 2-((2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)-2H-1,2,3-triazol-4-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1007] F26. A bifunctional compound 2-((3-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)isoxazol-5-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1008] F27. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-cyclopropyl-N-(6-(dimethylamino)pyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1009] F28. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-cyano-N-(6-(dimethylamino)pyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1010] F29. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)hex-2-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1011] F30. A heterobifunctional compound 2-((4-(4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)butyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1012] F31. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-cyclopropylpyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1013] F32. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1014] F33. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridino-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(1-methyl-1H-pyrrolo[3,2-b]pyridino-5-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1015] F34. A heterobifunctional compound 2-((3-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1016] F35.4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-(3-((3-((6-(dimethylamino)pyridazin-3-yl)carbamoyl)-6-(methylamino)pyridin-2-yl)amino)cyclobutyl)ethyl)piperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[1017] F36. A heterobifunctional compound 2-((5-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)amino)-5-oxopentyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1018] F37. A heterobifunctional compound 2-((4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionylamino)butyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1019] F38. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1020] F39. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1021] F40. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6,7-dihydro-5H-cyclopentano[b]pyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1022] F41. A heterobifunctional compound 2-((2-(3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)ethyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1023] F42.2-(4-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)piperazin-1-yl)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1024] F43. A bifunctional compound 2-((trans-4-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclohexyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1025] F44. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-cyclopropyl-N-(6-cyclopropyl-5-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1026] F45. A heterobifunctional compound 2-((3-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)cyclobutyl)amino)-6-cyclopropyl-N-(6-cyclopropyl-5-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1027] F46. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(4-(dimethylamino)phenyl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1028] F47. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(5-(dimethylamino)pyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1029] F48. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(4-(dimethylamino)cyclohexyl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1030] F49. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(1-methyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1031] F50. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1032] F51. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1033] F52. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1034] F53. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-cyclopropyl-4-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1035] F54. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-ethylnicotinamide or a pharmaceutically acceptable salt thereof.

[1036] F55. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(3-(dimethylamino)cyclopentyl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1037] F56. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(4-cyclopropyl-5-methylthiazolyl-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1038] F57. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropyl-5-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1039] F58. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(dimethylamino)pyridin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1040] F59. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-(cyclobutylamino)-N-(6-(dimethylamino)pyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1041] F60. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)hexyl)amino)-6-cyclopropyl-N-(6-cyclopropyl-5-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1042] F61. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-cyclopropyl-3-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1043] F62. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1044] F63. A bifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-isopropylnicotinamide or a pharmaceutically acceptable salt thereof.

[1045] F64. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(3-(dimethylamino)cyclobutyl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1046] F65. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(3-((dimethylamino)methyl)cyclobutyl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1047] F66. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1048] F67. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(dimethylamino)spiro[3.3]hept-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1049] F68. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(trifluoromethyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1050] F69. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6,7-dihydro-5H-cyclopentano[b]pyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1051] F70. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1052] F71. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-N-methyl-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1053] F72. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1054] F73. A heterobifunctional compound 2-((trans-4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)methyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1055] F74. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropylpyridin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1056] F75. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(methylamino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1057] F76. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-isopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1058] F77. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-(methylamino)-N-(6-oxo-1,6-dihydropyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1059] F78. A heterobifunctional compound 2-((6-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)amino)spiro[3.3]hept-2-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1060] F79. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1061] F80. A heterobifunctional compound 2-((3-((3-(4-(6-(((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionylamino)methyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1062] F81.4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-((6-((3-((6-(dimethylamino)pyridazin-3-yl)carbamoyl)-6-(methylamino)pyridin-2-yl)amino)spiro[3.3]hept-2-yl)methyl)piperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[1063] F82. A heterobifunctional compound 2-((6-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-3-oxopropyl)spiro[3.3]hept-2-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1064] F83. A heterobifunctional compound 2-((6-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propyl)spiro[3.3]hept-2-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1065] F84. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)spiro[3.3]hept-2-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1066] F85. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-(tert-butylamino)-N-(6-(dimethylamino)pyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1067] F86. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(2-cyclopropylpyridin-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1068] F87. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropyl-5-(trifluoromethyl)pyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1069] F88. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-(dimethylamino)pyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1070] F89. A heterobifunctional compound 2-((2-(1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperazin-4-yl)ethyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1071] F90. A bifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyanopyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1072] F91. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(methylamino)-N-(6-(trifluoromethyl)pyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1073] F92. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5-methyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1074] F93. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1-methyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1075] F94. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1-methyl-1H-pyrazol-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1076] F95. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5-isopropyl-1-methyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1077] F96. A heterobifunctional compound 2-((6-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)amino)spiro[3.3]hept-2-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1078] F97. A heterobifunctional compound 2-((2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1079] F98. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5-cyclopropyl-1-methyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1080] F99. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1-isopropyl-5-methyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1081] F100. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(methylamino)-N-(1H-pyrazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1082] F101. A heterobifunctional compound 2-((3-(a heterobifunctional compound 2-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)amino)-2-oxoethyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1083] F102. A heterobifunctional compound 2-((3-(1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)azacyclobutane-3-yl)propyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1084] F103. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1085] F104. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-aminopyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1086] F105. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-(methylamino)-N-(6-methylpyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1087] F106. A heterobifunctional compound 2-((1-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)pyrrolidine-3-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1088] F107. A heterobifunctional compound 2-((1-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)azacyclobutane-3-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1089] F108. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-methoxypyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1090] F109. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(5,6-dimethylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1091] F110. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-6-(methylamino)-N-(6-(methylamino)pyridazin-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1092] F111. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-isopropyl-5-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1093] F112. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(5-chloro-6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1094] F113. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-cyclopropyl-5-fluoropyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1095] F114. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropyl-3-fluoropyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1096] F115. A heterobifunctional compound 2-((2-(1-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)cyclopropane-1-carbonyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1097] F116. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-methoxy-5-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1098] F117. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-methylpropionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1099] F118. A bifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2,2-dimethylpropionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1100] F119. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-isopropylnicotinamide or a pharmaceutically acceptable salt thereof.

[1101] F120. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[1102] F121. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(trifluoromethyl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1103] F122. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(methylamino)-N-(6-oxo-1,6-dihydropyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1104] F123. A heterobifunctional compound 2-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(5-methyl-6-oxo-1,6-dihydropyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1105] F124. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-ethylnicotinamide or a pharmaceutically acceptable salt thereof.

[1106] F125. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropyl-5-methoxypyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1107] F126. A heterobifunctional compound 2-(((trans-4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)methyl)amino)-6-(methylamino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1108] F127. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1109] F128. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropyl-5-fluoropyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1110] F129. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1111] F130. A heterobifunctional compound 2-((4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1112] F131. A bifunctional compound 2-(((trans-4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)methyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1113] F132. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5-cyano-6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1114] F133. A heterobifunctional compound 2-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-carbonyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1115] F134.4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(6-((3-((6-(dimethylamino)pyridazin-3-yl)carbamoyl)-6-(methylamino)pyridin-2-yl)amino)spiro[3.3]hept-2-yl)piperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[1116] F135. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1117] F136. A heterobifunctional compound 2-((3-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)cyclopentyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1118] F137. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(methylamino)-N-(pyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1119] F138. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-cyclopropyl-N-(6-cyclopropylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1120] F139. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1121] F140. A heterobifunctional compound 2-((6-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carbonyl)spiro[3.3]hept-2-yl)amino)-N-(6-(dimethylamino)pyridazine-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1122] F141. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-cyano-N-(6-cyclopropylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1123] F142.6-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-6'-cyano-N-(4,5-dimethylthiazolyl-2-yl)-[2,3'-bipyridine]-5-carboxamide or a pharmaceutically acceptable salt thereof.

[1124] F143. A heterobifunctional compound 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)(methyl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1125] F144. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(1-methyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1126] F145. A heterobifunctional compound 2-(((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperazin-4-yl)methyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1127] F146. A heterobifunctional compound 2-(((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)piperazin-4-yl)methyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1128] F147. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)spiro[3.3]hept-2-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1129] F148. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1130] F149. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1131] F150. A heterobifunctional compound 2-((3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionylamino)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1132] F151.4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(3-((3-((6-(dimethylamino)pyridazin-3-yl)carbamoyl)-6-(methylamino)pyridin-2-yl)amino)cyclobutyl)piperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[1133] F152. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1-methyl-1H-imidazol-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1134] F153. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1-methyl-1H-pyrazol-5-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1135] F154. A heterobifunctional compound 2-(((trans-4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)methyl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1136] F155. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)-2-azaspiro[3.3]hept-6-yl)amino)-6-(methylamino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1137] F156. A heterobifunctional compound 2-((3-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-4-oxobutyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1138] F157. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)ethyl)carbamoyl)cyclobutyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1139] F158. A bifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)-2-azaspiro[3.4]oct-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1140] F159. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(isoxazo-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1141] F160. A bifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(methylamino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1142] F161. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-methoxypyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1143] F162. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1144] F163. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1145] F164. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)methyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1146] F165. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1147] F166.4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-((3-((3-((6-(dimethylamino)pyridazin-3-yl)carbamoyl)-6-(methylamino)pyridin-2-yl)amino)cyclobutyl)methyl)piperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[1148] F167. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-methylpropionylamino)methyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1149] F168. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1150] F169.4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-((trans-4-(((3-((6-(dimethylamino)pyridazin-3-yl)carbamoyl)-6-(methylamino)pyridin-2-yl)amino)methyl)cyclohexyl)methyl)piperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[1151] F170. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-6-(methylamino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1152] F171. A heterobifunctional compound 2-((2-(1-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)cyclopropane-1-carbonyl)-2-azaspiro[3.3]hept-6-yl)amino)-6-(methylamino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1153] F172. A heterobifunctional compound 2-((3-((1-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)cyclopropane-1-formamido)methyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1154] F173. A heterobifunctional compound 2-((2-(1-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)cyclopropane-1-carbonyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1155] F174. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-methylpropionylamino)spiro[3.3]hept-2-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1156] F175. A heterobifunctional compound 2-((2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-methylpropionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1157] F176. A heterobifunctional compound 2-((2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-methylpropionyl)-2-azaspiro[3.3]hept-6-yl)amino)-6-(methylamino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1158] F177. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropyl-5-(dimethylamino)pyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1159] F178. A heterobifunctional compound 2-((3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-3-oxopropoxy)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1160] F179. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1,2-dimethyl-1H-imidazol-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1161] F180. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-aminopyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1162] F181. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(methylamino)-N-(6-(methylamino)pyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1163] F182. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5,6-dimethylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1164] F183. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1-methyl-1H-pyrrolo-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1165] F184. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-(difluoromethyl)pyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1166] F185. A heterobifunctional compound 2-((3-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-3-oxopropyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1167] F186. A heterobifunctional compound 2-((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)azacyclobutane-3-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1168] F187. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)azacyclobutane-3-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1169] F188. A heterobifunctional compound 2-(((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)methyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1170] F189. A heterobifunctional compound 2-((6-((1-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-1-oxopropane-2-yl)oxy)spiro[3.3]hept-2-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1171] F190. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(isopropylamino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1172] F191. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-methyl-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1173] F192. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-methyl-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1174] F193. A heterobifunctional compound 2-(((cis-4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)methyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1175] F194.2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1176] F195. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(2-isopropyl-1-methyl-1H-imidazol-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1177] F196. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)amino)-6-(methylamino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1178] F197. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1179] F198. A bifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)amino)-6-(methylamino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1180] F199. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(isopropylamino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1181] F200. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperazin-4-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1182] F201. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)pyrrolidine-3-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1183] F202. A heterobifunctional compound 2-((3-((4-((4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1184] F203. A heterobifunctional compound 2-((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)piperazin-4-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1185] F204. A heterobifunctional compound 2-(((trans-4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-3-oxopropyl)cyclohexyl)methyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1186] F205. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1187] F206. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1188] F207. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[1189] F208. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2,2-difluoropropionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1190] F209. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-methylnicotinamide or a pharmaceutically acceptable salt thereof.

[1191] F210. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-ethylnicotinamide or a pharmaceutically acceptable salt thereof.

[1192] F211. A heterobifunctional compound 2-((1-(4-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)butyryl)azacyclobutane-3-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1193] F212. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-isopropylnicotinamide or a pharmaceutically acceptable salt thereof.

[1194] F213. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-6-cyclopropyl-N-(1,5-dimethyl-1H-pyrazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1195] F214. A heterobifunctional compound 2-(((4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-oxoethoxy)cyclohexyl)methyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1196] F215. A bifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5-cyclopropylisoxazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1197] F216. A heterobifunctional compound 2-((6-((1-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropane-2-yl)oxy)spiro[3.3]hept-2-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1198] F217. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1199] F218. A heterobifunctional compound 2-((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)pyrrolidine-3-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1200] F219. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclopentyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1201] F220. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5-methoxy-6-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1202] F221. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5-fluoro-6-methylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1203] F222. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1204] F223. A heterobifunctional compound 2-((trans-4-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionylamino)cyclohexyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1205] F224. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)butyryl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1206] F225. A bifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-((methyl-d3)amino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1207] F226. A heterobifunctional compound 2-((6-((1-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-methyl-1-oxopropane-2-yl)oxy)spiro[3.3]hept-2-yl)amino)-6-((methyl-d3)amino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1208] F227. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(5-isopropylisoxazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1209] F228. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperidin-4-yl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1210] F229. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperidin-4-yl)amino)-6-(methylamino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1211] F230. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperidin-4-yl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1212] F231. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperidin-4-yl)amino)-6-((methyl-d3)amino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1213] F232. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-((methyl-d3)amino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1214] F233. A heterobifunctional compound 2-((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2,2-difluoropropionyl)azacyclobutane-3-yl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1215] F234. A heterobifunctional compound 2-((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2,2-difluoropropionyl)azacyclobutane-3-yl)amino)-6-((methyl-d3)amino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1216] F235. A bifunctional compound 2-((2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)-2-azaspiro[3,4]octyl-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1217] F236. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperidin-4-yl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1218] F237. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1219] F238. A bifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1-isopropyl-2-methyl-1H-imidazol-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1220] F239. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-cyclopropyl-5-fluoropyridin-2-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1221] F240. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1222] F241. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1223] F242. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionylamino)cyclobutyl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1224] F243. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2-methylpropionylamino)cyclobutyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1225] F244. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1226] F245. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1227] F246. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-6-(methylamino)-N-(5-methyloxazol-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1228] F247. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(4,5-dimethyloxazol-2-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1229] F248. A heterobifunctional compound 2-((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2,2-difluoropropionyl)azacyclobutane-3-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1230] F249. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)-2,2-difluoropropionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1231] F250. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperazin-4-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1232] F251.6-((5-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)pentyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide or a pharmaceutically acceptable salt thereof.

[1233] F252. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperidin-4-yl)amino)-N-(6-cyclopropylpyridin-2-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1234] F253. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1235] F254. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1236] F255. A heterobifunctional compound 2-((3-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)cyclobutyl)amino)-4-chloro-N-(6-cyclopropyl-5-methylpyridin-2-yl)benzamide or a pharmaceutically acceptable salt thereof.

[1237] F256.4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-N-(2-(3-((5-chloro-a heterobifunctional compound 2-((6-cyclopropyl-5-methylpyridin-2-yl)carbamoyl)phenyl)amino)cyclobutyl)ethyl)piperazine-1-carboxamide or a pharmaceutically acceptable salt thereof.

[1238] F257. A heterobifunctional compound 2-((3-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)cyclobutyl)amino)-4-chloro-N-(6-(dimethylamino)pyridazin-3-yl)benzamide or a pharmaceutically acceptable salt thereof.

[1239] F258. A heterobifunctional compound 2-((3-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethyl)cyclobutyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-4-fluorobenzamide or a pharmaceutically acceptable salt thereof.

[1240] F259. A bifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-4-chloro-N-(5-methylisoxazol-3-yl)benzamide or a pharmaceutically acceptable salt thereof.

[1241] F260. A bifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-4-fluoro-N-(5-methylisoxazol-3-yl)benzamide or a pharmaceutically acceptable salt thereof.

[1242] F261. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

[1243] F262. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

[1244] F263. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-5-fluorobenzamide or a pharmaceutically acceptable salt thereof.

[1245] F264. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-4-fluorobenzamide or a pharmaceutically acceptable salt thereof.

[1246] F265. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-fluorobenzamide or a pharmaceutically acceptable salt thereof.

[1247] F266. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(1,5-dimethyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)benzamide or a pharmaceutically acceptable salt thereof.

[1248] F267. A heterobifunctional compound 2-((2-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-2,2-dimethylpiperazin-1-yl)propionyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1249] F268. A heterobifunctional compound 2-((2-(2-(4-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazin-1-yl)acetyl)-2-azaspiro[3.3]hept-6-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1250] F269. A heterobifunctional compound 2-((1-(2-(4-((6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)methyl)piperazin-1-yl)acetyl)azacyclobutane-3-yl)amino)-N-(6-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1251] F270. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperidin-4-yl)amino)-6-((methyl-d3)amino)-N-(6-methylpyridin-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1252] F271. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclopentyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(methylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1253] F272. A heterobifunctional compound 2-((6-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)spiro[3.3]hept-2-yl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1254] F273. A heterobifunctional compound 2-((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)pyrrolidine-3-yl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1255] F274. A heterobifunctional compound 2-((1-(3-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)propionyl)pyrrolidine-3-yl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1256] F275. A bifunctional compound 2-(((trans-4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)methyl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1257] F276. A heterobifunctional compound 2-(((trans-4-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclohexyl)methyl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1258] F277. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1259] F278. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-((methyl-d3)amino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1260] F279. A heterobifunctional compound 2-((1-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetyl)piperidin-4-yl)amino)-N-(2-cyclopropyl-1-methyl-1H-imidazol-4-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1261] F280. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)cyclobutyl)amino)-N-(6-(dimethylamino)pyridazin-3-yl)-6-(isopropylamino)nicotinamide or a pharmaceutically acceptable salt thereof.

[1262] F281. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-6-(methylamino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1263] F282. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-6-(isopropylamino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1264] F283. A heterobifunctional compound 2-((3-((2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)methyl)cyclobutyl)amino)-6-((methyl-d3)amino)-N-(5-methylisoxazol-3-yl)nicotinamide or a pharmaceutically acceptable salt thereof.

[1265] F284. A heterobifunctional compound 2-((3-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)pip...

Claims

1. A heterobifunctional compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is a protein binding moiety (PBM) capable of binding to CCND, CDK4, and / or CDK6; p is an integer from 0 to 4; and q is an integer from 0 to 3; provided that the compound of Formula (I) is not: 2-(3-(2-(2-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3- d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)ethoxy)ethoxy)propionamido)-N- (4,5-dimethylthiazol-2-yl)-6-methylnicotinamide; or 2-((7-(2-(4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2- yl)amino)pyridin-3-yl)piperazin-1-yl)acetamido)heptyl)amino)-N-(4,5-dimethylthiazol-2-yl)-6- methylnicotinamide.

2. The heterobifunctional compound of claim 1, having the structure of Formula (II): or a pharmaceutically acceptable salt thereof.

3. The heterobifunctional compound of claim 1 or 2, having the structure of Formula (III): or a pharmaceutically acceptable salt thereof. L 1 is a bond or a bivalent linker; L 2 is a bond, -NH-, -N(Ci-C3alkyl)-, -NHC(O)-, -N(Ci-C3alkyl)C(O)-, -C(O)NH-, -C(O)N(Ci-C3alkyl)-, -O-, -Ci-C4-alkylene-, -C2-C4-alkenylene-, or -C2-C4-alkynylene-; Q is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 10 cycloalkyl or 4-10 membered heterocyclyl; each R 1 is independently R 1A , R 1B , R 1C , R 1D , or R 1E ; Each R 1A Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl, wherein each of the C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl is optionally surrounded by one or more R 4A replace; each R 1B , R 1C , R 1D , and R 1E are independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, D, halo, CN, NO2, NR 5A R 5B , C(=O)R 5A , C(=O)OR 5A , OC(=O)R 5A , C(O)NR 5A R 5B , N(R 5A )C(O)R 5B , C3-C 10 cycloalkyl, C3-C 10 cycloalkoxy, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein each said C1-C6 alkyl, C1-C6 heteroalkyl, or C1-C6 alkoxy is optionally substituted with one or more R 4B , and each said C3-C 10 cycloalkyl, C3-C 10 cycloalkoxy, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 4C ; R 2 is H or C1-C3alkyl; each R 3 is independently R 3A , R 3B , or R 3C ; or two R 3 together with the atom to which they are attached can form a C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein each said C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 6A ; Each R 3A R 3B and R 3C All are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, D, halogenated, CN, NO2, NR 7A R 7B C(=O)R 7A C(=O)OR 7A OC(=O)R 7A C(O)NR 7A R 7B 、N(R 7A )C(O)R 7B C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 heteroalkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 6B Replace, and each of the C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 6C replace; Each R 4A R 4B and R 6B They are all independently C1-C6 alkoxy, oxo, OH, D, halogenated, CN, or NR. 8A R 8B ; each R 4C , R 6A , and R 6C is independently C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halo, CN, or NR 9A R 9B ; each R 5A , R 5B , R 7A , R 7B , R 8A , R 8B , R 9A , and R 9B are each independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein each said C1-C6 alkyl or C1-C6 heteroalkyl is optionally substituted with one or more R 10A , and each said C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 10B ; or R 5A and R 5B , R 7A and R 7B , R 8A and R 8B , or R 9A and R 9B may, together with the N atom to which they are attached, form a 4-10 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, wherein each said 4-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with one or more R 10C ; Each R 10A They are all independently C1-C6 alkoxy, oxo, OH, D, halogenated, CN, or NR. 11A R 11B ; each R 10B and R 10C are independently C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halo, CN, or NR 12A R 12B ; each R 11A , R 11B , R 12A , and R 12B are independently H, C1-C4alkyl, or C3-C6cycloalkyl; 4. The heterobifunctional compound of any one of claims 1 to 3, having the structure of Formula (IV): or a pharmaceutically acceptable salt thereof.

5. The heterobifunctional compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Q is selected from: wherein * indicates the point of attachment.

6. The heterobifunctional compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Q is selected from: wherein * indicates the point of attachment.

7. The heterobifunctional compound of claim 3, having the structure of Formula (V): or a pharmaceutically acceptable salt thereof, wherein: Q is C6 aryl or 6-membered heteroaryl.

8. The heterobifunctional compound of claim 7, having the structure of Formula (V-A), (V-B), (V-C), or (V-D): or a pharmaceutically acceptable salt thereof, wherein: Q is C6 aryl or 6-membered heteroaryl.

9. The heterobifunctional compound of claim 3, having the structure of Formula (VI): or a pharmaceutically acceptable salt thereof, wherein: Q is 5-membered heteroaryl.

10. The heterobifunctional compound of claim 4, having the structure of Formula (VII): or a pharmaceutically acceptable salt thereof, wherein: Q is C6 aryl or 6-membered heteroaryl.

11. The heterobifunctional compound of claim 10, having the structure of Formula (VII-A), (VII-B), (VII-C), or (VII-D): or a pharmaceutically acceptable salt thereof, wherein: Q is C6 aryl or 6-membered heteroaryl.

12. The heterobifunctional compound of claim 4, having the structure of Formula (VIII): or a pharmaceutically acceptable salt thereof, wherein: Q is 5-membered heteroaryl. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ X 3 is N or CR 1B ; X 4 is N or CR 1C ; X 5 is N or CR 1D ; and X 6 is N or CR 1E . ​ ​ ​ ​ ​ ​ ​ ​ X 3 is N or CR 1B ; X 4 is N or CR 1C ; X 5 is N or CR 1D ; and X 6 is N or CR 1E . ​ ​ ​ 13. The heterobifunctional compound of any one of claims 1-12, wherein A is a PBM of the structure of Formula (A): or a pharmaceutically acceptable salt thereof, wherein: X A 1 , X A 2 , Y A 1 and Y A 2 each independently is CR A 4 or N; R A 1 is NR A 5 R A 6 , N(R A 5 )C(=O)R A 6 , optionally substituted C6-C 12 aryl or optionally substituted 5-13 membered heteroaryl; R A 2 is hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 heteroalkyl, C3-C8 cycloalkyl, or 3-8 membered heterocyclyl; or R A 1 and R A 2 Together with the atoms to which they are attached, they can optionally form optionally substituted C3-C8 cycloalkyl groups, 3-8 membered heterocyclic groups, C6-C... 12 Aryl or 5-13 heteroaryl groups; L 3 is a divalent group selected from -R A 3A -R A 3B - wherein R A 3A and R A 3B each independently 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 -, C1-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, C1-C8heteroalkylene, C2-C8heteroalkenylene, C1-C8haloalkylene, C3-C 12 cycloalkylene, 3-12 membered heterocyclylene, C6-C 12 arylene, or 5-13 membered heteroarylene, provided that two -O- and / or -S- are not adjacent; Each R A 4 All are independently selected from: 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, 3-8 membered heterocyclic, C6-C 12 Aryl or 5-13 heteroaryl groups; R A 5 and R A 6 Independently selected from: hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or R A 5 and R A 6 together with the atom to which they are attached optionally form a 3-20 membered heterocyclyl ring; and R A 7 R A 8 R A 9 and R A 10 Each is independently selected from: hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or R A 8 and R A 9 Together with the atoms to which they are attached, they can optionally form 3-20 member heterocyclic base rings.

14. The heterobifunctional compound of claim 13, wherein A is a PBM of Formula (A) of the structure of Formula (Al), (A2), or (A3): or a pharmaceutically acceptable salt thereof, wherein: Y A 3 is CR A 19 or N; R A 11 R A 14 and R A 18 Each group is 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 3-8 membered heterocyclic, C6-C 12 Aryl or 5-13 heteroaryl groups; R A 12 and R A 15 are each independently selected from R A 20 , COR A 20 , CO2R A 20 or CONR A 20 R A 21 wherein R A 20 and R A 21 are independently selected from hydrogen, halogen, CN, NO2, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C1-C8 alkoxyalkyl, C1-C8 heteroalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, or 3-8 membered heterocyclyl, or R A 20 and R A 21 together with the atoms to which they are attached optionally form a 3-20 membered heterocyclyl ring; R A 13 is selected from hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylamino, C1-C8 heteroalkyl, C3-C8 cycloalkyl, or 3-8 membered heterocyclyl; R A 16 and R A 17 Each is 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, 3-8 membered heterocyclic, C6-C 12 aryl or 5-13 heteroaryl; or R A 16 and R A 17 together with the atoms on which they are attached optionally form a C3-C8cycloalkyl or 3-8 membered heterocyclyl; and R A 19 independently selected from hydrogen, halogen, CN, NO2, C1-C8alkyl, C1-C8haloalkyl, C1-C8hydroxyalkyl, C1-C8alkoxyalkyl, C1-C8heteroalkyl, C1-C8alkoxy, C1-C8alkylamino, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, or 3-8 membered heterocyclyl; and m A is 0, 1 or 2.

15. The heterobifunctional compound of claim 13, wherein A is a PBM of Formula (A) of the structure of Formula (A4): or a pharmaceutically acceptable salt thereof, wherein: X A 3 is CR A 25 or N; R A 22 selected from: hydrogen, C1-C8alkyl, C1-C8haloalkyl, C1-C8hydroxyalkyl, C1-C8alkoxyalkyl, C1-C8heteroalkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C2-C8heterocyclyl, C6-C10aryl, and 3-13 membered heteroaryl; and 12 aryl or 3-13 membered heteroaryl; and R A 23 R A 24 R A 25 each independently is selected from hydrogen, halogen, CN, NO2, C1-C8alkyl, C1-C8haloalkyl, C1-C8hydroxyalkyl, C1-C8alkoxyalkyl, C1-C8heteroalkyl, C1-C8alkoxy, C1-C8alkylamino, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, or C2-C8heterocyclyl.

16. The heterobifunctional compound of any one of claims 1-12, wherein A is a PBM of Formula (A) of the structure of any one of Formula (A5), (A6), (A7), (A8), or (A9):

17. The heterobifunctional compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 16, wherein L 1 is a bond or a bivalent linker of formula (L-1): wherein: each A is independently selected from the group consisting of a bond, R L and B L are each independently a divalent moiety selected from the group consisting of a bond, R L a , R L a -R L b , R L a C(O)R L b , R L a C(O)OR L b , R L a OC(O)R L b , R L a C(O)N(R L 1 )R L b , R L a N(R L 1 )C(O)R L b , R L a C(S)N(R L 1 )R L b , R L a N(R L 1 )C(S)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 )SO2R L b 、R L a N(R L 1 )R L b 和R L a N(R L 1 )C(O)N(R L 2 )R L b ; each R L a and R L b are each independently selected from the group consisting of a bond, R L r , (Ci-C8alkylene)-R L r , R L r -(Ci-C8alkylene), (Ci-C8alkylene)-R L r -(Ci-C8alkylene), Ci-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, C2-C8heteroalkylene, C3-C8heteroalkenylene, and C3-C8heteroalkynylene, wherein each said Ci-C8alkylene, C2-C8alkenylene, C2-C8alkynylene, C2-C8heteroalkylene, C3-C8heteroalkenylene, or C3-C8heteroalkynylene moiety is optionally substituted with one or more R L c ; each R L r is independently selected from the group consisting of C3-C 12 cycloalkylene, 3-12 membered heterocyclylene, C6-C 12 arylene, and 5-13 membered heteroarylene, wherein each said C3-C 12 cycloalkylene or 3-12 membered heterocyclylene is optionally substituted with one or more R L d , and each said C6-C 12 arylene or 5-13 membered heteroarylene is optionally substituted with one or more R L e ; each R L 1 and R L 2 is independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, 3-12 membered heterocyclyl, C6-C 12 aryl, and 5-13 membered heteroaryl, wherein each said C1-C8 alkyl, C2-C8 alkenyl, or C2-C8 alkynyl is optionally substituted with one or more R L f , each said C3-C 12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more R L g , and each said C6-C 12 aryl or 5-13 membered heteroaryl is optionally substituted with one or more R L h ; 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 atom to which they are attached optionally form a C3-C 12 carbocyclyl or 3-12 membered heterocyclyl; Each R L c and R L f All are independently selected from: F, OH, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl) and N(C1-C4 alkyl)(C3-C6 cycloalkyl); Each R L d and R L g All are independently selected from: F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl), and N(C1-C4 alkyl)(C3-C6 cycloalkyl); and Each R L e and R L h All are independently selected from: halogen, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C3-C6 cycloalkoxy, oxo, CN, NH2, NH(C1-C4 alkyl), N(C1-C4 alkyl)2, NH(C3-C6 cycloalkyl), and N(C1-C4 alkyl)(C3-C6 cycloalkyl); or two R L c R L d R L e R L f R L g and R L h with the atom to which they are attached optionally form a C3-C 12 carbocyclyl or 3-12 membered heterocyclyl.

18. The heterobifunctional compound or salt of claim 17, wherein L 1 comprises one or more R selected from formula (L-2), formula (L-3), formula (L-4), formula (L-5), and formula (L-6) L r moieties: wherein: X R ' and Y R ' are independently selected from N and CR R b ; A R 1 , B R 1 , C R 1 and D R 1 at each occurrence is independently selected from the group consisting of: a bond, O, CO, SO, SO2, C(O)NR R b , S(O)2NR R b , NR R b and CR R b R R c ; A R 2 , B R 2 , C R 2 , D R 2 and E R 2 is independently at each occurrence selected from N and CR R b ; A R 3 is independently at each occurrence selected from N and C, and B R 3 , C R 3 , D R 3 and E R 3 is independently at each occurrence selected from N, O, S, NR R b and CR R b ; R R b and R R c independently at each occurrence is selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8alkyl, optionally substituted C2-C8alkenyl, optionally substituted C2-C8alkynyl, optionally substituted C1-C8heteroalkyl, optionally substituted C2-C8heteroalkenyl, optionally substituted C2-C8heteroalkynyl, optionally substituted C1-C8alkoxy, optionally substituted C1-C8alkoxyalkyl, optionally substituted C1-C8haloalkyl, optionally substituted C1-C8hydroxyalkyl, optionally substituted C1-C8alkylamino, and optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-12 membered carbocyclyl, optionally substituted 3-12 membered cycloalkoxy, optionally substituted 3-12 membered carbocyclyl amino, optionally substituted 4-12 membered heterocyclyl, optionally substituted C6-C 12 aryl, and optionally substituted 5-13 membered heteroaryl; or two R R b and R R c with the atom to which they are attached optionally form a C3-C 12 carbocyclyl or 3-12 membered heterocyclyl; and m R 1 , n R 1 , o R 1 and p R 1 is independently selected from 0, 1, 2, 3, 4 and 5.

19. The heterobifunctional compound or salt of claim 17 or 18, wherein R L r is selected from:

20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

21. A compound of Formula (XIII): or a salt thereof, wherein: Z 1 is L 1 -Z 2 or L 1 -G; L 1 is a bond or a bivalent linker; Z 2 H, D, halo, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, wherein each said C1-C4 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with halo, OH, oxo, C1-C4 alkoxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2; 10 H, D, halo, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl, wherein each said C1-C4 alkyl, C3-C6 cycloalkyl, or 4-10 membered heterocyclyl is optionally substituted with halo, OH, oxo, C1-C4 alkoxy, NH2, NH(C1-C4-alkyl), N(C1-C4-alkyl)2; 10 H, D, halo, C1-C4 alkyl, C3-C6 cycloalkyl, or 4-10 G is a reactive functional group; L 2 is a bond, -NH-, -N(Ci-C3alkyl)-, -NHC(O)-, -N(Ci-C3alkyl)C(O)-, -C(O)NH-, -C(O)N(Ci-C3alkyl)-, -O-, -Ci-C4-alkylene-, -C2-C4-alkenylene-, or -C2-C4-alkynylene-; Q is C6-C 10 aryl, 5-10 membered heteroaryl, C3-C 10 cycloalkyl or 4-10 membered heterocyclyl; each R 1 is independently R 1A , R 1B , R 1C , R 1D or R 1E ; Each R 1A Each is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl, wherein each of the C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 heteroalkyl is optionally surrounded by one or more R 4A replace; each R 1B , R 1C , R 1D , and R 1E is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, D, halo, CN, NO2, NR 5A R 5B , C(=O)R 5A , C(=O)OR 5A , OC(=O)R 5A , C(O)NR 5A R 5B , N(R 5A )C(O)R 5B , C3-C 10 cycloalkyl, C3-C 10 cycloalkoxy, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein each said C1-C6 alkyl, C1-C6 heteroalkyl, or C1-C6 alkoxy is optionally substituted with one or more R 4B , and each said C3-C 10 cycloalkyl, C3-C 10 cycloalkoxy, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 4C ; R 2 is H or C1-C3alkyl; each R 3 is independently R 3A , R 3B , or R 3C ; or two R 3 together with the atom to which they are attached can form a C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein each said C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 6A ; Each R 3A R 3B and R 3C All are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, OH, D, halogenated, CN, NO2, NR 7A R 7B C(=O)R 7A C(=O)OR 7A OC(=O)R 7A C(O)NR 7A R 7B 、N(R 7A )C(O)R 7B C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 aryl or 5-10 heteroaryl, wherein each of the C1-C6 alkyl, C1-C6 heteroalkyl or C1-C6 alkoxy groups is optionally surrounded by one or more R groups. 6B Replace, and each of the C3-C 10 cycloalkyl, C3-C 10 Cycloalkoxy, 4-10 membered heterocyclic group, C6-C 10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more R groups. 6C replace; each R 4A , R 4B , and R 6B is independently C1-C6alkoxy, oxo, OH, D, halo, CN, or NR 8A R 8B ; each R 4C , R 6A , and R 6C is independently C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halo, CN, or NR 9A R 9B ; each R 5A , R 5B , R 7A , R 7B , R 8A , R 8B , R 9A , and R 9B are each independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl, wherein each said C1-C6 alkyl or C1-C6 heteroalkyl is optionally substituted with one or more R 10A , and each said C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, or 5-10 membered heteroaryl is optionally substituted with one or more R 10B ; or R 5A and R 5B , R 7A and R 7B , R 8A and R 8B or R 9A and R 9B may form, together with the N atom to which they are attached, a 4-10 membered heterocyclyl ring or a 5-10 membered heteroaryl ring, wherein each of said 4-10 membered heterocyclyl or 5-10 membered heteroaryl is optionally substituted with one or more R 10C ; each R is independently C1-C6alkoxy, oxo, OH, D, halo, CN, or NR 10A R 11A R 11B ; Each R 10B and R 10C Each is independently a C1-C4 alkyl, C1-C6 alkoxy, oxo, OH, D, halogen, CN, or NR. 12A R 12B ; each R 11A , R 11B , R 12A , and R 12B are independently H, C1-C4alkyl, or C3-C6cycloalkyl; p is an integer from 0 to 4; and q is an integer from 0 to 3; with the proviso that the compound of Formula (XIII) is not: 2-amino-N-(4,5-dimethylthiazol-2-yl)-6-methylnicotinamide; (2-(2-(3-((3-((4,5-dimethylthiazol-2-yl)carbamoyl)-6-methylpyridin-2-yl)amino)-3- oxopropoxy)ethoxy)ethyl)carbamic acid tert-butyl ester; 2-(3-(2-(2-aminoethoxy)ethoxy)propanoylamino)-N-(4,5-dimethylthiazol-2-yl)-6- methylnicotinamide; (7-((6-chloro-3-((4,5-dimethylthiazol-2-yl)carbamoyl)-pyridin-2-yl)amino)heptyl)carbamic acid tert-butyl ester; (7-((3-((4,5-dimethylthiazol-2-yl)carbamoyl)-6-methylpyridin-2-yl)amino)heptyl)carbamic acid tert-butyl ester; or 2-((7-aminopentyl)amino)-N-(4,5-dimethylthiazol-2-yl)-6-methylnicotinamide.

22. The compound of claim 21, having the structure of Formula (XIII-A), (XIII-B), (XIII-C), or (XIII-D): or a salt thereof.

23. The compound or salt of claim 21 or 22, wherein Q is selected from: wherein * indicates the point of attachment.

24. The compound or salt of any one of claims 21 to 23, Z 1 is L 1 -G.

25. The compound or salt according to any one of claims 21 to 24, wherein G is selected from: protected or unprotected primary or secondary amines, carboxylic acids, carboxylic esters, halogenated, hydroxylated, C1-C4 alkoxy, C1-C4 haloalkoxy, formyl, C1-C4 alkyl sulfonate, C1-C4 haloalkyl sulfonate, C6-C 10 Aryl sulfonates, boric acids, borate esters and azides.

26. The compound or salt of any one of claims 21 to 23, wherein Z 1 is L 1 -Z 2 .

27. The compound or salt of any one of claims 21 to 26, wherein L 1 is a bond.

28. The compound or salt of any one of claims 21 to 26, wherein L 1 is a bivalent linker of Formula (L).

29. The compound or salt of any one of claims 21 to 26, wherein L 1 is a bivalent linker of Formula (L-1).

30. The compound or salt of any one of claims 21 to 26, wherein L 1 is a bivalent linker of Formula (J).

31. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the heterobifunctional compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof.

32. A method of degrading one or more proteins selected from CCND, CDK4, or CDK6, comprising administering the heterobifunctional compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof.

33. A method of degrading a protein selected from CCND, CDK4 and / or CDK6, comprising contacting the protein with the heterobifunctional compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein the contacting comprises contacting a cell comprising the protein with the heterobifunctional compound and results in degradation of the target protein.

34. A method of identifying a compound capable of degrading a protein selected from the group consisting of CCND, CDK4 and / or CDK6, comprising the steps of: (1) providing a test system for monitoring the degradation of the protein; and (2) determining in the test system whether a given test compound results in degradation of the protein. (1) providing a test system for monitoring the degradation of the protein; and (2) determining in the test system whether a given test compound results in degradation of the protein.

Images