Bicyclic substituted glutarimide celecoxib binder

Abstract

The present invention provides a degron compound that binds to cereblon, which is a component of the E3 ubiquitin ligase. The degrons provided herein can be used, either alone or covalently linked to a tail, to modulate the activity of cereblon. Alternatively, the degron can be linked to a targeting ligand that binds to a target protein for proteolysis.

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 349,509, filed Jun. 6, 2022, the entire disclosure of which is incorporated herein by reference for all purposes.

[0002] The present invention provides degron compounds that bind to cereblon, a component of the E3 ubiquitin ligase. The degrons provided herein can be used, alone or covalently linked to a tail, to modulate the activity of cereblon. Alternatively, the degron can be linked to a targeting ligand that binds to a target protein for proteolysis.

Background Art

[0003] Proteolysis is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excessive proteins is achieved by the ubiquitin - proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, the cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neurodegeneration and myopathy, the morphogenesis of neural circuitry, the regulation of cell - surface receptors, ion channels, and the secretory pathway, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection.

[0004] The covalent attachment of multiple ubiquitin molecules to the terminal lysine residue by an E3 ubiquitin ligase labels the protein for proteasomal degradation, and the protein is digested into small peptides and ultimately its constituent amino acids, which become the building blocks of new proteins. Defects in proteasomal degradation have been associated with various clinical disorders, including, in particular, Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0005] Drugs such as thalidomide and its analogs lenalidomide and pomalidomide have attracted attention as immunomodulatory agents and anti-cancer agents, particularly in multiple myeloma (Non-Patent Documents 1, 2, 3, 4, and 5). The exact mechanism of action of thalidomide, lenalidomide, and pomalidomide in treatment is unknown, but the compounds exhibit activity. Thalidomide and its analogs have been shown to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (see Non-Patent Document 6). Cereblon is part of an E3 ubiquitin ligase complex that interacts with damaged DNA-binding protein 1, forms an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (known as RBX1), and functions as a substrate receptor for selecting proteins for ubiquitination. Binding of lenalidomide to cereblon promotes subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and proteasomal degradation (see Non-Patent Documents 7 and 8).

[0006] With the discovery that thalidomide binds to the cereblon E3 ubiquitin ligase, research has been conducted to investigate the incorporation of thalidomide and certain derivatives into compounds for the destruction of targeted proteins. Celgene has disclosed imides for similar uses, including those in Patent Documents 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, and 27.

[0007] Patent applications describing compounds capable of binding to an E3 ubiquitin ligase and a target protein for degradation filed by C4 Therapeutics, Inc. include the following: Patent Document 28, titled "Neurotrophic Tyrosine Receptor Kinase (NTRK) Degrading Compounds"; Patent Document 29, titled "Selected Compounds for Targeted Degradation of BRD9"; Patent Document 30, titled "Compounds for Targeting Degradation of IRAK4 Proteins"; Patent Document 31, titled "Compounds for Targeting Degradation of IRAK4 Proteins"; Patent Document 32, titled "EGFR Degraders to Treat Cancer Metastasis to the Brain or CNS"; Patent Document 33, titled "Tricyclic Heterobifunctional Compounds for Degradation of Targeted Proteins"; Patent Document 34, titled "Tricyclic Compounds to Degrade Neosubstrates for Medical Therapy"; Patent Document 35, titled "Tricyclic Ligands for Degradation of IKZF2 or IKZF4"; Patent Document 36, titled "Advantageous Therapies for Disorders Mediated by Ikaros or Aiolos".Patent Document 37, title: "Heterobifunctional Compounds as Degraders of BRAF"; Patent Document 38, title: "BRAF Degraders"; Patent Document 39, title: "Compounds for Targeted Degradation of BRD9"; Patent Document 40, title: "Isoindolinone And Indazole Compounds For The Degradation Of EGFR"; Patent Document 41, title: "Bifunctional Compounds"; Patent Document 42, title: "Bifunctional Compounds for the Treatment of Cancer"; Patent Document 43, title: "Tricyclic Degraders of Ikaros and Aiolos"; Patent Document 44, title: "Heterocyclic Compounds for Medical Treatment"; Patent Document 45, title: "Targeted Protein Degradation"; Patent Document 46, title: "Spirocyclic Compounds"; Patent Document 47, title: "Compounds for the degradation of BRD9 or MTH1"; Patent Document 48, title: "Cereblon binders for the Degradation of Ikaros"; Patent Document 49, title: "Spirocyclic Compounds"; Patent Document 50, title: "Degraders and Degrons for Targeted Protein Degradation";Patent Document 51, title "N / O-Linked Degrons and Degronimers for Protein Degradation"; Patent Document 52, title "Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation"; Patent Document 53, title "Heterocyclic Degronimers for Target Protein Degradation"; Patent Document 54, title "Spirocyclic Degronimers for Target Protein Degradation"; Patent Document 55, title "C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation"; and Patent Document 56, title "Bromodomain Targeting Degronimers for Target Protein Degradation".;

[0008] Other examples of patent applications describing proteolytic compounds include: Patent Document 57, Patent Document 58, Patent Document 59, Patent Document 60, Patent Document 61, Patent Document 62, Patent Document 63, Patent Document 64, Patent Document 65, Patent Document 66, Patent Document 67, Patent Document 68, Patent Document 69, Patent Document 70, Patent Document 71, Patent Document 72, Patent Document 73, Patent Document 74, Patent Document 75, Patent Document 76, Patent Document 77, Patent Document 78, Patent Document 79, Patent Document 80, Patent Document 81, Patent Document 79, Patent Document 82, Patent Document 83, Patent Document 84, Patent Document 85, Patent Document 86, Patent Document 87, Patent Document 88, Patent Document 89, Patent Document 90, Patent Document 91, Patent Document 92, Patent Document 93, Patent Document 94, Patent Document 95, Patent Document 96, Patent Document 97, Patent Document 98, Patent Document 99, Patent Document 99, Patent Document 100, Patent Document 101, Patent Document 102, Patent Document 103, Patent Document 104, and Patent Document 105.

Prior Art Documents

Patent Documents

[0009]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Patent Document 13

Patent Document 14

Patent Document 15

Patent Document 16

Patent Document 17

Patent Document 18

Patent Document 19

Patent Document 20

Patent Document 21

Patent Document 22

Patent Document 23

Patent Document 24

Patent Document 25

Patent Document 26

Patent Document 27

Patent Document 28

Patent Document 29

Patent Document 30

Patent Document 31

Patent Document 90

Patent Document 91

Patent Document 92

Patent Document 93

Patent Document 94

Patent Document 95

Patent Document 96

Patent Document 97

Patent Document 98

Patent Document 99

Patent Document 100

Patent Document 101

Patent Document 102

Patent Document 103

Patent Document 104

Patent Document 105

Non-Patent Document

[0010]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Summary of the Invention

Problems to be Solved by the Invention

[0011] An object of the present invention is to provide a new compound, method, composition, and manufacturing method useful for degrading a selected protein in vivo.

Means for Solving the Problems

[0012] Provided are cereblon-binding compounds (degrons) having a specific bicyclic substituent at the C3 position of glutarimide. These specific bicyclic substituents correspond to the bicyclics of the following formulas IA, IIA, IIIA, IVA, VA, VIA, VIIA, VIIIA, IXIA, XA, XIA, XIIA, XIIIA, XIVA, XVA, and XVI A, as well as the embodiments described herein.

Chemical formula

[0013] The degrons described can be used to treat disorders mediated by cereblon, or disorders mediated by proteins that are degraded by cereblon when the degrons described herein bind to cereblon. Alternatively, the degrons described herein can be used as intermediates for synthesizing heterobifunctional compounds (Degraders) for targeted proteolysis. In certain embodiments, the degron comprises a linking moiety (tail) that can react with a suitably prepared targeting ligand or targeting ligand precursor to form a Degrader. Also provided are Degraders comprising degrons described herein that can be attached directly to a targeting ligand or attached to a targeting ligand via a linker.

Chemical formula

[0014] The degron compound serves as a "molecular glue" that can bind to the cereblon E3 ligase, thereby creating a new surface on the E3 ligase and enhancing the interaction and binding with the targeted protein. As a result of this interaction, the targeted protein can be ubiquitinated by the cereblon E3 ligase and degraded by the proteasome. In some embodiments, the cereblon-binding affinity of the degron enables the degradation of proteins associated with, but not limited to, cancer and the diseases described in more detail below.

[0015] For example, a compound of formula IA is a degron and can thus be used as part of a therapeutic active compound that modifies the surface of cereblon, an intermediate for making a degrader, or a heterobifunctional compound (degrader) that degrades a target protein.

[0016] In certain embodiments, a compound of formula IA, formula IIA, formula IIIA, formula IVA, formula VA, formula VIA, formula VIIA, formula VIIIA, formula IXA, formula XA, formula XIA, formula XIIA, formula XIIIA, formula XIVA, formula XVA, or formula XVI in a pharmaceutically acceptable carrier optionally for forming a pharmaceutical composition:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0017] In certain embodiments, provided is a degron of formula XVIIAa, formula XVIIAb, formula XVIIAc, formula XVIIAd, or formula XVIIAe:

Chemical formula

Chemical formula

[0018] The degron described herein can be used alone (i.e., not as part of a degrader) as a cereblon in vivo binder, which can be administered to a host in need thereof, such as a human, in an effective amount, optionally as a pharmaceutically acceptable salt, and optionally in a pharmaceutically acceptable composition, for any therapeutic indication that can be treated by modulating the function or activity of a cereblon-containing E3 ubiquitin ligase protein complex, including, but not limited to, the uses known for cereblon binders including thalidomide, pomalidomide, and lenalidomide. The binding of the degron described herein to cereblon can induce a change in the protein conformation of cereblon and enable the degradation of the target protein. In certain embodiments, the degron described herein is a "molecular glue" that causes target degradation of a target protein, such as a protein having a C2H2 zinc finger degron motif.

[0019] Non-limiting examples of proteins that may be degraded or downregulated by degrons include ARID2, CDK1, CDK12-Cyclin K, CDK13, CK1α, CSNK1A1, Cyclin K, E4F1, FAM83F, GSPT1, GSPT2, GZF1, IKZF1, IKZF2, IKZF3, IKZF4, ILF2, Myc, ODC1, p63, PDE6D, AB28, RARα-ZBTB16, RBM23, RBM39, RBM39, RNF166, SALL4, WBP4, ZBTB16, ZBTB16-RARα, ZBTB39, ZFP91, ZFP91, ZFP91, ZMYM2-FGFR1, ZMYM2-FLT3, ZNF198, ZNF276, ZNF276, ZNF517, ZNF582, ZNF653, ZNF654, ZNF692, ZNF787, ZNF827, and ZNF98. In certain embodiments, the target protein degraded by the degron of the present invention is selected from ARID2, aromatase, β-catenin, CDK12, NRF2, PDE6D, CK1α, Cyclin K, GSPT1, FAM83, ILF2, ZBTB16, and ZMYM2. In certain embodiments, the target protein degraded by the degron of the present invention is selected from IKZF1, IKZF2, IKZF3, and IKZF4.

[0020] Non-limiting examples of disorders that may be treated by the degrons described herein include abnormal cell proliferation, including tumors or cancers, or myeloproliferative or lymphoproliferative disorders such as B-cell lymphoma or T-cell lymphoma, multiple myeloma, Waldenström macroglobulinemia, Wiskott-Aldrich syndrome, or post-transplant lymphoproliferative disorder; immune disorders including autoimmune disorders such as Addison's disease, celiac disease, dermatomyositis, Graves' disease, thyroiditis, multiple sclerosis, pernicious anemia, reactive arthritis, lupus, or type I diabetes; heart dysfunction diseases including hypercholesterolemia; infectious diseases including viral or bacterial infections; and inflammatory conditions including asthma, chronic peptic ulcer, tuberculosis, rheumatoid arthritis, periodontitis, ulcerative colitis, Crohn's disease, or hepatitis.

[0021] In certain embodiments, the degrons described herein are used to degrade proteins that mediate multiple myeloma, colorectal cancer, Hodgkin lymphoma, or non-Hodgkin lymphoma.

[0022] In certain embodiments, the degrons described herein can activate cereblon, reduce or alter its natural activity. Further non-limiting examples of the use of cereblon binders are for treating hematological disorders such as multiple myeloma, myelodysplastic syndromes, cancer, tumors, abnormal cell proliferation, HIV / AIDS, Crohn's disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis, Behcet's disease, tuberculosis, and myelofibrosis.

[0023] In other aspects, the degron has a tail portion. For example, the formula:

Chemical formula

Chemical formula

[0024] In certain embodiments When used in a divalent structure

Chemical formula

Chemical formula

[0025] In certain embodiments, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI or Formula VII:

Chemical formula

[0026] In other aspects, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIV, Formula XV, Formula XVI or Formula XVII: [Chemical formula] a degrader compound of TIFF2025523393000020.tif211170TIFF2025523393000021.tif170170, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof is provided, wherein, the targeting ligand is a chemical moiety that binds to a target protein, the target protein is a selected protein that causes or contributes to a disease, the linker is a bivalent linking group, and all other variable parts are as defined herein.

[0027] In certain embodiments, the targeting ligand is a means for binding to a target protein, and the targeting ligand is a chemical moiety. In certain embodiments, the term targeting ligand as used in the formulas or claims of the present invention is defined as a mean-plus-function under 35 U.S.C. § 112(f). In certain embodiments, the targeting ligand is a chemical moiety described in this patent application, e.g., a chemical moiety described in the figures.

[0028] The structure of the degrader is typically selected to be sufficiently stable to maintain a shelf life of at least 2, 3, 4, or 5 months under ambient conditions. To achieve this, each R group described herein must be sufficiently stable to maintain the corresponding desired shelf life of at least 2, 3, 4, or 5 months under ambient conditions. Those skilled in the art are well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under appropriate conditions.

[0029] Also, regardless of the presence or absence of any substituents, all R groups should be interpreted in a non-redundant manner (i.e., as is known in the art, alkyl substituted with alkyl is redundant, but for example, alkoxy substituted with alkoxy is not redundant).

[0030] The degraders provided herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, can be used to treat disorders mediated by a selected target protein that binds to a targeting ligand. Accordingly, in some embodiments, provided is a method of treating a host having a disorder mediated by a target protein, the method comprising administering to the host, typically a human, an effective amount of a degrader described herein or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition.

[0031] In certain embodiments, the selected target protein is derived from a gene that has undergone an amplification, translocation, rearrangement, copy number polymorphism, change, deletion, mutation, or inversion event that causes or is caused by a medical disorder. In certain aspects, the selected target protein has been post-translationally modified by one or a combination of phosphorylation, acetylation, acylation (including propionylation and crotylation), N-linked glycosylation, amidation, hydroxylation, methylation, polymethylation, O-linked glycosylation, pyroglutamylation, myristoylation, farnesylation, geranylgeranylation, ubiquitination, SUMOylation, or sulfation that causes or is caused by a medical disorder. In another embodiment, the target protein can be covalently modified by a targeting ligand functionalized to covalently bind to the target protein, and the covalent bond can be irreversible or reversible.

[0032] One non-limiting example of a disorder treatable by such a compound is abnormal cell proliferation such as a tumor or cancer, the target protein is an oncogenic protein or a signal transduction mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell proliferation.

[0033] The compounds and methods are presented for the treatment of patients having a disorder mediated by a protein targeted for selective degradation, which optionally comprises administering to a human patient in need thereof, in a pharmaceutically acceptable carrier (composition), an effective amount of one or a combination of the degrons or degraders of the invention described herein.

[0034] In certain embodiments, the disorder is selected from neoplasms, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteinopathies, proteinopathies, or fibrotic disorders.

[0035] In one embodiment, the invention provides a degron covalently linked to a targeting ligand via a linker that can have different lengths and functionalities. In one embodiment, the resulting degron-linker-targeting ligand compound is used to treat the disorders described herein. In one embodiment, the degron is directly linked to the targeting ligand (i.e., the linker is a bond).

[0036] In certain embodiments, the linker can be any chemically stable group that attaches the degron to the targeting ligand. Examples of linkers are described in Section IV (Linkers). In typical embodiments, the linker has a chain of 2 to 14, 15, 16, 17, 18, 19, or 20 or more carbon atoms, with at least one of the carbon atoms replaceable by a heteroatom such as O, N, S, or P, such that the resulting molecule has a storage life stable for at least 2 months, 3 months, 6 months, or 1 year as part of a pharmaceutically acceptable dosage form and is itself pharmaceutically acceptable.

[0037] In certain embodiments, the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive atoms within the chain. For example, the chain may include one or more ethylene glycol units, and in some embodiments, the linker may have at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more consecutive, partially consecutive, or non-consecutive ethylene glycol units. In certain embodiments, the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 branches, which can independently be alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl substituents, and in one embodiment, each branch has 10, 8, 6, 4, 3, 2, or 1 carbon.

[0038] In one embodiment, the target protein is a protein that is not druggable in the classical sense in that it has no binding pocket or active site that can be inhibited or otherwise bound and cannot be readily allosterically controlled. In another embodiment, the target protein is a protein that is druggable in the classical sense. Examples of target proteins are shown below.

[0039] In certain embodiments, the invention provides administration of an effective amount of a degron or degrader compound to treat a patient, such as a human, having an infectious disease, and the treatment optionally in combination with another bioactive agent targets a target protein of the infectious pathogen or a target protein of the host (degrader), or acts through binding to cereblon or its E3 ubiquitin ligase (degron), or acts through an independent mechanism.

[0040] A disease state or pathological condition can be caused by other exogenous pathogens such as microbial pathogens or viruses (non-limiting examples include HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, SARS-CoV2, flavivirus, pestivirus, rotavirus, influenza virus, coronavirus, EBV, viral pneumonia, drug-resistant virus, avian influenza virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, or hepadnavirus), bacteria (including but not limited to gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococci, streptococci, Escherichia coli, Salmonella, Helicobacter pylori, meningococcus, gonococcus, Chlamydiaceae, Mycoplasmataceae, etc.), fungi, protozoa, helminths, worms, prions, parasites, or other microorganisms.

[0041] In certain embodiments, the degron or degrader compound has at least one desired isotope substitution of an atom in an amount that exceeds the natural abundance of the isotope, i.e., is enriched.

[0042] In one embodiment, the degron or degrader compound contains deuterium atoms or a plurality of deuterium atoms.

[0043] The compounds of the present invention can provide important clinical benefits to patients for the treatment of disease states and pathological conditions particularly regulated by the protein of interest.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In this specification, the singular forms also include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present application, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference to form a part of this specification. The references cited herein are not admitted to be prior art to the present application. In case of conflict, this specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0045] Other features and advantages of the present application will be apparent from the following detailed description and claims.

[0046] Accordingly, the present invention includes at least the following features: (a) A degron compound as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof; (b) Use of a degron compound as described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof, which binds to cereblon as a molecular glue and results in the degradation of a target protein; (c) A degron having a tail, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives), or prodrug thereof, or its therapeutic use; (d) A degrader compound as described herein, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives), or prodrug thereof; (e) A degrader compound for the treatment of a disorder mediated by a target protein, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, wherein the compound comprises a targeting ligand for the target protein and the degron is optionally linked to the targeting ligand through a linker; (f) Use of an effective amount of a degron compound in the treatment of a patient, typically a human, having a disorder responsive to such treatment, including altering cereblon-based ubiquitination of a protein, such as abnormal cell proliferation, such as a tumor or cancer, immune disorder or autoimmune disorder or inflammatory disorder, heart disorder, infectious disease, or other disorder responsive to such treatment; (g) Use of an effective amount of a degrader compound in the treatment of a patient, typically a human, having any of the disorders described herein mediated by a target protein, including abnormal cell proliferation, such as a tumor or cancer, immune disorder or autoimmune disorder or inflammatory disorder, heart disorder, infectious disease, or other disorder responsive to such treatment; (h) Use of a degron or degrader, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, in the manufacture of a medicament for the treatment of a medical disorder, as further described herein; (i) A method of manufacturing a medicament for the therapeutic treatment of a disorder of a host, characterized in that a degron or degrader is used in the manufacture; (j) A degron or degrader, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, useful for the treatment of abnormal cell proliferation, such as cancer, in a host, including any of the cancers described herein; (k) Use of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, in the manufacture of a medicament for the treatment of abnormal cell proliferation, such as cancer, including any of the cancers described herein; (l) A method for manufacturing a medicament intended for therapeutic use for treating abnormal cell proliferation such as cancer, including any cancer in the host described herein, characterized in that a degron or a degrader is used in the manufacture; (m) A degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, which is useful for treating a tumor in a host, including any of the tumors described herein; (n) Use of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, which is useful for treating a tumor in a host, including any of the tumors described herein; (o) A method for manufacturing a medicament intended for the therapeutic treatment of a tumor in a host, including any of the tumors described herein, characterized in that a degron or degrader compound is used in the manufacture; (p) A degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative (including deuterated derivatives) or prodrug thereof, in the manufacture of a medicament for treating an immune disorder, autoimmune disorder or inflammatory disorder in a host; (q) Use of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, in the manufacture of a medicament for treating an immune disorder, autoimmune disorder or inflammatory disorder in a host; (r) A method for manufacturing a medicament intended for the therapeutic treatment of an immune disorder, autoimmune disorder or inflammatory disorder in a host, characterized in that a degron or degrader compound is used in the manufacture; (s) A degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, which is useful for treating viral infections in a host, including infections such as HIV, HBV, HCV, SARS-CoV2, and RSV; (t) Use of a degron or degrader compound, or a pharmaceutically possible salt, isotope derivative (including deuterated derivative) or prodrug thereof, in the manufacture of a medicament for the treatment of viral infections in a host, such as infections including HIV, HBV, HCV, SARS-CoV2, and RSV; (u) A method for manufacturing a medicament intended for the therapeutic treatment of viral infections in a host, such as infections including HIV, HBV, HCV, SARS-CoV2, and RSV, characterized in that a degron or degrader compound is used in the manufacture; (v) A pharmaceutical preparation comprising a therapeutically effective amount of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, together with a pharmaceutically acceptable carrier or excipient; (w) A degron or degrader compound as described herein as a mixture of enantiomers or diastereomers (related ones), including racemates; (x) A degron or degrader compound as described herein in an enriched form of enantiomers or diastereomers (related ones), including isolated enantiomers or diastereomers (i.e., having a purity greater than 85%, 90%, 95%, 97%, or 99%); and (y) A process for the preparation of a therapeutic product containing an effective amount of a degron or degrader compound, or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, optionally together with a pharmaceutically acceptable carrier or excipient.

Brief Description of the Drawings

[0047]

Figure 1A-1C

Figure 1D-1F

Figure 1G

Figure 1H-1J

Figure 1K-1Q

Figure 1R-1S

Figure 1T

Figure 1U

Figure 1V

Figure 1W

Figure 1X

Figure 1Y-1Z

Figure 1AA

Figure 1BB-1CC

Figure 1DD

Figure 1EE-1FF

Figure 1GG-1MM

Figure 1NN

Figure 1OO

Figure 1PP

Figure 1QQ-1TT

Figure 1UU

Figure 1VV-1WW

Figure 1XX

Figure 1YY

Figure 1ZZ

Figure 1AAA

Figure 1BBB-1CCC

Figure 1DDD

Figure 1EEE-1FFF

Figure 1GGG

Figure 1HHH-1III

Figure 1JJJ-1KKK

Figure 1LLL

Figure 2A

Figure 2B-2C

Figure 2D

Figure 2E

Figure 2F

Figure 2F

Figure 2G-2H

Figure 2G-2H

Figure 2I-2J

Figure 2I-2J

Figure 2K-2M

Figure 2N-2P

Figure 2Q

Figure 2R-2S

Figure 2T-2U

Figure 2V

Chemical formula

Figure 2W

Figure 2X-2NN

Figure 2OO-2UU

Figure 2VV

Figure 2WW-2YY

Figure 2ZZ-2FFF

Figure 2GGG

Figure 2HHH

Figure 2III

Figure 2JJJ-2KKK

Figure 2LLL

Figure 2MMM

Figure 2NNN

Figure 2OOO

Figure 2PPP

Figure 2QQQ

Figure 2RRR-2TTT

Figure 2UUU

Figure 2VVV

Figure 2WWW

Figure 2XXX

Figure 2YYY

Figure 2ZZZ

Figure 2AAAA

Figure 2BBBB

Figure 2CCCC

Figure 2DDDD

Figure 2EEEE-2FFFF

Figure 2GGGG-2JJJJ

Figure 2KKKK

Figure 2LLLL-2MMMM

Figure 2NNNN

Figure 2OOOO

Figure 2PPPP-2SSSS

Figure 2TTTT-2ZZZZ

Figure 2AAAAA-2EEEEE

Figure 2FFFFF-2GGGGG

Figure 2HHHHH

Figure 2IIIII

Figure 2JJJJJ

Figure 2KKKKK

Figure 2LLLLL-2MMMMM

Figure 2NNNNN-2OOOOO

Figure 2PPPPP-2QQQQQ

Figure 2RRRRR

Figure 2SSSSS

Figure 2TTTTT

Figure 2UUUUU-2XXXXX

Figure 2YYYYY

Figure 2ZZZZZ

Figure 3A-3B

Figure 3C

Figure 3D-3E

Figure 3F-3G

Figure 3H-3I

Figure 3J-3L

Figure 3M

Figure 3N-3O

Figure 3P-3R

Figure 3S-3T

Figure 3U

Figure 3V-3W

Figure 3X

Figure 3Y

Figure 3Z-3SS

Figure 3TT

Figure 3UU-3WW

Figure 3XX-3AAA

Figure 3BBB

Figure 3CCC-3EEE

Figure 3FFF-3HHH

Figure 3 III-3 JJJ

Figure 3 KKK-3 LLL

Figure 3 MMM

Figure 3 NNN-3 QQQ

Figure 3 RRR

Figure 3 SSS-3 XXX

Figure 3 YYY

Figure 3 ZZZ

Figure 3 AAAA

Figure 3 BBBB

Figure 3 CCCC

Figure 3 DDDD-3 FFFF

Figure 3 GGGG

Figure 3 HHHH-3 OOOO

Figure 3 PPPP

Figure 3 QQQQ

Figure 3 RRRR

Figure 3 SSSS

Figure 3 TTTT

Figure 3 UUUU-3 VVVV

Figure 3 WWWW

Figure 3 XXXX-3 YYYY

Figure 3 ZZZZ-3 DDDDD

Figure 3 EEEEE

Figure 3 FFFFF-3 GGGGG

Figure 3 HHHHH

Figure 3 IIIII

Figure 3 JJJJJ

Figure 3 KKKKK-3 MMMMM

Figure 3 NNNNN

Figure 3 OOOOO-3 PPPPP

Figure 3 QQQQQ-3 TTTTT

Figure 3 UUUUU

Figure 3 VVVVV

Figure 3 WWWWW

Figure 3 XXXXX-3 YYYYY

Figure 3 ZZZZZ

Figure 4 A-4 B

Figure 4 C-4 P

Figure 4 Q-4 R

Figure 4 S

Figure 4 T-4 AA

Figure 4 BB

Figure 4 CC

Figure 4 DD-4 EE

Figure 5 A

Figure 5 B

Figure 5 C-5 D

Figure 5 E

Figure 5 F

Figure 5 G

Figure 5 H

Figure 5 I

Figure 5 J

Figure 5 K-5 M

Figure 5 N

Figure 5 O

Figure 5 P-5 Q

Figure 5 R-5 S

Figure 5 T

Figure 5 U-5 V

Figure 5 W-5 X

Figure 5 Y-5 Z

Figure 5 AA

Figure 5 BB-5 CC

Figure 5 DD

Figure 5 EE

Figure 5 FF-5 GG

Figure 5 HH

Figure 5 II-5 JJ

Figure 5 KK-5 LL

Figure 5 MM

Figure 5 NN

Figure 5 OO-5 PP

Figure 5 QQ

Figure 5 RR

Figure 5 SS

Figure 5 TT

Figure 5 UU

Figure 5 VV

Figure 5 WW

Figure 6 A-6 B

Figure 6 C-6 D

Figure 6 E-6 G

Figure 6 H-6 I

Figure 6 J

Figure 6 K-6 L

Figure 6 M-6 N

Figure 6 O

Figure 6 P

Figure 6 Q

Figure 6 R

Figure 6 S-6 T

Figure 6 U

Figure 6 V-6 W

Figure 6 X

Figure 6 Y

Figure 6 Z-6 AA

Figure 6 BB

Figure 7 A-7 C

Figure 7 D

Figure 7 E

Figure 7 F

Figure 8 A-8 S

Figure 8 T-8 V

Figure 8 W-8 X

Figure 8 Y

Figure 8 Z-8 AA

Figure 8 BB-8 CC

Figure 8 DD-8 EE

Figure 8 FF

Figure 8 GG

Figure 8 HH-8 II

Figure 8 JJ

Figure 8 KK-8 LL

Figure 8 MM

Figure 8 NN-8 OO

Figure 88 PP-8 VV

Figure 8 WW-8 XX

Figure 8 YY

Figure 8 ZZ-8 AAA

Figure 8 BBB-8 EEE

Figure 8FFF-8III

Figure 8JJJ

Figure 8KKK-8MMM

Figure 8NNN-8OOO

Figure 8PPP

Figure 8QQQ-8SSS

Figure 8TTT

Figure 8UUU-8YYY

Figure 8ZZZ-8CCCC

Figure 8DDDD-8FFFF

Figure 8GGGG

Figure 8HHHH

Figure 8IIII-8LLLL

Figure 8MMMM

Figure 8NNNN

Figure 8OOOO

Figure 8PPPP-8QQQQ

Figure 8RRRR

Figure 8SSSS-8VVVV

Figure 8WWWW-8AAAAA

Figure 8BBBBB-8FFFFF

Figure 8GGGGG-8JJJJJ

Figure 8KKKKK-8PPPPP

Figure 9

Figure 10A-10B

Figure 11A-11B

Figure 12A-12C

Figure 13

Figure 14A-14C

Figure 15

Figure 16

Figure 17A-17C

Figure 18A-18C

Figure 19A-19D

Figure 20A-20D

Figure 21A-21J

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30A-30B

Figure 31

Figure 32

Figure 33

Figure 34

Figure 35A-35B

Figure 36A

Figure 37A-37C

Figure 38

Figure 39

Figure 40

Figure 41

Figure 42

Figure 43

Figure 44

Figure 45

Figure 46

Figure 47

Figure 48

Figure 49

Figure 50

Figure 51

Figure 52

Figure 53

Figure 54

Figure 55

Figure 56

Figure 57

Figure 58

Figure 59

Figure 60

Figure 61

Figure 62

Figure 63

Figure 64A-64E

Figure 65A-65B

Figure 66A-66C

Figure 67A-67B

Figure 68A-68B

Figure 69

Figure 70

Figure 71

Figure 72

Figure 73A-73B

Figure 74A-74M

Figure 75A-75B

Figure 76

Figure 77

Figure 78

Figure 79A-79J

DETAILED DESCRIPTION OF THE INVENTION

[0048] I. DEFINITIONS Compounds are described using their official names. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0049] Compounds of any of the formulas described herein can exist in isomeric forms such as racemates, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N-oxides, or rotamers, as if each were specifically recited, unless specifically excluded by context.

[0050] The terms "a" and "an" are not intended to denote a limitation of quantity but rather the presence of at least one of the items being referred to. The term "or" means "and / or". The recitation of a range of values is intended to serve simply as a convenient method of referring individually to each separate value falling within the range, unless otherwise specified herein, and each separate value is hereby incorporated by reference as if it were individually recited herein. All endpoints of the ranges are included within the range and can be combined independently. All methods described herein can be performed in a suitable order, unless otherwise specified herein or clearly precluded by context. The use of the word "example" or "exemplary" (e.g., "such as") is intended merely to better illustrate the invention and does not denote a limitation of the scope of the invention, unless otherwise recited in the claims.

[0051] The present invention includes degron or degrader compounds having isotope substitution of at least one desired atom at an amount exceeding the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., having the same number of protons but different numbers of neutrons.

[0052] Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F,31 P, 32 P, 35 S, 36 Cl and 125 I, respectively. In a non-limiting embodiment, an isotope-labeled compound can be used in metabolic studies (e.g., 14 using 2 C), kinetic studies (e.g., 3 using 18 H or

[0053] H), detection or imaging techniques including drug or substrate tissue distribution assays or radiotherapy of patients, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT). In particular,

[0054]

[0055] 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds and prodrugs of the present invention can generally be prepared by replacing readily available non-isotope-labeled reagents with isotope-labeled reagents and performing the schemes or procedures disclosed in the following examples and preparations.

[0053] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced by deuterium. In certain embodiments, the isotope is enriched at 90%, 95% or 99% or more at any position of the subject. In a non-limiting embodiment, deuterium is enriched at 90%, 95% or 99% at the desired position.

[0054] In a non-limiting embodiment, substitution of a hydrogen atom by a deuterium atom can be effected in a degron or degrader compound.

[0055] In a non-limiting embodiment, substitution of a hydrogen atom by a deuterium atom is effected in one or more groups selected from R or a variable part, a linker, and a targeting ligand as described herein. For example, any of the groups may be methyl, ethyl, or methoxy, or an alkyl residue may be deuterated if containing these by substitution (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In certain other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated.

[0056] The compounds of the present invention may form solvates with solvents (including water). Accordingly, in one non-limiting embodiment, the present invention includes compounds in solvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO. Solvates can be in liquid form or solid form.

[0057] A dash symbol ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -(C=O)NH2 is attached via the carbon of the carbonyl (C=O) group.

[0058] "Alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one non-limiting embodiment, alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, alkyl is C1 or C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges used herein indicate alkyl groups having each member of the range described as a separate species. For example, the term C1-C6 alkyl as used herein refers to straight-chain or branched-chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as a separate species, and thus each subset is considered to be separately disclosed. For example, the term C1-C4 alkyl as used herein refers to straight-chain or branched-chain alkyl groups having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as a separate species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane, and 2,3-dimethylbutane. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, when a term containing "alk" is used, "cycloalkyl" or "carbocyclic(al)" may be part of its definition, unless clearly excluded by the context. For example, without limitation, terms such as alkyl, alkoxy, haloalkyl, etc. may be considered to include the cyclic forms of alkyl, unless clearly excluded by the context.

[0059] In one embodiment, "alkyl" is C1-C 10It is alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1 or C2 alkyl.

[0060] In one embodiment, "alkyl" contains 1 carbon.

[0061] In one embodiment, "alkyl" contains 2 carbons.

[0062] In one embodiment, "alkyl" contains 3 carbons.

[0063] In one embodiment, "alkyl" contains 4 carbons.

[0064] In one embodiment, "alkyl" contains 5 carbons.

[0065] In one embodiment, "alkyl" contains 6 carbons.

[0066] Non-limiting examples of "alkyl" include methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0067] Additional non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0068] Additional non-limiting examples of "alkyl" include sec-butyl, sec-pentyl, and sec-hexyl.

[0069] Additional non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0070] Additional non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and active pentyl.

[0071] In one embodiment, "cycloalkyl" is C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3 or C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl or C6-C8 cycloalkyl.

[0072] In one embodiment, "cycloalkyl" has 3 carbons.

[0073] In one embodiment, "cycloalkyl" has 4 carbons.

[0074] In one embodiment, "cycloalkyl" has 5 carbons.

[0075] In one embodiment, "cycloalkyl" has 6 carbons.

[0076] In one embodiment, "cycloalkyl" has 7 carbons.

[0077] In one embodiment, "cycloalkyl" has 8 carbons.

[0078] In one embodiment, "cycloalkyl" has 9 carbons.

[0079] In one embodiment, "cycloalkyl" has 10 carbons.

[0080] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.

[0081] Additional non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, where the point of attachment of each group is on the cycloalkyl ring.

[0082] For example, [Chemistry] is a "cycloalkyl" group.

[0083] However, [Chemistry] is an "aryl" group.

[0084] "Alkenyl" is a linear or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at any stable point along the chain. The specified ranges used herein indicate alkenyl groups having each member of the ranges described as independent species as above for the alkyl moiety. Examples of alkenyl radicals include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term "alkenyl" also includes "cis" and "trans" alkenyl configurations, or alternatively "E" and "Z" alkenyl configurations. The term "alkenyl" also encompasses cycloalkyl or carbocyclic groups having at least one point of unsaturation.

[0085] "Alkynyl" is a branched or straight-chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can occur at any stable point along the chain. The specified ranges used herein indicate alkynyl groups having each member of the ranges described as independent species as above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. The term "alkynyl" also encompasses cycloalkyl or carbocyclic groups having at least one triple bond.

[0086] "Alkylene" is a divalent saturated hydrocarbon. Alkylene has, for example, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, 1 to 6 carbon atoms, or the indicated number of carbon atoms, and can be, for example, C1 or C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene or C1-C6 alkylene.

[0087] "Alkenylene" is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenylene has, for example, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or the indicated number of carbon atoms, and can be, for example, C2-C4 alkenylene.

[0088] "Alkynylene" is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylene has, for example, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or the indicated number of carbon atoms, and can be, for example, C2-C4 alkynylene.

[0089] "Halo" and "halogen" each independently refer to fluorine, chlorine, bromine or iodine.

[0090] "Haloalkyl" is a branched or straight-chain alkyl group substituted with one or more of the above halo atoms up to the maximum allowable number of halogen atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Perhaloalkyl" means an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.

[0091] In one embodiment, "haloalkyl" is C1-C 10It is haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, or C1 or C2 haloalkyl.

[0092] In one embodiment, "haloalkyl" has one carbon.

[0093] In one embodiment, "haloalkyl" has one carbon and one halogen.

[0094] In one embodiment, "haloalkyl" has one carbon and two halogens.

[0095] In one embodiment, "haloalkyl" has one carbon and three halogens.

[0096] In one embodiment, "haloalkyl" has two carbons.

[0097] In one embodiment, "haloalkyl" has three carbons.

[0098] In one embodiment, "haloalkyl" has four carbons.

[0099] In one embodiment, "haloalkyl" has five carbons.

[0100] In one embodiment, "haloalkyl" has six carbons.

[0101] Non-limiting examples of "haloalkyl" include

Chemical formula

[0102] Additional non-limiting examples of "haloalkyl" include

Chemical formula

[0103] Additional non-limiting examples of "haloalkyl" include [Chemical formula] include.

[0104] Additional non-limiting examples of "haloalkyl" include [Chemical formula] include.

[0105] "Chain" refers to a straight chain where all other chains, whether long or short or both, can be considered pendant. When two or more chains can be considered equally as the main chain, "chain" refers to the one that leads to the simplest representation of the molecule.

[0106] "Haloalkoxy" refers to a haloalkyl group as defined herein attached via an oxygen bridge (the oxygen of the alcohol radical).

[0107] "Heterocycloalkyl" is an alkyl group as defined herein substituted with a heterocyclo group as defined herein.

[0108] "Arylalkyl" is an alkyl group as defined herein substituted with an aryl group as defined herein.

[0109] Non-limiting examples of "arylalkyl" include [Chemical formula] include.

[0110] In one embodiment, "arylalkyl" is [Chemical formula] It is.

[0111] In one embodiment, "arylalkyl" refers to a C2 alkyl group substituted with an aryl group.

[0112] Non-limiting examples of "arylalkyl" include

Chemical formula

[0113] In one embodiment, "arylalkyl" refers to a C3 alkyl group substituted with an aryl group.

[0114] "Heteroarylalkyl" is an alkyl group as defined herein substituted with a heteroaryl group as defined herein.

[0115] As used herein, "aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., where 6, 10, or 14 π electrons are shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms within an aromatic ring system (a radical of "C 6~14 aryl"). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl", e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14"Aryl", for example anthracyl. "Aryl" also includes a ring system in which one or more of the aryl rings defined above are fused with one or more carbocyclic or heterocyclic groups and the radical or point of attachment is on the aryl ring. In such cases, the number of carbon atoms continues to specify the number of carbon atoms in the aryl ring system. One or more fused carbocyclic or heterocyclic groups may optionally contain one, two or three heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, and may be a 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic group, for example forming a 3,4-methylenedioxyphenyl group. In one non-limiting embodiment, the aryl group is pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In certain embodiments, the aryl group is unsubstituted C 6~14 is aryl.

[0116] In one embodiment, "aryl" is a 6-carbon aromatic group (phenyl).

[0117] In one embodiment, "aryl" is a 10-carbon aromatic group (naphthyl).

[0118] In one embodiment, "aryl" is a 6-carbon aromatic group condensed to a heterocycle with the point of attachment being the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline and dihydrobenzofuran, where the point of attachment of each group is on the aromatic ring.

[0119] For example,

Chemical formula

[0120] However,

Chemical formula

[0121] In one embodiment, "aryl" is a six-carbon aromatic group fused to a cycloalkyl, where the point of attachment is an aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, where the point of attachment of each group is on the aromatic ring.

[0122] For example,

Chemical formula

[0123] However,

Chemical formula

[0124] The terms "heterocyclyl", "heterocyclic" and "heterocycle" include saturated and partially saturated heteroatom-containing ring radicals, where the heteroatoms can be selected from nitrogen, sulfur and oxygen. Heterocyclic rings include monocyclic 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered rings, and 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered, 15-membered or 16-membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). Heterocycles do not include rings containing -O-O-, -O-S- or -S-S- moieties.

[0125] Examples of saturated heterocyclic groups include saturated 3-, 4-, 5- or 6-membered heteromonocyclic groups containing 1, 2, 3 or 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl), saturated 3-, 4-, 5- or 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1, 2 or 3 nitrogen atoms (e.g., morpholinyl), and saturated 3-, 4-, 5- or 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1, 2 or 3 nitrogen atoms (e.g., thiazolidinyl). Examples of partially saturated heterocyclyl radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.

[0126] Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, isoquinolin-1(2H)-onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]imidazol-2-onyl, benzo[d]thiazol-2(3H)-onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl and dihydrothiazolyl.

[0127] The terms "heterocyclyl", "heterocyclic", and "heterocycle" groups include moieties in which a heterocyclic radical is fused / condensed with an aryl or heteroaryl radical, such as unsaturated fused heterocyclic groups containing one, two, three, four, or five nitrogen atoms, such as indoline, isoindoline, unsaturated fused heterocyclic groups containing one or two oxygen atoms and one, two, or three nitrogen atoms, unsaturated fused heterocyclic groups containing one or two sulfur atoms and one, two, or three nitrogen atoms, and saturated, partially unsaturated, and unsaturated fused heterocyclic groups containing one or two oxygen or sulfur atoms.

[0128] In one embodiment, "heterocyclic" refers to a cyclic ring having one nitrogen and three, four, five, six, seven, or eight carbon atoms.

[0129] In one embodiment, "heterocyclic" refers to a cyclic ring having one nitrogen, one oxygen, and three, four, five, six, seven, or eight carbon atoms.

[0130] In one embodiment, "heterocyclic" refers to a cyclic ring having two nitrogens and three, four, five, six, seven, or eight carbon atoms.

[0131] In one embodiment, "heterocyclic" refers to a cyclic ring having one oxygen and three, four, five, six, seven, or eight carbon atoms.

[0132] In one embodiment, "heterocyclic" refers to a cyclic ring having one sulfur and three, four, five, six, seven, or eight carbon atoms.

[0133] Non-limiting examples of "heterocyclic" include aziridine, oxirane, thiirane, azetidine, 1,3-diazetidine, oxetane, and thietane.

[0134] Additional non-limiting examples of "heterocyclic" include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine, and imidazolidine.

[0135] Additional non-limiting examples of "heterocyclic ring" include tetrahydrofuran, 1,3-dioxolane, tetrahydrothiophene, 1,2-oxathiolane, and 1,3-oxathiolane.

[0136] Additional non-limiting examples of "heterocyclic ring" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiane, 1,3-dithiane, 1,4-dithiane, morpholine, and thiomorpholine.

[0137] Additional non-limiting examples of "heterocyclic ring" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, where the attachment point of each group is on the heterocyclic ring.

[0138] For example,

Chem.

[0139] However,

Chem.

[0140] Non-limiting examples of "heterocyclic ring" include

Chem.

[0141] Additional non-limiting examples of "heterocyclic ring" include

Chem.

[0142] Additional non-limiting examples of "heterocyclic ring" include

Chem.

[0143] Non-limiting examples of the "heterocyclic ring" include [Chemical formula] also include

[0144] Non-limiting examples of the "heterocyclic ring" include [Chemical formula] also include

[0145] Additional non-limiting examples of the "heterocyclic ring" include [Chemical formula] include

[0146] Additional non-limiting examples of the "heterocyclic ring" include [Chemical formula] include

[0147] The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., 6, 10, or 14 π electrons are shared in a cyclic arrangement and having 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S), wherein the ring nitrogen and sulfur atoms (if plural) are optionally oxidized and the nitrogen atoms (if plural) are optionally quaternized. Examples include unsaturated 5- or 6-membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom such as pyranyl, 2-furyl, 3-furyl; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom such as 2-thienyl, 3-thienyl; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl); unsaturated 5- or 6-membered heteromonocyclic groups containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms such as thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), but are not limited thereto. Additional examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl.

[0148] In one embodiment, "heteroaryl" is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.

[0149] Non-limiting examples of 5-membered "heteroaryl" groups include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.

[0150] Additional non-limiting examples of 5-membered "heteroaryl" groups include

Chemical formula

[0151] In one embodiment, "heteroaryl" is a 6-membered aromatic group (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl) containing 1, 2, or 3 nitrogen atoms.

[0152] Non-limiting examples of 6-membered "heteroaryl" groups having 1 or 2 nitrogen atoms include

Chemical formula

[0153] In one embodiment, "heteroaryl" is a 9-membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.

[0154] Non-limiting examples of bicyclic "heteroaryl" groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azaindazole, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole, and benzothiazole.

[0155] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [Chemical formula] etc.

[0156] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [Chemical formula] etc.

[0157] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [Chemical formula] etc.

[0158] In one embodiment, "heteroaryl" is a 10-membered bicyclic aromatic group containing one or two atoms selected from nitrogen, oxygen, and sulfur.

[0159] Non-limiting examples of bicyclic "heteroaryl" groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.

[0160] Additional non-limiting examples of bicyclic "heteroaryl" groups include: [Chemical formula] etc.

[0161] In one embodiment, the groups described herein that can be substituted with one, two, three, or four substituents are substituted with one substituent.

[0162] In one embodiment, the groups described herein that can be substituted with one, two, three, or four substituents are substituted with two substituents.

[0163] In one embodiment, the groups described herein that may be substituted with one, two, three, or four substituents are substituted with three substituents.

[0164] In one embodiment, the groups described herein that may be substituted with one, two, three, or four substituents are substituted with four substituents.

[0165] "Aliphatic" refers to saturated or unsaturated straight-chain, branched, or cyclic hydrocarbons. As used herein, "aliphatic" is intended to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and encompasses each of these definitions. In one embodiment, "aliphatic" is used to denote an aliphatic group having from 1 to 20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or poly-unsaturated, or alkynyl. The unsaturated aliphatic group can be in the cis or trans configuration. In one embodiment, the aliphatic group contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms.

[0166] In one embodiment, the aliphatic group contains from 1 to about 8 carbon atoms. In certain embodiments, the aliphatic group is C1 or C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges used herein denote aliphatic groups having each member of the ranges described as independent species. For example, the term C1-C6 aliphatic as used herein denotes straight-chain or branched alkyl, alkenyl, or alkynyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms, each of which is intended to be described as an independent species. For example, the term C1-C4 aliphatic as used herein denotes straight-chain or branched alkyl, alkenyl, or alkynyl groups having 1, 2, 3, or 4 carbon atoms, each of which is intended to be described as an independent species. In one embodiment, the aliphatic group is substituted with one or more functional groups such that a stable moiety is formed.

[0167] The term "heteroaliphatic" refers to an aliphatic moiety containing at least one heteroatom, such as an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon or boron atom, instead of a carbon atom in the chain. In one embodiment, the heteroatom is only nitrogen. In one embodiment, the heteroatom is only oxygen. In one embodiment, the heteroatom is only sulfur.

[0168] As used herein, "heteroaliphatic" is intended to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl and heterocycloalkynyl moieties. In one embodiment, "heteroaliphatic" is used to denote a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having from 1 to 20 carbon atoms. Non-limiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O-haloalkyl, etc.

[0169] "Dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, oral dosage forms, sublingual dosage forms, topical dosage forms, gels, mucosal dosage forms, etc. "Dosage form" may also include an implant, such as an optical implant.

[0170] "Effective amount", as used herein, means an amount that produces a therapeutic or prophylactic effect.

[0171] As used herein, "endogenous" refers to any substance that is from or produced within a living organism, cell, tissue or system.

[0172] As used herein, the term "exogenous" refers to any substance introduced from outside or produced externally to an organism, cell, tissue or system.

[0173] As used herein, the term "modulate" means to mediate a detectable increase or decrease in the level of response in a subject as compared to the level of response in the subject in the absence of treatment or compound, and / or as compared to the level of response in an untreated subject that is otherwise identical. This term encompasses disturbing or otherwise affecting an intrinsic signal or response to mediate a beneficial therapeutic response in a subject, preferably a human, by disturbing and / or affecting the same.

[0174] "Parenteral" administration of a pharmaceutical composition includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.) or intracardiac injection, or infusion.

[0175] As used herein, the terms "peptide", "polypeptide" and "protein" are used interchangeably and refer to a compound composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present in the sequence of a protein or peptide is usually of the same order as that found in nature. A polypeptide includes any peptide or protein containing two or more amino acids joined to each other by peptide bonds. As used herein, this term refers to both short chains generally referred to in the art as, for example, peptides, oligopeptides and oligomers, and longer chains generally referred to in the art as proteins, of which there are many types. "Polypeptide" includes, in particular, bioactive fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins. Polypeptides include natural peptides, recombinant peptides, synthetic peptides or combinations thereof.

[0176] As used herein, "treating" a disease means reducing the frequency or severity of at least one sign or symptom of the disease or disorder experienced by a subject (i.e., palliative treatment), or reducing the cause or effect of the disease or disorder (i.e., disease-modifying treatment).

[0177] Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as limiting the scope of the invention. The description of a range should be considered to specifically disclose all possible sub-ranges and individual numerical values within that range. For example, a description of a range such as 1 to 6 should be considered to specifically disclose sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within that range, such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0178] As used herein, a "pharmaceutical composition" is a composition comprising at least one active agent and at least one other substance such as a carrier. "Pharmaceutical combinations" are combinations of at least two active agents that can be combined in a single dosage form or administered together in separate dosage forms, and the active agents are indicated to be used in combination for treating any disorder described herein.

[0179] As used herein, "pharmaceutically acceptable salts" are derivatives of the disclosed compounds in which the parent compound is modified by making non-toxic inorganic and organic acids or their base addition salts. The salts of the present compounds can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in the free acid form with a stoichiometric amount of an appropriate base (hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg or K), or reacting these compounds in the free base form with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are typical when practicable. The salts of the present compounds further include solvates of the compounds and the salts of the compounds.

[0180] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids and quaternary ammonium salts. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nSalts prepared from organic acids such as -COOH (where n is from 0 to 4), or from different acids that generate the same counterion, may be mentioned. A further list of more suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0181] The term "carrier" as used in the pharmaceutical compositions / combinations of the present invention refers to a diluent, excipient or vehicle administered together with the active compound.

[0182] "Pharmaceutically acceptable excipients" generally means excipients that are safe, non-toxic and not biologically or otherwise inappropriate for administration to a host (usually a human), and are useful in the preparation of pharmaceutical compositions / combinations. In one embodiment, excipients acceptable for veterinary use are employed.

[0183] "Patient" or "host" or "subject" is a human or non-human animal in need of treatment or prevention of any of the disorders specifically described herein, which can be regulated, for example, by a natural (wild-type) or modified (non-wild-type) protein that degrades and can bring about a therapeutic effect according to the present invention. Usually, the host is a human. "Host" may alternatively refer to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0184] The "therapeutically effective amount" of the pharmaceutical compositions / combinations of the present invention means an amount effective to bring about a therapeutic effect such as improvement of symptoms or reduction or alleviation of the disease itself when administered to a host.

[0185] II. Compounds of the present invention In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, of formula IAa, formula IAb, or formula IAc:

Chemical formula

[0186] In certain embodiments, the degron compound of the present invention is

Chem.

[0187] In certain embodiments, the degron compound of the present invention is

Chem.

[0188] In certain embodiments, the degron compound of the present invention is

Chem.

[0189] In certain embodiments, the degron compound of the present invention is

Chem.

[0190] In certain embodiments, the degron compound of the present invention is

Chem.

[0191] In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula IIAa, formula IIAb, or formula IIAc:

Chemical formula

[0192] In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula IIIAa, formula IIIAb, or formula IIIAc:

Chemical formula

[0193] In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula IVAa, formula IVAb, or formula IVAc:

Chemical formula

[0194] In certain embodiments, the compounds of the invention are of the formula:

Chemical formula

[0195] In certain embodiments, the compounds of the invention are of the formula:

Chemical formula

[0196] In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula VAa, formula VAb, or formula VAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above.

[0197] In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula VIAa, formula VIAb, or formula VIAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above.

[0198] In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula VIIAa, formula VIIAb, or formula VIIAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above.

[0199] In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula VIIIAa, formula VIIIAb, or formula VIIIAc: [Chemical formula] a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, is provided, wherein all variable parts are as defined above.

[0200] In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, of formula IXAa, formula IXAb, or formula IXAc: [Chemical formula] a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, is provided, wherein all variable parts are as defined above.

[0201] In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, of formula XAa, formula XAb, or formula XAc: [Chemical formula] a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, is provided, wherein all variable parts are as defined above.

[0202] In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, of formula XIAa, formula XIAb, or formula XIAc: [Chemical formula] a degron compound, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, is provided, wherein all variable parts are as defined above.

[0203] In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula XIIAa, formula XIIAb, or formula XIIAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above.

[0204] In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula XIIIAa, formula XIIIAb, or formula XIIIAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above.

[0205] In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula XIVAa, formula XIVAb, or formula XIVAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, wherein all variable parts are as defined above.

[0206] In certain embodiments, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, a degron compound of formula XVAa, formula XVAb, or formula XVAc: [Chemical formula] is provided, or a pharmaceutically acceptable salt, N-oxide, isotope derivative or prodrug thereof, In the formula, all variable parts are as defined above.

[0207] In certain embodiments, optionally, a degron compound of formula XVIAa, formula XVIAb, or formula XVIAc:

Chemical formula

[0208] In certain embodiments, optionally, a degron compound of formula XVIIAa, formula XVIIAb, formula XVIIAc, formula XVIIAd or formula XVIIAe:

Chemical formula

[0209] In certain embodiments, the present invention relates to a compound of formula IA:

Chemical formula

[0210] In certain embodiments, the compounds of the present invention are

Chemical formula

[0211] In certain embodiments, the compounds of the present invention are

Chemical formula

[0212] In certain embodiments, the compounds of the present invention are

Chemical formula

[0213] In certain embodiments, the compounds of the present invention are

Chemical formula

[0214] In certain embodiments, the compounds of the present invention are

Chemical formula

[0215] In certain embodiments, the compounds of the present invention are

Chemical formula

[0216] In another aspect, optionally, in a pharmaceutically acceptable carrier for forming a pharmaceutical composition, Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, or Formula XVII:

Chemical formula

[0217] In certain embodiments,

Chemical formula

Chemical formula

[0218] In certain embodiments,

Chemical formula

Chemical formula

[0219] In certain embodiments,

Chemical formula

Chemical formula

[0220] In certain embodiments,

Chemical formula

Chemical formula

[0221] In certain embodiments, the compounds of the present invention are

Chemical formula

[0222] In certain embodiments, the formula:

Chemical formula

[0223] Alternative positions of the linker, A ring, and B ring In another aspect, compounds are provided in which the A ring, B ring, or linker is attached to one position to the left or right of its depicted position. If the previous linkage position was a carbon on an aromatic ring, the carbon can be replaced with X 5 and X 5 is N, CH, or CR 5 is.

[0224] For example, in this aspect, the compound of formula I is

Chemical formula

[0225] Additional non-limiting formulas of this embodiment include

Chemical formula

[0226] Additional non-limiting formulas of this embodiment include

Chemical formula

[0227] In certain embodiments, the compound of the present invention has the formula:

Chemical formula

[0228] In certain embodiments, the compound of the present invention has the formula:

Chemical formula

[0229] In certain embodiments, the compound of the present invention has the formula:

Chemical formula

[0230] R 1 embodiment In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is alkyl. In certain embodiments, R 1is alkenyl. In certain embodiments, R 1 is alkynyl. In certain embodiments, R 1 is halogen.

[0231] R 2 embodiments In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is alkyl. In certain embodiments, R 2 is haloalkyl. In certain embodiments, R 2 is alkenyl. In certain embodiments, R 2 is alkynyl. In certain embodiments, R 2 is aryl. In certain embodiments, R 2 is heteroaryl. In certain embodiments, R 2 is a heterocycle. In certain embodiments, R 2 is -C(O)R 9 wherein.

[0232] R 5 embodiments In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is alkyl. In certain embodiments, R 5 is haloalkyl. In certain embodiments, R 5 is alkenyl. In certain embodiments, R 5 is alkynyl. In certain embodiments, R5 is a halogen. In certain embodiments, R 5 is aryl. In certain embodiments, R 5 is heteroaryl. In certain embodiments, R 5 is a heterocyclic ring. In certain embodiments, R 5 is cyano. In certain embodiments, R 5 is nitro. In certain embodiments, R 5 is -NR 7 R 8 wherein. In certain embodiments, R 5 is -OR 7 wherein. In certain embodiments, R 5 is -SR 7 wherein. In certain embodiments, R 5 is -C(O)R 9 wherein. In certain embodiments, R 5 is -C(S)R 9 wherein. In certain embodiments, R 5 is -S(O)R 9 wherein. In certain embodiments, R 5 is -S(O)2R 9 wherein. In certain embodiments, R 5 is -OC(S)R 9 wherein. In certain embodiments, R 5 is -NR 7 S(O)R 9 wherein. In certain embodiments, R 5 is -NR 7 S(O)2R 9 wherein. In certain embodiments, R 5 is -P(O)(R 9 )2. In certain embodiments, R 5 is SP(O)(R 9 )2. In certain embodiments, R 5 is NR 7 P(O)(R 9 )2. In certain embodiments, R 5 is -OP(O)(R 9 )2.

[0233] Embodiments of R 5b In certain embodiments, R 5b is hydrogen. In certain embodiments, R 5b is alkyl. In certain embodiments, R 5b is alkenyl. In certain embodiments, R 5b is alkynyl. In certain embodiments, R 5b is aryl. In certain embodiments, R 5b is heteroaryl. In certain embodiments, R 5b is a heterocycle. In certain embodiments, R 5b is -C(O)alkyl. In certain embodiments, R 5b is -C(S)R 9 . In certain embodiments, R 5b is -S(O)R 9 . In certain embodiments, R 5b is -S(O)2R 9 .

[0234] Embodiments of R 5cEmbodiment In certain embodiments, R 5c is hydrogen. In certain embodiments, R 5c is alkyl. In certain embodiments, R 5c is haloalkyl. In certain embodiments, R 5c is alkenyl. In certain embodiments, R 5c is alkynyl. In certain embodiments, R 5c is halogen. In certain embodiments, R 5c is aryl. In certain embodiments, R 5c is heteroaryl. In certain embodiments, R 5c is a heterocyclic ring. In certain embodiments, R 5c is cyano. In certain embodiments, R 5c is nitro. In certain embodiments, R 5c is -OR 7 wherein. In certain embodiments, R 5c is -SR 7 wherein. In certain embodiments, R 5c is -C(O)R 9 wherein. In certain embodiments, R 5c is -C(S)R 9 wherein. In certain embodiments, R 5c is -S(O)R 9 wherein. In certain embodiments, R 5c is -S(O)2R 9 wherein. In certain embodiments, R 5cis -OC(S)R 9 is. In certain embodiments, R 5c is -NR 7 S(O)R 9 is. In certain embodiments, R 5c is -NR 7 S(O)2R 9 is. In certain embodiments, R 5c is -P(O)(R 9 )2. In certain embodiments, R 5c is SP(O)(R 9 )2. In certain embodiments, R 5c is NR 7 P(O)(R 9 )2. In certain embodiments, R 5c is -OP(O)(R 9 )2.

[0235] R 6 embodiments In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is alkyl. In certain embodiments, R 6 is alkenyl. In certain embodiments, R 6 is alkynyl. In certain embodiments, R 6 is halogen.

[0236] R 7 embodiments In certain embodiments, R 7 is hydrogen. In certain embodiments, R 7 is alkyl. In certain embodiments, R 7is a haloalkyl. In certain embodiments, R 7 is an alkenyl. In certain embodiments, R 7 is an alkynyl. In certain embodiments, R 7 is an aryl. In certain embodiments, R 7 is a heteroaryl. In certain embodiments, R 7 is a heterocycle. In certain embodiments, R 7 is C(O)R 14 is.

[0237] R 8 embodiments In certain embodiments, R 8 is hydrogen. In certain embodiments, R 8 is an alkyl. In certain embodiments, R 8 is a haloalkyl. In certain embodiments, R 8 is an alkenyl. In certain embodiments, R 8 is an alkynyl. In certain embodiments, R 8 is an aryl. In certain embodiments, R 8 is a heteroaryl. In certain embodiments, R 8 is a heterocycle. In certain embodiments, R 8 is C(O)R 14 is.

[0238] R 9 embodiments In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is alkyl. In certain embodiments, R 9 is haloalkyl. In certain embodiments, R 9 is alkenyl. In certain embodiments, R 9 is alkynyl. In certain embodiments, R 9 is aryl. In certain embodiments, R 9 is heteroaryl. In certain embodiments, R 9 is a heterocycle. In certain embodiments, R 9 is -NR 7 R 8 wherein. In certain embodiments, R 9 is -OR 7 wherein. In certain embodiments, R 9 is -SR 7 wherein.

[0239] R 10 embodiments In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 is alkyl. In certain embodiments, R 10 is haloalkyl. In certain embodiments, R 10 is alkenyl. In certain embodiments, R 10 is alkynyl. In certain embodiments, R 10 is haloalkyl. In certain embodiments, R 10 is halogen. In certain embodiments, R10 is aryl. In certain embodiments, R 10 is haloalkyl. In certain embodiments, R 10 is hydrogen. In certain embodiments, R 10 is alkyl. In certain embodiments, R 10 is heteroaryl. In certain embodiments, R 10 is heterocyclic. In certain embodiments, R 10 is cyano. In certain embodiments, R 10 is nitro. In certain embodiments, R 10 is -NR 11 R 13 is. In certain embodiments, R 10 is -OR 11 is. In certain embodiments, R 10 is -SR 11 is. In certain embodiments, R 10 is -C(O)R 14 is. In certain embodiments, R 10 is -C(S)R 14 is. In certain embodiments, R 10 is -S(O)R 14 is. In certain embodiments, R 10 is -S(O)2R 14 is. In certain embodiments, R 10 is -NR 11 S(O)2R 14 is. In certain embodiments, R 10 is -P(O)(R 14 )2. In certain embodiments, R 10 is -NR 11 P(O)(R 14 )2. In certain embodiments, R 10 is -OP(O)(R 14 )2.

[0240] Embodiments of R 11 In certain embodiments, R 11 is hydrogen. In certain embodiments, R 11 is alkyl. In certain embodiments, R 11 is haloalkyl. In certain embodiments, R 11 is alkenyl. In certain embodiments, R 11 is alkynyl. In certain embodiments, R 11 is aryl. In certain embodiments, R 11 is heteroaryl. In certain embodiments, R 11 is a heterocycle. In certain embodiments, R 11 is -C(O)R 14 . In certain embodiments, R 11 is -C(S)R 14 . In certain embodiments, R 11 is -S(O)R 14 . In certain embodiments, R 11 is -S(O)2R 14 . In certain embodiments, R 11 is -P(O)(R 14 )2.

[0241] Embodiments of R​12 Embodiment In a particular embodiment, R 12 is hydrogen. In a particular embodiment, R 12 is alkyl. In a particular embodiment, R 12 is haloalkyl. In a particular embodiment, R 12 is alkenyl. In a particular embodiment, R 12 is alkynyl. In a particular embodiment, R 12 is alkynyl. In a particular embodiment, R 12 is halogen. In a particular embodiment, R 12 is aryl. In a particular embodiment, R 12 is a heterocyclic ring. In a particular embodiment, R 12 is heteroaryl. In a particular embodiment, R 12 is cyano. In a particular embodiment, R 12 is nitro. In a particular embodiment, R 12 is -NR 11 R 13 wherein. In a particular embodiment, R 12 is -OR 11 wherein. In a particular embodiment, R 12 is -SR 11 wherein.

[0242] R 13 Embodiment In a particular embodiment, R 13 is hydrogen. In a particular embodiment, R 13 is alkyl. In certain embodiments, R 13 is haloalkyl. In certain embodiments, R 13 is alkenyl. In certain embodiments, R 13 is alkynyl. In certain embodiments, R 13 is aryl. In certain embodiments, R 13 is heteroaryl. In certain embodiments, R 13 is a heterocycle. In certain embodiments, R 13 is -C(O)R 14 wherein. In certain embodiments, R 13 is -C(S)R 14 wherein. In certain embodiments, R 13 is -S(O)R 14 wherein. In certain embodiments, R 13 is -S(O)2R 14 wherein. In certain embodiments, R 13 is -P(O)(R 14 )2.

[0243] R 14 Embodiments In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is alkyl. In certain embodiments, R 14 is haloalkyl. In certain embodiments, R 14 is alkenyl. In certain embodiments, R 14 is alkynyl. In certain embodiments, R 14is aryl. In certain embodiments, R 14 is heteroaryl. In certain embodiments, R 14 is a heterocyclic ring. In certain embodiments, R 14 is amino. In certain embodiments, R 14 is hydroxyl. In certain embodiments, R 14 is alkoxy. In certain embodiments, R 14 is -N(H)(alkyl). In certain embodiments, R 14 is -N(alkyl)2.

[0244] Embodiments of R 15a In certain embodiments, R 15a is hydrogen. In certain embodiments, R 15a is alkyl. In certain embodiments, R 15a is haloalkyl. In certain embodiments, R 15a is alkenyl. In certain embodiments, R 15a is alkynyl. In certain embodiments, R 15a is halogen. In certain embodiments, R 15a is aryl. In certain embodiments, R 15a is heteroaryl. In certain embodiments, R 15a is a heterocyclic ring. In certain embodiments, R 15a is cyano. In certain embodiments, R 15a ​is nitro. In certain embodiments, R 15a is amino. In certain embodiments, R 15a is hydroxyl. In certain embodiments, R 15a is alkoxy. In certain embodiments, R 15a is -N(H)(alkyl). In certain embodiments, R 15a is -N(alkyl)2.

[0245] R 15b embodiments In certain embodiments, R 15b is hydrogen. In certain embodiments, R 15b is alkyl. In certain embodiments, R 15b is haloalkyl. In certain embodiments, R 15b is alkenyl. In certain embodiments, R 15b is alkynyl. In certain embodiments, R 15b is halog...

Claims

1. formula: 【Chemistry 1】 【change】 During the ceremony, m is 0, 1, 2, 3, or 4. n is 0, 1, 2, or 3. p is either 0 or 1, Q is O, S, NR 17, or CR 17 R 18. X1, X2, and X3 are selected independently from N, CH, and CR5. X 4 is N, CH, or CR 5, 【Chemistry 2】 These are cycloalkyl, heterocyclic, or heteroaryl compounds. R1 and R6 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, and halogen, or R1 and R6 are combined to form CH2 or CH2CH2 crosslinks. Each R2 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -C(O)R9, and each of them except hydrogen is optionally substituted with one, two, three, or four substituents independently selected from R10. Alternatively, R2 is a halogen, Each R 5 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 7 R 8, -OR 7, -SR 7, -C(O)R 9, -C(S)R 9, -S(O)R 9, -S(O)2 R 9, -OC(O)R 9, -OC(S)R 9, -OS(O)R 9, -OS(O)2 R 9, -SC(O)R 9, -NR 7 C(O)R 9, -NR 7 C(S)R 9, -NR 7 S(O)R 9, -NR 7 S(O)2 R 9, -P(O)(R 9)2 -SP(O)(R9)2, -NR7P(O)(R9)2, and -OP(O)(R9)2 are independently selected, and each of them except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R10. R7 and R8 are independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, and -C(O)R14, respectively, and each of them except hydrogen is optionally substituted with one, two, three, or four substituents independently selected from R16. Each R9 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -NR7, R8, -OR7, and -SR7, and each of them is optionally substituted with one, two, three, or four substituents independently selected from R10. Each R 10 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 11 R 13, -OR 11, -SR 11, -C(O)R 14, -C(S)R 14, -S(O)R 14, -S(O)2 R 14, -OC(O)R 14, -OC(S)R 14, -OS(O)R 14, -OS(O)2 R 14, -NR 11 C(O)R 14, -NR 11 C(S)R 14, -NR 11 S(O)R 14, -NR 11 S(O)2 R 14, -P(O)(R 14) 2, -NR 11 P(O)(R 14) 2, and -OP(O)(R 14) 2 are independently selected, and each of them except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R 15a. R11 and R13 are, in each case, independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, -C(O)R14, -C(S)R14, -S(O)R14, -S(O)2R14, and -P(O)(R14)2, and each of them is optionally substituted with one, two, three, or four substituents independently selected from R15b. Each R 12 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 11, R 13, -OR 11, and -SR 11, and each of them except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R 15c. Each R14 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclic, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2, and each of them except hydrogen is optionally substituted with one, two, three, or four substituents independently selected from R15d. R 15a, R 15b, R 15c, R 15d, R 15e, R 15f, and R 15g are, in each case, independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, amino, hydroxyl, alkoxy, -N(H)(alkyl), and -N(alkyl)2. Each R 16 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 11 R 13, -OR 11, -SR 11, -C(O)R 14, -C(S)R 14, -S(O)R 14, -S(O)2 R 14, -OC(O)R 14, -OC(S)R 14, -OS(O)R 14, -OS(O)2 R 14, -NR 11 C(O)R 14, -NR 11 C(S)R 14, -NR 11 S(O)R 14, -NR 11 S(O)2 R 14, -P(O)(R 14) 2, -NR 11 P(O)(R 14) 2, and -OP(O)(R 14) 2 are independently selected, and each of them except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R 15e, Each R 17 is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, -C(O)R 14, -C(S)R 14, -S(O)R 14, and -S(O)2R 14, and each of them except hydrogen is optionally substituted with one, two, three, or four substituents independently selected from R 15f. R 18 includes hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, halogen, aryl, heteroaryl, heterocyclic, cyano, nitro, -NR 11 R 13, -OR 11, -SR 11, -OC(O)R 14, -OC(S)R 14, -OS(O)R 14, -OS(O)2 R 14, -NR 11 C(O)R 14, -NR 11 C(S)R 14, -NR 11 S(O)R 14, -NR 11 S(O)2 R 14, -P(O)(R 14)2, -NR 11 P(O)(R 14)2, and -OP(O)(R 14)2 Selected from, each of the elements except hydrogen, halogen, cyano, and nitro is optionally substituted with one, two, three, or four substituents independently selected from R 15g. A targeted ligand is a chemical part that binds to a target protein. A target protein is a selected protein that causes or contributes to a disease. The linker is given by formula LI: 【Transformation 3】 It is the divalent chemical part, During the ceremony, X ３１ and X ３２ These are independently, in each case, bond, heterocycle, aryl, heteroaryl, bicycle, and -NR ２７ -, -CR ４０ R ４１ -, -O-, -C(O)-, -C(NR ２７ )-, -C(S)-, -S(O)-, -S(O) ２ Selected from - and -S-, each of the heterocycle, aryl, heteroaryl, and bicycle is R ４０ It is optionally substituted with one, two, three, or four substituents independently selected from the original molecule. R ２０ 、R ２１ 、R ２２ 、R ２３ 、and R ２４ are each, independently in each case, selected from the group consisting of bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO ２ -, -S(O)-, -C(S)-, -C(O)NR ２７ -, -NR ２７ C(O)-, -O-, -S-, -NR ２７ -, -C(R ４０ R ４０ ), -P(O)(OR ２６ ), -P(O)(OR ２６ ), bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and carbocycle, and each of them is optionally substituted with one, two, three, or four substituents independently selected from R ４０ . R ２６ In each case, these are independently selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic elements. R ２７ Independently, in each case, is selected from the group consisting of hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, -C(O) (aliphatic, aryl, heteroaliphatic, or heteroaryl), -C(O)O (aliphatic, aryl, heteroaliphatic, or heteroaryl), alkenes, and alkynes. R ４０ Independently, in each case, hydrogen and R ２７ Alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH (aliphatic, including alkyl), -N (aliphatic, including alkyl) ２ , - NHSO ２ (Aliphatic, alkyl-containing), -N(Aliphatic, alkyl-containing)SO ２ Alkyl, -NHSO ２ (aryl, heteroaryl, or heterocyclic), -N(alkyl)SO ２ (aryl, heteroaryl, or heterocyclic), -NHSO ２ Alkenyl, -N(alkyl)SO ２ Alkenil, - NHSO ２ Alkinyl, -N(alkyl)SO ２ Selected from the group consisting of alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl, R ４１ is aliphatic, aryl, heteroaryl, or hydrogen. A compound, or a pharmaceutically acceptable salt thereof.

2. formula: 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. formula: 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. formula: 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. formula: 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. A, 【Transformation 8】 The compound according to any one of claims 1 to 5.

7. The compound according to any one of claims 1 to 5, wherein m is 0.

8. The compound according to any one of claims 1 to 5, wherein m is 1.

9. The compound according to any one of claims 1 to 5, wherein m is 2.

10. The compound according to any one of claims 1 to 5, wherein m is 3.

11. R ２ The compound according to any one of claims 1 to 5, wherein the compound is a halogen.

12. The compound according to any one of claims 1 to 5, wherein p is 1.

13. R ６ and R １ However, both CH ２ A compound according to any one of claims 1 to 5, which forms a crosslink.

14. R ６ and R １ The compound according to any one of claims 1 to 5, wherein the compound is hydrogen.

15. The aforementioned compound, 【Chemistry 9】 The compound according to claim 1, which is selected from or a pharmaceutically acceptable salt thereof.

16. The linker, formula: 【Chemistry 10】 A compound according to any one of claims 1 to 5, which is a linker.

17. X ３１ The compound according to claim 16, wherein the bond is a combination.

18. X ３１ The compound according to claim 16, wherein the compound is a heterocycle, -NR27-, or -C(O)-.

19. X ３２ The compound according to claim 16, wherein the bond is a combination.

20. X ３２ The compound according to claim 16, wherein the compound is a heterocycle, -NR27-, or -C(O)-.

21. R ２０ The compound according to claim 16, wherein the bond is a combination.

22. R ２０ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic.

23. R ２１ The compound according to claim 16, wherein the bond is a combination.

24. R ２１ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic.

25. R ２２ The compound according to claim 16, wherein the bond is a combination.

26. R ２２ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic.

27. R ２３ The compound according to claim 16, wherein the bond is a combination.

28. R ２３ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic.

29. R ２４ The compound according to claim 16, wherein the bond is a combination.

30. R ２４ However, CH ２ The compound according to claim 16, which is heterocyclic, aryl, or bicyclic.

31. The compound is 【Chemistry 11】 The compound according to claim 1, which is selected from or a pharmaceutically acceptable salt thereof.

32. The compound according to any one of claims 1 to 5, wherein the targeted ligand is the chemical portion shown in the figure.

33. X １ The compound according to any one of claims 1 to 5, wherein the compound is CH.

34. X ２ The compound according to any one of claims 1 to 5, wherein the compound is CH.

35. X ３ The compound according to any one of claims 1 to 5, wherein the compound is CH.

36. The compound according to any one of claims 1 to 4, wherein Q is O or S.

37. The compound according to any one of claims 1 to 5, wherein X1, X2, and X3 are CH.

38. The compound according to claim 37, wherein Q is O.

39. The compound according to claim 37, wherein R1 and R6 are H.

40. at least one R ２ The compound according to any one of claims 1 to 5, wherein the compound is fluorine.

41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

42. A pharmaceutical composition for treating a target protein-mediated disorder in humans, comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

43. The pharmaceutical composition according to claim 42, wherein the disorder is abnormal cell proliferation.

44. The pharmaceutical composition according to claim 42, wherein the disorder is an immune system disorder.

45. Use of a compound or a pharmaceutically acceptable salt thereof, or a composition thereof, according to any one of claims 1 to 5, in the manufacture of a pharmaceutical product for treating a target protein-mediated disorder in humans.

46. The use according to claim 45, wherein the aforementioned disorder is abnormal cell proliferation.

47. The use according to claim 45, wherein the impairment is an immune system disorder.

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