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WO2020051564A1 - Composés polycycliques et méthodes pour la dégradation ciblée de polypeptides du fibrosarcome rapidement accéléré - Google Patents

Composés polycycliques et méthodes pour la dégradation ciblée de polypeptides du fibrosarcome rapidement accéléré Download PDF

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Publication number
WO2020051564A1
WO2020051564A1 PCT/US2019/050114 US2019050114W WO2020051564A1 WO 2020051564 A1 WO2020051564 A1 WO 2020051564A1 US 2019050114 W US2019050114 W US 2019050114W WO 2020051564 A1 WO2020051564 A1 WO 2020051564A1
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optionally substituted
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Inventor
Andrew P. Crew
Keith R. Hornberger
Jing Wang
Craig M. Crews
Saul Jaime-Figueroa
Hanqing Dong
Yimin Qian
Kurt Zimmerman
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Yale University
Arvinas Operations Inc
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Yale University
Arvinas Operations Inc
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Priority to IL281188A priority Critical patent/IL281188B2/en
Priority to EP19773614.3A priority patent/EP3846907A1/fr
Priority to IL319737A priority patent/IL319737A/en
Priority to CA3109981A priority patent/CA3109981A1/fr
Priority to CN202411258198.3A priority patent/CN119192142A/zh
Priority to AU2019335516A priority patent/AU2019335516B2/en
Priority to CN202411258205.XA priority patent/CN119101049A/zh
Priority to CN202411258195.XA priority patent/CN119219628A/zh
Priority to KR1020217009937A priority patent/KR102642203B1/ko
Priority to MX2021002559A priority patent/MX2021002559A/es
Priority to CN201980073600.1A priority patent/CN113164775B/zh
Application filed by Yale University, Arvinas Operations Inc filed Critical Yale University
Priority to JP2021512854A priority patent/JP2022500368A/ja
Priority to KR1020247005115A priority patent/KR20240028539A/ko
Publication of WO2020051564A1 publication Critical patent/WO2020051564A1/fr
Priority to MX2024015414A priority patent/MX2024015414A/es
Priority to MX2024015415A priority patent/MX2024015415A/es
Anticipated expiration legal-status Critical
Priority to AU2022228150A priority patent/AU2022228150B2/en
Priority to JP2023127233A priority patent/JP2023159166A/ja
Priority to AU2024219653A priority patent/AU2024219653A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
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    • C07—ORGANIC CHEMISTRY
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N

Definitions

  • the description provides bifunctional compounds comprising a target protein binding moiety and an E3 ubiquitin ligase binding moiety, and associated methods of use.
  • the bifunctional compounds are useful as modulators of targeted ubiquitination, especially with respect to Rapidly Accelerated Fibrosarcoma (RAF) proteins, which are degraded and/or otherwise inhibited by bifunctional compounds according to the present disclosure.
  • RAF Rapidly Accelerated Fibrosarcoma
  • E3 ubiquitin ligases confer substrate specificity for ubiquitination, and therefore, are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates.
  • the development of ligands of E3 ligases has proven challenging, in part due to the fact that they must disrupt protein-protein interactions.
  • recent developments have provided specific ligands which bind to these ligases.
  • Tumor suppressor gene p53 plays an important role in cell growth arrest and apoptosis in response to DNA damage or stress (A. Vazquez, et al. Nat. Rev. Drug. Dis. (2008), 7, 979-982), and inactivation of p53 has been suggested as one of the major pathway for tumor cell survival (A. J. Levine, et al. Nature (2000), 408, 307-310).
  • M. Hollstein, et al. Science (1991), 233, 49-53) patients with wild type p53 were often found p53 down regulation by MDM2 through the protein-protein interaction of p53 and MDM2 (P. Chene, et al. Nat.
  • MDM2 keeps p53 at low concentration.
  • p53 level increases, and that also causes increase in MDM2 due to the feedback loop from p53/MDM2 auto regulatory system.
  • p53 regulates MDM2 at the transcription level
  • MDM2 regulates p53 at its activity level (A. J. Levine, et al. Genes Dev. (1993) 7, 1126-1132).
  • MDM2 binds to N-terminal domain of p53 and blocks expression of p53-responsive genes (J. Momand, et al. Cell (1992), 69, 1237-1245). Second, MDM2 shuttles p53 from nucleus to cytoplasm to facilitate proteolytic degradation (J. Roth, et al. EMBO J. (1998), 17, 554-564). Lastly, MDM2 carries intrinsic E3 ligase activity of conjugating ubiquitin to p53 for degradation through ubiquitin- dependent 26s proteasome system (UPS) (Y. Haupt, et al. Nature (1997) 387, 296-299). As such, because MDM2 functions as E3 ligase, recruiting MDM2 to a disease causing protein and effectuating its ubiquitination and degradation is an approach of high interest for drug discovery.
  • UPS ubiquitin- dependent 26s proteasome system
  • VHL von Hippel-Lindau
  • VCB the substrate recognition subunit of the E3 ligase complex
  • the primary substrate of VHL is Hypoxia Inducible Factor 1a (HIF-1a), a transcription factor that upregulates genes such as the pro- angiogenic growth factor VEGF and the red blood cell inducing cytokine erythropoietin in response to low oxygen levels.
  • HIF-1a Hypoxia Inducible Factor 1a
  • VHL Von Hippel Lindau
  • Cereblon is a protein that in humans is encoded by the CRBN gene. CRBN orthologs are highly conserved from plants to humans, which underscores its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (ROC1). This complex ubiquitinates a number of other proteins. Through a mechanism which has not been completely elucidated, cereblon ubquitination of target proteins results in increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates a number of developmental processes, such as limb and auditory vesicle formation. The net result is that this ubiquitin ligase complex is important for limb outgrowth in embryos. In the absence of cereblon, DDB1 forms a complex with DDB2 that functions as a DNA damage-binding protein.
  • DDB1 forms a complex
  • IAPs Inhibitors of Apotosis Proteins
  • the human IAP family includes 8 members, and numerous other organisms contain IAP homologs.
  • IAPs contain an E3 ligase specific domain and baculoviral IAP repeat (BIR) domains that recognize substrates, and promote their ubiquitination. IAPs promote ubiquitination and can directly bind and inhibit caspases.
  • Caspases are proteases (e.g. caspase-3, caspase-7 and caspace-9) that implement apoptosis. As such, through the binding of caspases, IAPs inhibit cell death.
  • DIABLO also known as second mitrochondria-derived activator of caspases or SMAC
  • HTRA2 also known as Omi
  • SMAC interacts with essentially all known IAPs including XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survivin.
  • IAPs including XIAP, c-IAP1, c-IAP2, NIL-IAP, Bruce, and survivin.
  • the first four amino acids (AVPI) of mature SMAC bind to a portion of IAPs, which is believed to be essential for blocking the anti-apoptotic effects of IAPs.
  • Bifunctional compounds such as those that are described in U.S. Patent Application Publications 2015-0291562 and 2014-0356322 (incorporated herein by reference), function to recruit endogenous proteins to an E3 ubiquiuin ligase for degradation.
  • the publications describe bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and/or otherwise inhibited by the bifunctional compounds.
  • RAF Rapidly Accelerated Fibrosarcoma
  • current BRaf inhibitors such as, vemurafenib and dabrafenib
  • diseases or disorders such as, melanoma, lung cancer, pancreatic cancer, and/or colorectal cancers
  • resistance mutations can emerge in response to BRaf/MEK inhibitor therapy.
  • the p61 splice variant can emerge in melanoma patients treated with BRaf/MEK inhibitor therapy, which leaves these patients with no clinical options.
  • BRaf/MEK inhibitor therapy Currently marketed agents also bind to and cause paradoxical activation of wild-type BRaf, which results in clinical complications.
  • the family of hypoactive Class III BRaf mutants that signal through heterodimerization with CRaf constitute 40% of BRaf mutations in non-small cell lung cancer (NSCLC), and also appear sporadically across other cancers, cannot be targeted with any currently approved or clinical-stage BRaf inhibitors.
  • NSCLC non-small cell lung cancer
  • Class I BRAF mutants (V600E, V600K, V600D) have high kinase activity, are Ras and dimerization independent, and are sensitive to vemuragenib.
  • Class II BRAF mutants has high to intermediate kinase activity, are Ras- independent and dimerization dependent, and are insensitive to vemurafenib.
  • Class III BRAF mutatns have lot to no kinase activity, are Ras and dimerization dependent, and are insensitive to vemurafenib.
  • the present disclosure describes bifunctional compounds which function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation, and methods of using the same.
  • the present disclosure provides bifunctional or proteolysis targeting chimeric (PROTAC) compounds, which find utility as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein.
  • An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of targeted polypeptides from virtually any protein class or family.
  • the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer (e.g., renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma), cardiofaciocutaneous syndrome, neurofibromatosis type 1, Costello syndrome, Noonan Syndrome, LEOPARD (Lentigo, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retarded growth, Deafness) syndrome.
  • cancer e.g., renal cell carcinoma, pancreatic cancer, colorectal cancer, lung cancer, ovarian cancer, thyroid cancer, pilocytic astrocytoma, prostate cancer, gastric cancer, hepatocellular carcinoma, and melanoma
  • cardiofaciocutaneous syndrome e.g., neurofibromato
  • the disclosure provides bifunctional or PROTAC compounds, which comprise an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubquitin ligase or “ULM” group), and a moiety that binds a target protein (i.e., a protein/polypeptide targeting ligand or“PTM” group) such that the target protein/polypeptide is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein.
  • E3 ubiquitin ligase binding moiety i.e., a ligand for an E3 ubquitin ligase or “ULM” group
  • a target protein i.e., a protein/polypeptide targeting ligand or“PTM” group
  • the ULM ubiquitination ligase modulator
  • VHL Von Hippel-Lindau E3 ubiquitin ligase binding moiety
  • CLM cereblon E3 ubiquitin ligase binding moiety
  • MDM2 mouse double miniute 2 homolog
  • E3 ubiquitin ligase binding moiety MLM
  • IAP IAP E3 ubiquitin ligase binding moiety
  • the structure of the bifunctional compound can be depicted as: [0017]
  • the respective positions of the PTM and ULM moieties e.g., VLM, CLM, MLM or ILM
  • the bifunctional compounds as described herein can be synthesized such that the number and position of the respective functional moieties can be varied as desired.
  • the bifunctional compound further comprises a chemical linker (“L”).
  • L a chemical linker
  • PTM is a protein/polypeptide targeting moiety
  • L is a linker, e.g., a bond or a chemical group coupling PTM to ULM
  • ULM is a IAP E3 ubiquitin ligase binding moiety, or a Von Hippel-Lindau E3 ubiquitin ligase (VHL) binding moiety (VLM), or a cereblon E3 ubiquitin ligase binding moiety (CLM), or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase binding moiety (MLM).
  • VHL Von Hippel-Lindau E3 ubiquitin ligase
  • CLM cereblon E3 ubiquitin ligase binding moiety
  • MDM2 mouse double minute 2 homolog
  • the structure of the bifunctional compound can be depicted as: wherein: PTM is a protein/polypeptide targeting moiety;“L” is a linker (e.g. a bond or a chemical linker group) coupling the PTM and at least one of VLM, CLM, MLM, ILM, or a combination thereof; VLM is Von Hippel-Lindau E3 ubiquitin ligase binding moiety that binds to VHL E3 ligase; CLM is cereblon E3 ubiquitin ligase binding moiety that binds to cereblon; MLM is an MDM2 E3 ubiquitin ligase binding moiety; and ILM is a IAP binding moiety which binds to IAP.
  • PTM is a protein/polypeptide targeting moiety
  • “L” is a linker (e.g. a bond or a chemical linker group) coupling the PTM and at least one of VLM, CLM, MLM, ILM,
  • the ILM is an AVPI tetrapeptide fragment.
  • the ILM of the bifunctional compound comprises the amino acids alanine (A), valine (V), proline (P), and isoleucine (I) or their unnatural mimetics, respectively.
  • the amino acids of the AVPI tetrapeptide fragment are connected to each other thorugh amide bonds (i.e.,–C(O)NH– or–NHC(O)–).
  • the compounds as described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers or a combination thereof.
  • ILM comprises chemical moieties such as those described herein.
  • VLM can be hydroxyproline or a derivative thereof.
  • other contemplated VLMs are included in U.S. Patent Application Publication No. 2014/03022523, which as discussed above, is incorporated herein in its entirety.
  • the CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide.
  • the chemical group is a phthalimido group, or an analog or derivative thereof.
  • the CLM is thalidomide, lenalidomide, pomalidomide, analogs thereof, isosteres thereof, or derivatives thereof.
  • Other contemplated CLMs are described in U.S. Patent Application Publication No. 2015/0291562, which is incorporated herein in its entirety.
  • MLM can be nutlin or a derivative thereof.
  • other contemplated MLMs are included in U.S. Patent Application 15/206,497 filed 11 July 2016, which as discussed above, is incorporated herein in its entirety.
  • the MLM of the bifunctional compound comprises chemical moieties such as substituted imidazolines, substituted spiro-indolinones, substituted pyrrolidines, substituted piperidinones, substituted morpholinones, substituted pyrrolopyrimidines, substituted imidazolopyridines, substituted thiazoloimidazoline, substituted pyrrolopyrrolidinones, and substituted isoquinolinones.
  • the MLM comprises the core structures mentioned above with adjacent bis-aryl substitutions positioned as cis- or trans-configurations.
  • “L” is a bond.
  • the linker“L” is a connector with a linear non-hydrogen atom number in the range of 1 to 20.
  • the connector“L” can contain, but not limited to the functional groups such as ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone.
  • the linker can contain aromatic, heteroaromatic, cyclic, bicyclic and tricyclic moieties. Substitution with halogen, such as Cl, F, Br and I can be included in the linker. In the case of fluorine substitution, single or multiple fluorines can be included.
  • VLM is a derivative of trans-3-hydroxyproline, where both nitrogen and carboxylic acid in trans-3-hydroxyproline are functionalized as amides.
  • CLM is a derivative of piperidine-2,6-dione, where piperidine-2,6-dione can be substituted at the 3-position, and the 3-substitution can be bicyclic hetero-aromatics with the linkage as C-N bond or C-C bond.
  • Examples of CLM can be, but not limited to, pomalidomide, lenalidomide and thalidomide and their derivatives.
  • the description provides therapeutic compositions comprising an effective amount of a compound as described herein or salt form thereof, and a pharmaceutically acceptable carrier.
  • the therapeutic compositions modulate protein degradation in a patient or subject, for example, an animal such as a human, and can be used for treating or ameliorating disease states or conditions which are modulated through the degraded protein.
  • the therapeutic compositions as described herein may be used to effectuate the degradation of proteins of interest for the treatment or amelioration of a disease, e.g., cancer.
  • the present disclosure provides a method of ubiquitinating/degrading a target protein in a cell.
  • the method comprises administering a bifunctional compound as described herein comprising an ILM and a PTM, a PTM and a VLM, or a PTM and a CLM, or a PTM and a MLM, preferably linked through a linker moiety, as otherwise described herein, wherein the VLM/ILM/CLM/MLM is coupled to the PTM through a linker to target protein that binds to PTM for degradation.
  • the PTM can be coupled to VLM or CLM or MLM or ILM through a linker to target a protein or polypeptide for degradation.
  • Degradation of the target protein will occur when the target protein is placed in proximity to the E3 ubiquitin ligase, thus resulting in degradation/inhibition of the effects of the target protein and the control of protein levels.
  • the control of protein levels afforded by the present disclosure provides treatment of a disease state or condition, which is modulated through the target protein by lowering the level of that protein in the cells of a patient.
  • the description provides methods for treating or ameliorating a disease, disorder or symptom thereof in a subject or a patient, e.g., an animal such as a human, comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound as described herein or salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective for treating or ameliorating the disease or disorder or symptom thereof in the subject.
  • a composition comprising an effective amount, e.g., a therapeutically effective amount, of a compound as described herein or salt form thereof, and a pharmaceutically acceptable carrier, wherein the composition is effective for treating or ameliorating the disease or disorder or symptom thereof in the subject.
  • the description provides methods for identifying the effects of the degradation of proteins of interest in a biological system using compounds according to the present disclosure.
  • Exemplary bifunctional compound comprises a protein targeting moiety (PTM; darkly shaded rectangle), a ubiquitin ligase binding moiety (ULM; lightly shaded triangle), and optionally a linker moiety (L; black line) coupling or tethering the PTM to the ULM.
  • PTM protein targeting moiety
  • ULM ubiquitin ligase binding moiety
  • L linker moiety
  • B Illustrates the functional use of the bifunctional compounds as described herein. Briefly, the ULM recognizes and binds to a specific E3 ubiquitin ligase, and the PTM binds and recruits a target protein bringing it into close proximity to the E3 ubiquitin ligase.
  • the E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein, and either alone or via the E2 protein catalyzes attachment of ubiquitin (dark circles) to a lysine on the target protein via an isopeptide bond.
  • the poly-ubiquitinated protein (far right) is then targeted for degradation by the proteosomal machinery of the cell.
  • Figure 2A Table 1A. Examplary protein targeting moieties and compounds of the present disclosure.
  • Figure 2B Table 1B. Exemplary protein targeting moieties and compounds of the present disclosure.
  • FIG. 1C Examplary protein targeting moieties and compounds of the present disclosure.
  • Figure 2D Table 1D. Examplary protein targeting moieties and compounds of the present disclosure.
  • Figure 3A Table 2A. Data of exemplary protein targeting moieties and compounds of the present disclosure.
  • Figure 3B Table 2B. Data of exemplary protein targeting moieties and compounds of the present disclosure.
  • Figure 3C Table 2C. Data of exemplary protein targeting moieties and compounds of the present disclosure.
  • Figure 3D Table 2D. Data of exemplary protein targeting moieties and compounds of the present disclosure.
  • FIG. 1 Exemplary bifunctional compound of the present disclosure induces mutant selective degradation of BRAF.
  • Figure 6A, 6B, and 6C Exemplary bifunctional compound of the present disclosure induces mutant BRAF degradation, inhibit cell proliferation, and suppresses MAPK signaling, while sparing wild-type BRAF.
  • Figure 7 Exemplary bifunctional compound of the present disclosure induces degradation of vemurafenib resistant mutant p61.
  • Figure 8A and 8B Exemplary bifunctional compound of the present disclosure induces degradation of mutant BRAF in vivo (a) and decreases tumor volume (B).
  • Figure 9A and 9B What mechanism underlies the selectivity of the exemplary bifunctional compound.
  • compositions and methods that relate to the surprising and unexpected discovery that an E3 ubiquitin ligase protein (e.g., inhibitors of apoptosis proteins (IAP), a Von Hippel-Lindau E3 ubiquitin ligase (VHL), a cereblon E3 ubiquitin ligase, or a mouse double minute 2 homolog (MDM2) E3 ubiquitin ligase) ubiquitinates a target protein once it and the target protein are placed in proximity by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein.
  • IAP inhibitors of apoptosis proteins
  • VHL Von Hippel-Lindau E3 ubiquitin ligase
  • MDM2 mouse double minute 2 homolog
  • the present disclosure provides such compounds and compositions comprising an E3 ubiquintin ligase binding moiety (“ULM”) coupled to a protein target binding moiety (“PTM”), which result in the ubiquitination of a chosen target protein, which leads to degradation of the target protein by the proteasome (see Figure 1).
  • ULM E3 ubiquintin ligase binding moiety
  • PTM protein target binding moiety
  • the present disclosure also provides a library of compositions and the use thereof.
  • the present disclosure provides compounds which comprise a ligand, e.g., a small molecule ligand (i.e., having a molecular weight of below 2,000, 1,000, 500, or 200 Daltons), which is capable of binding to a ubiquitin ligase, such as IAP, VHL, MDM2, or cereblon.
  • a ligand e.g., a small molecule ligand (i.e., having a molecular weight of below 2,000, 1,000, 500, or 200 Daltons)
  • a ubiquitin ligase such as IAP, VHL, MDM2, or cereblon.
  • the compounds also comprise a moiety that is capable of binding to target protein, in such a way that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and/or inhibition) of that protein.
  • Small molecule can mean, in addition to the above, that the molecule is non-peptidyl, that is, it is not generally considered a peptide, e.g., comprises fewer than 4, 3, or 2 amino acids.
  • the PTM, ULM or PROTAC molecule can be a small molecule.
  • a reference to "A and/or B", when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • co-administration and “co-administering” or“combination therapy” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time.
  • one or more of the present compounds described herein are coadministered in combination with at least one additional bioactive agent, especially including an anticancer agent.
  • the co-administration of compounds results in synergistic activity and/or therapy, including anticancer activity.
  • Deuterated small molecules contemplated are those in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by deuterium.
  • the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds.
  • the term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder. When the bond is shown, both a double bond and single bond are represented or understood within the context of the compound shown and well-known rules for valence interactions.
  • ubiquitin ligase refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein, targeting the substrate protein for degradation.
  • IAP an E3 ubiquitin ligase protein that alone or in combination with an E2 ubiquitin- conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein, and subsequently targets the specific protein substrates for degradation by the proteasome.
  • E3 ubiquitin ligase alone or in complex with an E2 ubiquitin conjugating enzyme is responsible for the transfer of ubiquitin to targeted proteins.
  • the ubiquitin ligase is involved in polyubiquitination such that a second ubiquitin is attached to the first; a third is attached to the second, and so forth.
  • Polyubiquitination marks proteins for degradation by the proteasome.
  • Mono- ubiquitinated proteins are not targeted to the proteasome for degradation, but may instead be altered in their cellular location or function, for example, via binding other proteins that have domains capable of binding ubiquitin.
  • different lysines on ubiquitin can be targeted by an E3 to make chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to make polyubiquitin, which is recognized by the proteasome.
  • patient or“subject” is used throughout the specification to describe an animal, preferably a human or a domesticated animal, to whom treatment, including prophylactic treatment, with the compositions according to the present disclosure is provided.
  • patient refers to that specific animal, including a domesticated animal such as a dog or cat or a farm animal such as a horse, cow, sheep, etc.
  • patient refers to a human patient unless otherwise stated or implied from the context of the use of the term.
  • the term“effective” is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an intended result.
  • the term effective subsumes all other effective amount or effective concentration terms, which are otherwise described or used in the present application.
  • the description provides compounds comprising an E3 ubiquitin ligase binding moiety (“ULM”) that is an IAP E3 ubiquitin ligase binding moiety (an“ILM”), a cereblon E3 ubiquitin ligase binding moiety (a“CLM”), a Von Hippel-Lindae E3 ubiquitin ligase (VHL) binding moiety (VLM), and/or a mouse double minute 2 homologue (MDM2) E3 ubiquitin ligase binding moiety (MLM).
  • the ULM is coupled to a target protein binding moiety (PTM) via a chemical linker (L) according to the structure:
  • L is a bond or a chemical linker group
  • ULM is a E3 ubiquitin ligase binding moiety
  • PTM is a target protein binding moiety.
  • ULM is inclusive of all ULMs, including those that bind IAP (i.e., ILMs), MDM2 (i.e., MLM), cereblon (i.e., CLM), and VHL (i.e., VLM).
  • ILM is inclusive of all possible IAP E3 ubiquitin ligase binding moieties
  • MLM is inclusive of all possible MDM2 E3 ubiquitin ligase binding moieties
  • VLM is inclusive of all possible VHL binding moieties
  • CLM is inclusive of all cereblon binding moieties.
  • the present disclosure provides bifunctional or multifunctional compounds (e.g., PROTACs) useful for regulating protein activity by inducing the degradation of a target protein.
  • the compound comprises an ILM or a VLM or a CLM or a MLM coupled, e.g., linked covalently, directly or indirectly, to a moiety that binds a target protein (i.e., a protein targeting moiety or a“PTM”).
  • the ILM/VLM/CLM/MLM and PTM are joined or coupled via a chemical linker (L).
  • the ILM binds the IAP E3 ubiquitin ligase
  • the VLM binds VHL
  • CLM binds the cereblon E3 ubiquitin ligase
  • MLM binds the MDM2 E3 ubiquitin ligase
  • the PTM recognizes a target protein and the interaction of the respective moieties with their targets facilitates the degradation of the target protein by placing the target protein in proximity to the ubiquitin ligase protein.
  • An exemplary bifunctional compound can be depicted as:
  • the bifunctional compound further comprises a chemical linker (“L”).
  • L a chemical linker
  • the PTM is a protein/polypeptide targeting moiety
  • the L is a chemical linker
  • the ILM is a IAP E3 ubiquitin ligase binding moiety
  • the CLM is a cereblon E3 ubiquitin ligase binding moiety
  • the VLM is a VHL binding moiety
  • the MLM is a MDM2 E3 ubiquitin ligase binding moiety.
  • the ULM (e.g., a ILM, a CLM, a VLM, or a MLM) shows activity or binds to the E3 ubiquitin ligase (e.g., IAP E3 ubiquitin ligase, cereblon E3 ubiquitin ligase, VHL, or MDM2 E3 ubiquitin ligase) with an IC50 of less than about 200 ⁇ M.
  • the IC50 can be determined according to any method known in the art, e.g., a fluorescent polarization assay.
  • the bifunctional compounds described herein demonstrate an activity with an IC50 of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 ⁇ M, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.
  • the compounds as described herein comprise multiple PTMs (targeting the same or different protein targets), multiple ULMs, one or more ULMs (i.e., moieties that bind specifically to multiple/different E3 ubiquitin ligase, e.g., VHL, IAP, cereblon, and/or MDM2) or a combination thereof.
  • the PTMs and ULMs e.g., ILM, VLM, CLM, and/or MLM
  • the ULMs can be for the same E3 ubiquintin ligase or each respective ULM can bind specifically to a different E3 ubiquitin ligase.
  • the PTMs can bind the same target protein or each respective PTM can bind specifically to a different target protein.
  • the ULMs are identical.
  • the compound comprising a plurality of ULMs e.g., ULM, ULM’, etc.
  • the compound comprising a plurality of ULMs further comprises multiple PTMs.
  • the PTMs are the same or, optionally, different.
  • the respective PTMs may bind the same protein target or bind specifically to a different protein target.
  • the compound may comprise a plurality of ULMs and/or a plurality of ULM’s.
  • the compound comprising at least two different ULMs, a plurality of ULMs, and/or a plurality of ULM’s further comprises at least one PTM coupled to a ULM or a ULM’ directly or via a chemical linker or both.
  • a compound comprising at least two different ILMs can further comprise multiple PTMs.
  • the PTMs are the same or, optionally, different.
  • wherein the PTMs are different the respective PTMs may bind the same protein target or bind specifically to a different protein target.
  • the PTM itself is a ULM (or ULM’), such as an ILM, a VLM, a CLM, a MLM, an ILM’, a VLM’, a CLM’, and/or a MLM’.
  • the description provides the compounds as described herein including their enantiomers, diastereomers, solvates and polymorphs, including pharmaceutically acceptable salt forms thereof, e.g., acid and base salt forms.
  • alkyl shall mean within its context a linear, branch-chained or cyclic fully saturated hydrocarbon radical or alkyl group, preferably a C1-C10, more preferably a C1-C6, alternatively a C 1 -C 3 alkyl group, which may be optionally substituted.
  • alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopen- tylethyl, cyclohexylethyl and cyclohexyl, among others.
  • the alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I).
  • compounds according to the present disclosure which may be used to covalently bind to dehalogenase enzymes.
  • These compounds generally contain a side chain (often linked through a polyethylene glycol group) which terminates in an alkyl group which has a halogen substituent (often chlorine or bromine) on its distal end which results in covalent binding of the compound containing such a moiety to the protein.
  • Alkynyl refers to linear, branch-chained or cyclic C 2 -C 10 (preferably C 2 -C 6 ) hydrocarbon radicals containing at least one CoC bond.
  • alkylene when used, refers to a–(CH2)n- group (n is an integer generally from 0-6), which may be optionally substituted.
  • the alkylene group preferably is substituted on one or more of the methylene groups with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halo groups, preferably from 1 to 3 halo groups or one or two hydroxyl groups, O-(C 1 -C 6 alkyl) groups or amino acid sidechains as otherwise disclosed herein.
  • an alkylene group may be substituted with a urethane or alkoxy group (or other group) which is further substituted with a polyethylene glycol chain (of from 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to which is substituted (preferably, but not exclusively on the distal end of the polyethylene glycol chain) an alkyl chain substituted with a single halogen group, preferably a chlorine group.
  • a polyethylene glycol chain of from 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units
  • the alkylene (often, a methylene) group may be substituted with an amino acid sidechain group such as a sidechain group of a natural or unnatural amino acid, for example, alanine, b-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.
  • an amino acid sidechain group such as a sidechain group of a natural or unnatural amino acid, for example, alanine, b-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methion
  • the term“unsubstituted” shall mean substituted only with hydrogen atoms.
  • a range of carbon atoms which includes C0 means that carbon is absent and is replaced with H.
  • a range of carbon atoms which is C 0 -C 6 includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for C 0 , H stands in place of carbon.
  • substituted or“optionally substituted” shall mean independently (i.e., where more than substituent occurs, each substituent is independent of another substituent) one or more substituents (independently up to five substitutents, preferably up to three substituents, often 1 or 2 substituents on a moiety in a compound according to the present disclosure and may include substituents which themselves may be further substituted) at a carbon (or nitrogen) position anywhere on a molecule within context, and includes as substituents hydroxyl, thiol, carboxyl, cyano (CoN), nitro (NO 2 ), halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl, especially a methyl group such as a trifluoromethyl), an alkyl group (preferably, C1-C10 , more preferably, C1-C6), aryl (especially phenyl and substituted phenyl for example benzyl or benzoyl), alkoxy group (
  • Substituents according to the present disclosure may include, for example–SiR1R2R3 groups where each of R1 and R2 is as otherwise described herein and R3 is H or a C1-C6 alkyl group, preferably R 1 , R 2 , R 3 in this context is a C 1 -C 3 alkyl group (including an isopropyl or t- butyl group).
  • Each of the above-described groups may be linked directly to the substituted moiety or alternatively, the substituent may be linked to the substituted moiety (preferably in the case of an aryl or heteraryl moiety) through an optionally substituted -(CH 2 ) m - or alternatively an optionally substituted -(OCH2)m-, -(OCH2CH2)m- or -(CH2CH2O)m- group, which may be substituted with any one or more of the above-described substituents.
  • Alkylene groups -(CH2)m- or -(CH 2 ) n - groups or other chains such as ethylene glycol chains, as identified above, may be substituted anywhere on the chain.
  • Preferred substitutents on alkylene groups include halogen or C 1 -C 6 (preferably C 1 -C 3 ) alkyl groups, which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or a sideshain of an amino acid as otherwise described herein and optionally substituted amide (preferably carboxamide substituted as described above) or urethane groups (often with one or two C0-C6 alkyl substitutents, which group(s) may be further substituted).
  • halogen or C 1 -C 6 (preferably C 1 -C 3 ) alkyl groups which may be optionally substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or a sideshain of an amino acid as otherwise described herein and optionally substituted amide (preferably carboxamide substituted as described above) or ure
  • the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C 1 -C 6 alkyl groups, preferably C 1 -C 4 alkyl group, most often methyl or O- methyl groups or a sidechain of an amino acid as otherwise described herein.
  • a moiety in a molecule may be optionally substituted with up to five substituents, preferably up to three substituents. Most often, in the present disclosure moieties which are substituted are substituted with one or two substituents.
  • substituted shall also mean within its context of use C1-C6 alkyl, C1-C6 alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxy, C 1 -C 6 ester (oxyester or carbonylester), C 1 -C 6 keto, urethane -O-C(O)-NR1R2 or–N(R1)-C(O)-O-R1, nitro, cyano and amine (especially including a C1-C6 alkylene-NR1R2, a mono- or di- C1-C6 alkyl substituted amines which may be optionally substituted with one or two hydroxyl groups).
  • R1 and R2 are each, within context, H or a C1-C6 alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine).
  • the term“substituted” shall also mean, within the chemical context of the compound defined and substituent used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein.
  • Alkylene groups may also be substituted as otherwise disclosed herein, preferably with optionally substituted C 1 -C 6 alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl is preferred, thus providing a chiral center), a sidechain of an amino acid group as otherwise described herein, an amido group as described hereinabove, or a urethane group O-C(O)-NR1R2 group where R 1 and R 2 are as otherwise described herein, although numerous other groups may also be used as substituents.
  • Various optionally substituted moieties may be substituted with 3 or more substituents, preferably no more than 3 substituents and preferably with 1 or 2 substituents.
  • aryl or“aromatic”, in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or condensed rings (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound to the compound according to the present disclosure at any available stable position on the ring(s) or as otherwise indicated in the chemical structure presented.
  • aryl groups in context, may include heterocyclic aromatic ring systems,“heteroaryl” groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic) such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be optionally substituted as described above.
  • heterocyclic aromatic ring systems “heteroaryl” groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic) such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as ind
  • heteroaryl groups include nitrogen-containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline
  • substituted aryl refers to an aromatic carbocyclic group comprised of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic, wherein the ring(s) are substituted with one or more substituents.
  • an aryl group can comprise a substituent(s) selected from: -(CH2)nOH, -(CH2)n-O-(C1-C6)alkyl, -(CH2)n-O-(CH2)n- (C1-C6)alkyl, -(CH2)n-C(O)(C0-C6) alkyl, -(CH2)n-C(O)O(C0-C6)alkyl, -(CH2)n-OC(O)(C0- C 6 )alkyl, amine, mono- or di-(C 1 -C 6 alkyl) amine wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halo (preferably F, Cl) groups, OH, COOH, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN group (each of which may be substituted in ortho-, meta- and/or para- positions of the pheny
  • Carboxyl denotes the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl , whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein.
  • heteroaryl or“hetaryl” can mean but is in no way limited to an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2, 3 or 4-azaindolizine) an optionally substituted benzimidazole, benzodiazole, benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably methyl substituted), an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole (preferably methyl and/or thiol substituted), an optionally substituted quinoline (including di
  • S c is CHR SS , NR URE , or O;
  • R HET is H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-Ra where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
  • R SS is H, CN, NO2, halo (preferably F or Cl), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O-(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups);
  • R URE is H, a C 1 -C 6 alkyl (preferably H or C 1 -C 3 alkyl) or a–C(O)(C 1 -C 6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted, and
  • Y C is N or C-R YC , where R YC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C 1 -C 6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-R a where R a is H or a C 1 -C 6 alkyl group (preferably C 1 -C 3 alkyl).
  • aralkyl and“heteroarylalkyl” refer to groups that comprise both aryl or, respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems according to the above definitions.
  • arylalkyl refers to an aryl group as defined above appended to an alkyl group defined above.
  • the arylalkyl group is attached to the parent moiety through an alkyl group wherein the alkyl group is one to six carbon atoms.
  • the aryl group in the arylalkyl group may be substituted as defined above.
  • Heterocycle refers to a cyclic group which contains at least one heteroatom, e.g., N, O or S, and may be aromatic (heteroaryl) or non-aromatic.
  • heteroaryl moieties are subsumed under the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described hereinabove.
  • heterocyclics include: azetidinyl, benzimidazolyl, 1,4- benzodioxanyl, 1,3- benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl,
  • Heterocyclic groups can be optionally substituted with a member selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl,—SO-substituted alkyl, —SO
  • heterocyclic groups can have a single ring or multiple condensed rings.
  • nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofur
  • heterocyclic also includes bicyclic groups in which any of the heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, and the like).
  • cycloalkyl can mean but is in no way limited to univalent groups derived from monocyclic or polycyclic alkyl groups or cycloalkanes, as defnied herein, e.g., saturated monocyclic hydrocarbon groups having from three to twenty carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • substituted cycloalkyl can mean but is in no way limited to a monocyclic or polycyclic alkyl group and being substituted by one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent groups have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Heterocycloalkyl refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P.
  • Substituted heterocycloalkyl refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P and the group is containing one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • hydrocarbyl shall mean a compound which contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.
  • lower alkyl refers to methyl, ethyl or propyl
  • lower alkoxy refers to methoxy, ethoxy or propoxy.
  • the W, X, Y, Z, G, G’, R, R’, R’’, Q1-Q4, and A can independently be covalently coupled to a linker and/or a linker to which is attached one or more PTM, ULM, ILM or ILM’ groups.
  • Neo-imide Compounds [0106] In one aspect the description provides compounds useful for binding and/or inhibiting cereblon. In certain embodiments, the compound is selected from the group consisting of chemical structures:
  • W3 is selected from C or N;
  • X of Formulas (a) through (e) is independently selected from the group absent, O, S and CH2;
  • Z of Formulas (a) through (e) is independently selected from the group absent, O, S or CH2 except that both X and Z cannot be absent or CH 2;
  • n" is an integer from 8 to 35 (e.g., 8, 9, 10, 11, 12, 13, 14, 15, 16, 17. 18. 19. 20. 21. 22. 23 24.25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35);
  • Q1– Q4 of Formulas (a) through (e) each independently represent a carbon C substituted with a group independently selected from H, R, N or N-oxide;
  • a of Formulas (a) through (e) is independently selected from the group H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;
  • R of Formulas (a) through (e) comprises, but is not limited to: H, -CONR’R”, -OR’, -NR’R”, -SR’, -SO 2 R’, -SO 2 NR’R”, -CR’R”-, -CR’NR’R”-, (-CR’O) n’ R”, halogen, optionally substituted-aryl (e.g., an optionally substituted C5-C7 aryl), optionally substituted alkyl- aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted C1-C6 alkyl, an optionally substituted C5-C7 aryl, or combinations thereof), optionally substituted- heteroaryl (e.g., an optionally substituted C5-C7 heteroaryl), unsubstituted or substituted linear or branched alkyl (e.g., a C1-C6 linear or branched alkyl optionally substituted with one
  • aryl optionally substituted (e.g., optionally substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3- C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted
  • each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6;
  • n and n’ of Formulas (a) through (e) are each individually an integer from 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);
  • the CLM comprises a chemical structure selected from the group:
  • cycloalkyl e.g., optionally substituted 3-6 member cycloalkyl, optionally substituted cyclopropyl group or optionally substituted cyclobutyl group
  • heterocycloalkyl e.g., an optionally substituted 3-6 member heterocyloalkyl
  • W 3 is selected from C or N;
  • X of Formulas (a) through (e) is independently selected from the group absent, O, S and CH 2 ;
  • Z of Formulas (a) through (e) is independently selected from the group absent, O, S, andCH 2 except that both X and Z cannot be absent or CH2;
  • Q1– Q4 of Formulas (a) through (e) each independently represent a carbon C substituted with a group independently selected from H, R, N or N-oxide;
  • a of Formulas (a) through (e) is independently selected from the group H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F;
  • R of Formulas (a) through (e) comprises, but is not limited to: H, -CONR’R”, -OR’, -NR’R”, -SR’, -SO2R’, -SO2NR’R”, -CR’R”-, -CR’NR’R”-, (-CR’O)n’R”, halogen, optionally substituted heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl), optionally substituted–aryl (e.g., an optionally substituted C5-C7 aryl), optionally substituted alkyl- aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted C1-C6 alkyl, an optionally substituted C5-C7 aryl, or combinations thereof), optional
  • optionally substituted optionally substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted
  • halogen alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substitutedcycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted-cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted-heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl), - P(O)(OR’)R”, -P(O)R’R”, -OP(O)(OR’)R”, -OP(O)R’R”, -Cl, -F, -Br, -I, -CF3, -CN, - NR’SO 2 NR’R”, -NR’
  • each of x, y, and z are independently 0, 1, 2, 3, 4, 5, or 6;
  • n and n’ of Formulas (a) through (e) are each individually an integer from 1-10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);
  • Formulas (a) through (e) represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific
  • the CLM or ULM comprises a chemical structure selected from the group:
  • a of Formula (g) is independently selected from a H, methyl, alkyl (e.g., a or C1-C6 alkyl (linear, branched, optionally substituted));
  • R of Formula (g) is independently selected from a H,, OH,, NH 2 , halogen, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), optionally substituted C1-C6 alkoxy, optionally substituted-cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted-heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl),optionally substituted-alkyl-aryl (e.g., an– alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), optionally substituted aryl (e.g., C5-C7 aryl), amine, amide, or carboxy);
  • optionally substituted linear or branched alkyl e.g., optionally substituted
  • n of Formulas (g) represent an integer from 1 to 4 (e.g., 1, 2, 3, or 4), wherein at least one R (e.g., at least one of OH, NH2, halogen, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., an– alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy) is modified to be covalently joined to a PTM, a chemical linker group (L), a ULM, CLM (or CLM’) or combination thereof; and of Formula (g) represents a bond that may be stereospecific ((R) or (S)) or non- stereospecific.
  • R e.g., at least one of OH, NH2, halogen, C1-C6 alkyl, C
  • the W, X, Y, Z, G, G’, R, R’, R’’, Q1- Q4, and Aof Formulas (a) through (g) [e.g., (a1), (b), (c), (d1), (e), (f), (a2), (d2), (a3), (a4), and (g)] can independently be covalently coupled to a linker and/or a linker to which is attached one or more PTM, ULM, CLM or CLM’ groups.
  • the CLM comprises from 1 to 4 R groups on Q1, Q2, Q3, Q4, or a combination, wherein each R is an independently selected functional groups or atoms, for example, OH, halogen, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted-cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl), optionally substituted- heterocyclyl (e.g., optionally substituted C3-C7 heterocyclyl), -alkyl-aryl (e.g., an–alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, cyano, or carboxy, and optionally, one of which is modified to be covalently joined to a PTM, a chemical linker group
  • the CLM is represented by the following structures with the dashed lines indicating linker attachment points:
  • CLMs include those shown below as well as those“hybrid” molecules that arise from the combination of 1 or more of the different features shown in the molecules below.
  • the CLM comprises a chemical structure selected from the group:
  • Q1, Q2, Q3, Q4, Q5 are each independently represent a carbon C or N substituted with a group independently selected from H, R’, N or N-oxide;
  • R 3 is selected from H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxyl);
  • R 4 is selected from H, alkyl, substituted alkyl
  • n 0-4;
  • the CLM is covalently joined to a PTM, a chemical linker group (L), a ULM, CLM (or CLM’) or combination thereof.
  • the CLM or CLM’ is covalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM’, or a combination thereof via an R group (such as, R, R 1 , R 2 , R 3 , R 4 or R’), W, X, or a Q group (such as, Q1, Q2, Q3, Q4, or Q5) of Formulas (h) through (ab).
  • R group such as, R, R 1 , R 2 , R 3 , R 4 or R’
  • W X
  • Q group such as, Q1, Q2, Q3, Q4, or Q5
  • the CLM or CLM’ is covalently joined to a PTM, a chemical linker group (L), a ULM, a CLM, a CLM’, or a combination thereof via W, X, R, R 1 , R 2 , R 3 , R 4 , R 5 , R’, Q1, Q2, Q3, Q4, and Q5 of Formulas (h) through (ab).
  • the W, X, R 1 , R 2 , R 3 , R 4 , R’, Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 of Formulas (h) through (ab) can independently be covalently coupled to a linker and/or a linker to which is attached to one or more PTM, ULM, ULM’, CLM or CLM’ groups.
  • CLMs include those shown below as well as“hybrid” molecules or compounds that arise from combining 1 or more featrues of the following compounds:
  • R 1 is selected from the group absent, H, CH, CN, C1-C3 alkyl;
  • R 2 is H or a C1-C3 alkyl
  • R 3 is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;
  • R 4 is methyl or ethyl
  • R 5 is H or halo
  • R 6 is H or halo
  • R of the CLM is H;
  • R’ is H or an attachment point for a PTM, a PTM’, a chemical linker group (L), a ULM, a CLM, a CLM’,
  • Q1 and Q2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl;
  • n is an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
  • R comprises : H, -CONR’R”, -OR’, -NR’R”, -SR’, -SO2R’, -SO2NR’R”, -CR’R”-, - CR’NR’R”-, (-CR’O) n’ R”, halogen, optionally substituted heterocyclyl, optionally substituted -aryl (e.g., an optionally substituted C5-C7 aryl), optionally substituted alkyl- aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted C1-C6 alkyl, an optionally substituted C5-C7 aryl, or combinations thereof), optionallys ubstituted heteroaryl (e.g., an optionally substituted C5-C7 aryl), -optionally substituted linear or branched alkyl (e.g., a C1-C6 linear or branched alkyl optionally substituted with one or more
  • optionally substituted e.g., optionally substituted with one or more halogen, alkyl, haloalky, fluoroalkyl, cycloalkyl (e.g., a C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted
  • cycloalkyl e.g., a C3-C6 cycloalkyl
  • aryl e.g., C5-C7 aryl
  • At least one R of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , or a combination thereof e.g., at least one of OH, NH2, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., an–alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy) is modified to be covalently joined to a PTM, a chemical linker group (L), a ULM, a CLM’ (e.g., CLM’ is an additional CLM that has the same or different structure as a first CLM), or a combination thereof.
  • the W, R 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 , and R of Formulas (ac) through (an) can independently be covalently coupled to a linker and/or a linker to which is attached one or more PTM, ULM, ULM’, CLM or CLM’ groups.
  • the R 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 , and R of Formulas (ac) through (an) can independently be covalently coupled to a linker and/or a linker to which is attached one or more PTM, ULM, ULM’, CLM or CLM’ groups.
  • the Q1, Q2, Q3, Q4, and R of Formulas (ac) through (an) can independently be covalently coupled to a linker and/or a linker to which is attached one or more PTM, ULM, ULM’, CLM or CLM’ groups.
  • R of Formulas (ac) through (an) is modified to be covalently joined to the linker group (L), a PTM, a ULM, a second CLM having the same chemical structure as the CLM, a CLM’, a second linker, or any multiple or combination thereof.
  • the CLM is selected from:
  • R’ is a halogen and R 1 is as described in any aspect or embodiment described herein.
  • the CLM can be imides that bind to cereblon E3 ligase.
  • These imides and linker attachment point can be but not limited to the following structures:
  • the ULM is a VLM and comprises a chemical structure of ULM-a:
  • a dashed line indicates the attachment of at least one PTM, another ULM or VLM or MLM or ILM or CLM (i.e., ULM’ or VLM’ or CLM’ or ILM’ or MLM’), or a chemical linker moiety coupling at least one PTM, a ULM’ or a VLM’ or a CLM’ or a ILM’ or a MLM’ to the other end of the linker;
  • R Y3 , R Y4 of Formula ULM-a are each independently selected from the group of H, optionally substituted linear or branched C 1-6 alkyl (e.g., optionally substituted by 1 or more halo), optionally substituted C1-6 alkoxyl (e.g., optionally substituted with 0-3 R P groups);
  • W 3 of Formula ULM-a is selected from the group of an optionally substituted T, an
  • optionally substituted–T-N(R 1a R 1b) X 3 optionally substituted–T-N(R 1a R 1b ), optionally substituted–T-Aryl, an optionally substituted–T-Heteroaryl, an optionally substituted T- biheteroaryl, an optionally substituted–T-Heterocycle, an optionally substituted–T- biheterocycle, an optionally substituted -NR 1 -T-Aryl, an optionally substituted -NR 1 -T- Heteroaryl or an optionally substituted -NR 1 -T-Heterocycle;
  • R 1 , R 1a , R 1b are each independently selected from the group consisting of H, linear or
  • each m’ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
  • W 4 of Formula ULM-a is an optionally substituted -NR 1 -T-Aryl, wherein the aryl group may be optionally substituted with an optionally substituted 5-6 membered heteroaryl, optionally substituted aryl, or optionally substituted alkoxy, an optionally substituted - NR 1 -T-Heteroaryl group or an optionally substituted -NR 1 -T-Heterocycle, wherein -NR 1 is covalently bonded to X 2 and R 1 is H or CH 3 , preferably H; and
  • n is 0 to 6, often 0, 1, 2, or 3, preferably 0 or 1.
  • W 5 is optionally substituted phenyl, an optionally substituted napthyl, or optionally
  • substituted 5-10 membered heteroaryl e.g., W 5 is optionally substituted with one or more [such as 1, 2, 3, 4, or 5] halo, CN, optionally substituted linear or branched C1-C12 alkyl optionally having one or more (e.g., 1, 2, 3, 4 or more) carbon atoms replaced with an oxygen atom, optionally substituted haloalkyl, optionally substituted alkoxy, hydroxy, or optionally substituted haloalkoxy);
  • R 14a, R 14b are each independently selected from the group of H, haloalkyl, optionally
  • each m’ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
  • R 1 is H, linear or branched C 1 -C 6 alkyl group optionally substituted by 1 or more halo or -OH groups;
  • W 6 is an optionally substituted 8-14 membered bicyclic heterocycle (e
  • R 15 is selected from the group of H, halogen, CN, OH, NO 2 , N R 14a R 14b , OR 14a , CONR 14a R 14b , NR14aCOR14b, SO2NR14aR14b, NR14a SO2R14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl.
  • W 5 of Formula ULM-a is selected from the group of an optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl (e.g., W 5 is optionally substituted with one or more [such as 1, 2, 3, 4, or 5] halo, CN, optionally substituted linear or branched C1-C12 alkyl optionally having one or more (e.g., 1, 2, 3, 4 or more) carbon atoms replaced with an oxygen atom, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, or hydroxy),
  • W 5 is optionally substituted with one or more [such as 1, 2, 3, 4, or 5] halo, CN, optionally substituted linear or branched C1-C12 alkyl optionally having one or more (e.g., 1, 2, 3, 4 or more) carbon atoms replaced with an oxygen atom, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted hal
  • R15 of Formula ULM-a is selected from the group of H, halogen, CN, OH, NO2, N
  • R 14a R 14b OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR 14a R 14b , NR 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
  • W 4 substituents for use in the present disclosure also include specifically (and without limitation to the specific compound disclosed) the W 4 substituents which are found in the identified compounds disclosed herein. Each of these W 4 substituents may be used in conjunction with any number of W 3 substituents which are also disclosed herein.
  • ULM-a is optionally substituted by 0-3 R P groups in the pyrrolidine moiety.
  • the W 3 , W 4 of Formula ULM-a can independently be covalently coupled to a linker which is attached one or more PTM groups.
  • dashed line indicates the site of attachment of at least one PTM, another ULM (ULM’) or a chemical linker moiety coupling at least one PTM or a ULM’ or both to ULM.
  • ULM is VHL and is represented by the structure:
  • W 3 of Formula ULM-b is selected from the group of an optionally substituted aryl, optionally
  • R 9 and R 10 of Formula ULM-b are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R9, R10, and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
  • R 11 of Formula ULM-b is selected from the group of an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,
  • R12 of Formula ULM-b is selected from the group of H or optionally substituted alkyl
  • R13 of Formula ULM-b is selected from the group of H, optionally substituted alkyl,
  • optionally substituted alkylcarbonyl optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;
  • R 1 is H, linear or branched C1-C6 alkyl group optionally substituted by 1 or more halo or -OH groups;
  • each m’ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
  • W 5 of Formula ULM-b is selected from the group of an optionally substituted phenyl or an optionally substituted 5-10 membered heteroaryl,
  • R 15 of Formula ULM-b is selected from the group of H, halogen, CN, OH, NO 2 , N R 14a R 14b , OR14a, CONR14aR14b, NR14aCOR14b, SO2NR14aR14b, NR14a SO2R14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
  • each R16 of Formula ULM-b is independently selected from the group of H, CN, halo,
  • optionally substituted alkyl optionally having one or more carbon atoms replaced with an oxygen atom (e.g., optionally substituted with CN or OH), optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
  • o of Formula ULM-b is 0, 1, 2, 3, or 4;
  • R 18 of Formula ULM-b is independently selected from the group of H, halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; and
  • p of Formula ULM-b is 0, 1, 2, 3, or 4, and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM’) or a chemical linker moiety coupling at least one PTM or a ULM’ or both to ULM.
  • R 15 of Formula wherein R 17 is H, halo, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-6 alkyl, optionally substituted C 1- 6alkenyl, and C1-6haloalkyl; and Xa is S or O.
  • R17 of Formula ULM-b is selected from the group methyl, ethyl, isopropyl, and cyclopropyl.
  • R15 of Formula ULM-b is selected from the group consisting of:
  • R 11 of Formula ULM-b is selected from the group consisting of:
  • ULM has a chemical structure selected from the group of:
  • R 1 of Formulas ULM-c, ULM-d, and ULM-e is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; R14a of Formulas ULM-c, ULM-d, and ULM-e is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl,
  • each m’ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
  • R15 of Formulas ULM-c, ULM-d, and ULM-e is selected from the group consisting of H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, cycloalkyl, or cycloheteroalkyl;
  • R3 of Formulas ULM-c, ULM-d, and ULM-e is absent or a bond or an optionally substituted 5 or 6 membered heteroaryl
  • dashed line indicates the site of attachment of at least one PTM, another ULM (ULM’) or a chemical linker moiety coupling at least one PTM or a ULM’ or both to ULM.
  • ULM comprises a group according to the chemical structure:
  • R14a of Formula ULM-f is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, (CH 2 ) m’ OCOCH 2 (CH 2 ) m’ OCH 2 (CH 2 ) m’ CO(CH 2 ) m’ OH, (CH2)m’OCOCH2(CH2)m’CO(CH2)m’OH, or cyclopropyl;
  • each m’ is individually an integer from 1 to 4 (e.g., 1, 2, 3, or 4);
  • R 9 of Formula ULM-f is H
  • R 10 of Formula ULM-f is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • R11 of Formula ULM-f is ;
  • p of Formula ULM-f is 0, 1, 2, 3, or 4;
  • each R18 of Formula ULM-f is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker;
  • R13 of Formula ULM-f is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl,
  • R15 of Formula ULM-f is selected from the group consisting of H, halogen, Cl, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl; optionally substituted cycloheteroalkyl;
  • the dashed line of Formula ULM-f indicates the site of attachment of at least one PTM
  • ULM another ULM (ULM’) or a chemical linker moiety coupling at least one PTM or a ULM’ or both to ULM.
  • the ULM is selected from the following structures:
  • n 0 or 1.
  • the ULM is selected from the following structures:
  • the phenyl ring in ULM-a1 through ULM -a15, ULM -b1 through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 is optionally substituted with fluorine, lower alkyl and alkoxy groups, and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM’) or a chemical linker moiety coupling at least one PTM or a ULM’ or both to ULM-a.
  • the phenyl ring in ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9 can be functionalized as the ester to make it a part of the prodrug.
  • the hydroxyl group on the pyrrolidine ring of ULM-a1 through ULM-a15, ULM-b1 through ULM-b12, ULM-c1 through ULM-c15 and ULM-d1 through ULM-d9, respectively, comprises an ester-linked prodrug moiety.
  • the ULM and where present, ULM’ are each independently a group according to the chemical structure: '
  • R 1’ of ULM-g is an optionally substituted C 1 -C 6 alkyl group, an optionally substituted - (CH2)nOH, an optionally substituted -(CH2)nSH, an optionally substituted (CH2)n-O-(C1- C6)alkyl group, an optionally substituted (CH2)n-WCOCW-(C0-C6)alkyl group containing an epoxide moiety WCOCW where each W is independently H or a C 1 -C 3 alkyl group, an optionally substituted -(CH2)nCOOH, an optionally substituted -(CH2)nC(O)-(C1-C6 alkyl), an optionally substituted -(CH2)nNHC(O)-R1, an optionally substituted -(CH2)nC(O)- NR 1 R 2 , an optionally substituted -(CH 2 ) n OC(O)-NR 1 R 2 , -(CH 2 O) n H, an optionally substituted
  • R 1 and R 2 of ULM-g are each independently H or a C 1 -C 6 alkyl group which may be
  • halogen groups preferably fluorine
  • R S of ULM-g is a C 1 -C 6 alkyl group, an optionally substituted aryl, heteroaryl or heterocycle group or a -(CH 2 ) m NR 1 R 2 group,;
  • X and X’ of ULM-g are each independently C ⁇ O, C ⁇ S, -S(O), S(O)2 , (preferably X and X’ are both C ⁇ O);
  • R 3’ of ULM-g is an optionally substituted alkyl, an optionally substituted–(CH 2 ) n - (O)u(NR1)v(SO2)w-alkyl, an optionally substituted–(CH2)n-C(O)u(NR1)v(SO2)w-NR1NR2N, an optionally substituted–(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -NR 1 C(O)R 1N , an optionally substituted–(CH 2 ) n -C(O) u (NR 1 ) v (SO 2 ) w -C(O)NR 1 R 2 , an optionally substituted–(CH 2 ) n - C(O)u(NR1)v(SO2)w-Aryl, an optionally substituted–(CH2)n-C(O)u(NR1)v(SO2)w- Heteroaryl, an optionally substituted–(CH 2 ) n -
  • R 1N and R 2N of ULM-g are each independently H, C 1 -C 6 alkyl which is optionally substituted with one or two hydroxyl groups and up to three halogen groups or an optionally substituted–(CH2)n-Aryl,–(CH2)n-Heteroaryl or–(CH2)n-Heterocycle group;
  • V of ULM-g is O, S or NR 1 ;
  • R 1 of ULM-g is the same as above;
  • R 1 and R1’ of ULM-g are each independently H or a C1-C3 alkyl group
  • each m’ of ULM-g is independently 0 or 1;
  • each n of ULM-g is independently 0, 1, 2, 3, 4, 5, 6;
  • each n’ of ULM-g is independently 0 or 1;
  • each u of ULM-g is independently 0 or 1;
  • each v of ULM-g is independently 0 or 1;
  • each w of ULM-g is independently 0 or 1;
  • any one or more of R 1’ , R 2’ , R 3’ , X and X’ of ULM-g is optionally modified to be covalently bonded to the PTM group through a linker group when PTM is not ULM’, or when PTM is ULM’, any one or more of R 1’ , R 2’ , R 3’ , X and X’ of each of ULM and ULM’ are optionally modified to be covalently bonded to each other directly or through a linker group, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
  • the ULM and when present, ULM’ are each independently a group according to the chemical structure:
  • any one or more of R 1’ , R 2’ and R 3’ of ULM-h are optionally modified to bind a linker group to which is further covalently bonded to the PTM group when PTM is not ULM’, or when PTM is ULM’, any one or more of R 1’ , R 2’ , R 3’ of each of ULM and ULM’ are optionally modified to be covalently bonded to each other directly or through a linker group, or
  • ULM and when present, ULM’, are each independently according to the chemical structure:
  • any one or more of R 1’ , R 2’ and R 3’ of ULM-I are optionally modified to bind a linker group to which is further covalently bonded to the PTM group when PTM is not ULM’, or when PTM is ULM’, any one or more of R 1’ , R 2’ , R 3’ of each of ULM and ULM’ are optionally modified to be covalently bonded to each other directly or through a linker group, or
  • R 1’ of ULM-g through ULM-i is preferably a hydroxyl group or a group which may be metabolized to a hydroxyl or carboxylic group, such that the compound represents a prodrug form of an active compound.
  • Exemplary preferred R 1’ groups include, for example, -(CH2)nOH, (CH2)n-O-(C1-C6)alkyl group, -(CH2)nCOOH, - (CH2O)nH, an optionally substituted -(CH2)nOC(O)-(C1-C6 alkyl), or an optionally substituted - (CH 2 ) n C(O)-O-(C 1 -C 6 alkyl), wherein n is 0 or 1.
  • R 1’ is or contains a carboxylic acid group, a hydroxyl group or an amine group
  • the hydroxyl group, carboxylic acid group or amine may be further chemically modified to provide a covalent link to a linker group to which the PTM group (including a ULM’ group) is bonded;
  • R 2’ of ULM-g through ULM-i is preferably an optionally substituted -NR 1 -T-Aryl, an optionally substituted -NR 1 -T-Heteroaryl group or an optionally substituted -NR 1 -T-Heterocycle, where R 1 is H or CH 3 , preferably H and T is an optionally substituted–(CH 2 ) n - group, wherein each one of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, an amino acid sidechain as otherwise described herein or a C1- C 3 alkyl group, preferably one or two methyl groups, which may be optionally substituted; and n is 0 to 6 (e.g., 0, 1, 2 or 3, such as 0 or 1).
  • T may also be a–(CH 2 O) n - group, a– (OCH2)n- group, a–(CH2CH2O)n- group, a–(OCH2CH2)n- group, all of which groups are optionally substituted.
  • Preferred Aryl groups for R 2’ of ULM-g through ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl or naphthyl group is optionally connected to a PTM group via a linker group to which is attached a PTM group (including a ULM’ group), a halogen (preferably F or Cl), an amine, monoalkyl- or dialkyl amine (preferably, dimethylamine), F, Cl, OH, COOH, C 1 -C 6 alkyl, preferably CH 3 , CF 3 , OMe, OCF3, NO2, or CN group (each of which may be substituted in ortho-, meta- and/or para- positions of the phenyl ring, preferably para-), an optionally substituted phenyl group (the phenyl group itself is optionally connected to a PTM via a linker group, including a ULM’ group), and/or at least
  • S c of ULM-g through ULM-i is CHR SS , NR URE , or O;
  • R HET of ULM-g through ULM-i is H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g.
  • R SS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally
  • substituted C 1 -C 6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted O-(C1-C6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted -C(O)(C1- C 6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • R URE of ULM-g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3 alkyl) or a–
  • R PRO of ULM-g through ULM-i is H, optionally substituted C 1 -C 6 alkyl or an optionally substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine,
  • R PRO1 and R PRO2 of ULM-g through ULM-i are each independently H, an optionally subsituted C 1 -C 3 alkyl group or together form a keto group;
  • each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), or an optionally substituted heterocycle, preferably tetrahydrofuran, tetrahydrothiene, piperidine, piperazine or morpholine (each of which groups when substituted, are preferably substituted with a methyl or halo (F, Br, Cl), each of which groups may be optionally connected to a PTM group (including a ULM’ group) via a linker group.
  • a PTM group including a ULM’ group
  • Preferred heteroaryl groups for R 2’ of ULM-g through ULM-i include an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole, an optionally substituted indolizine, an optionally substituted azaindolizine, an optionally substituted benzofuran, including an optionally substituted benzofuran, an optionally substituted isoxazole, an optionally substituted thiazole, an optionally substituted isothiazole, an optionally substituted thiophene, an optionally substituted pyridine (2-, 3, or 4-pyridine), an optionally substituted imidazole, an optionally substituted pyrrole, an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted oximidazole, or a group according to the chemical structure:
  • S c of ULM-g through ULM-i is CHR SS , NR URE , or O;
  • R HET of ULM-g through ULM-i is H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g.
  • CF3 optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-Ra where Ra of ULM-g through ULM-i is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
  • R SS of ULM-g through ULM-i is H, CN, NO 2 , halo (preferably F or Cl), optionally
  • substituted C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted O-(C1-C6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted -C(O)(C 1 - C 6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • R URE of ULM-g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3 alkyl) or a–
  • optionally substituted C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-Ra where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl), each of which groups may be optionally connected to a PTM group (including a ULM’ group) via a linker group.
  • C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups
  • O(C 1 -C 6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • an optionally substituted acetylenic group–CoC-Ra where Ra is H or a C1-C6 alky
  • Preferred heterocycle groups for R 2’ of ULM-g through ULM-i include tetrahydrofuran, tetrahydrothiene, tetrahydroquinoline, piperidine, piperazine, pyrrollidine, morpholine, oxane or thiane, each of which groups may be optionally substituted, or a group according to the chemical structure:
  • R PRO of ULM-g through ULM-i is H, optionally substituted C1-C6 alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group;
  • R PRO1 and R PRO2 of ULM-g through ULM-i are each independently H, an optionally
  • each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (often 0 or 1), each of which groups may be optionally connected to a PTM group (including a ULM’ group) via a linker group.
  • R 2’ substituents of ULM-g through ULM-i also include specifically (and without limitation to the specific compound disclosed) the R 2’ substituents which are found in the identified compounds disclosed herein (which includes the specific compounds which are disclosed in the present specification, and the figures which are attached hereto). Each of these R 2’ substituents may be used in conjunction with any number of R 3’ substituents which are also disclosed herein.
  • R 3’ of ULM-g through ULM-i is preferably an optionally substituted–T-Aryl, an optionally substituted–T-Heteroaryl, an optionally substituted–T-Heterocycle, an optionally substituted-NR 1 -T-Aryl, an optionally substituted -NR 1 -T-Heteroaryl or an optionally substituted-NR 1 -T-Heterocycle.
  • R 1 is H or a C1-C3 alkyl group, preferably H or CH 3
  • T is an optionally substituted–(CH 2 ) n - group, wherein each one of the methylene groups may be optionally substituted with one or two substituents, preferably selected from halogen, a C1-C6 alkyl group (linear, branched, optionally substituted) or the sidechain of an amino acid as otherwise described herein, preferably methyl, which may be optionally substituted; and n is 0 to 6,e.g.0, 1, 2, or 3 ( such as 0 or 1).
  • T may also be a– (CH2O)n- group, a–(OCH2)n- group, a–(CH2CH2O)n- group, a–(OCH2CH2)n- group, each of which groups is optionally substituted.
  • Preferred aryl groups for R 3’ of ULM-g through ULM-i include optionally substituted phenyl or naphthyl groups, preferably phenyl groups, wherein the phenyl or naphthyl group is optionally connected to a PTM group (including a ULM’ group) via a linker group and/or a halogen (preferably F or Cl), an amine, monoalkyl- or dialkyl amine (preferably, dimethylamine), an amido group (preferably a–(CH 2 ) m -NR 1 C(O)R 2 group where m, R 1 and R 2 are the same as above), a halo (often F or Cl), OH, CH 3 , CF 3 , OMe, OCF 3 , NO 2 , ,CN or a S(O) 2 R S group (R S is a a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocycle group or a
  • said substituent phenyl group is an optionally substituted phenyl group (i.e., the substituent phenyl group itself is preferably substituted with at least one of F, Cl, OH, SH, COOH, CH 3 , CF 3 , OMe, OCF 3 , NO 2 , CN or a linker group to which is attached a PTM group (including a ULM’ group), wherein the substitution occurs in ortho-, meta- and/or para- positions of the phenyl ring, preferably para-), a naphthyl group, which may be optionally substituted including as described above, an optionally substituted heteroaryl (preferably an optionally substituted isoxazole including a methylsubstituted isoxazole, an optionally substituted oxazole including a methylsubstituted oxazole, an optionally substituted thiazole including a methyl substituted thiazole, an optionally substituted pyrrole including a
  • methoxybenzylimidazole an oximidazole or methyloximidazole, an optionally substituted diazole group, including a methyldiazole group, an optionally substituted triazole group, including a methylsubstituted triazole group, a pyridine group, including a halo- (preferably, F) or methylsubstitutedpyridine group or an oxapyridine group (where the pyridine group is linked to the phenyl group by an oxygen) or an optionally substituted heterocycle (tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, morpholine, piperazine, tetrahydroquinoline, oxane or thiane.
  • a pyridine group including a halo- (preferably, F) or methylsubstitutedpyridine group or an oxapyridine group (where the pyridine group is linked to the phenyl group by an oxygen
  • PTM group including a ULM’ group
  • Preferred Heteroaryl groups for R 3’ of ULM-g through ULM-i include an optionally substituted quinoline (which may be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2, 3 or 4-azaindolizine) an optionally substituted benzimidazole, benzodiazole, benzoxofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably methyl substituted), an optionally substituted diazole, an optionally substituted triazole, a tetrazole, an optionally substituted be
  • S c of ULM-g through ULM-i is CHR SS , NR URE , or O;
  • R HET of ULM-g through ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally
  • substituted C 1 -C 6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-R a
  • R a is H or a C 1 -C 6 alkyl group (preferably C 1 -C 3 alkyl)
  • R SS of ULM-g through ULM-i is H, CN, NO 2 , halo (preferably F or Cl), optionally
  • substituted C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted O-(C 1 -C 6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted -C(O)(C1- C6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • R URE of ULM-g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3 alkyl) or a–
  • C 1 -C 6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-R a where R a is H or a C 1 -C 6 alkyl group (preferably C1-C3 alkyl).
  • Each of said heteroaryl groups may be optionally connected to a PTM group (including a ULM’ group) via a linker group.
  • Preferred heterocycle groups for R 3’ of ULM-g through ULM-i include
  • R PRO of ULM-g through ULM-i is H, optionally substituted C1-C6 alkyl or an optionally substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
  • R PRO1 and R PRO2 of ULM-g through ULM-i are each independently H, an optionally
  • each n of ULM-g through ULM-i is 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), wherein each of said Heteocycle groups may be optionally connected to a PTM group (including a ULM’ group) via a linker group.
  • R 3’ substituents of ULM-g through ULM-i also include specifically (and without limitation to the specific compound disclosed) the R 3’ substituents which are found in the identified compounds disclosed herein (which includes the specific compounds which are disclosed in the present specification, and the figures which are attached hereto). Each of these R 3’ substituents may be used in conjunction with any number of R 2’ substituents, which are also disclosed herein.
  • R 2’ of ULM-g through ULM-i is an optionally substituted -NR 1 -X R2’ -alkyl group, -NR 1 -X R2’ -Aryl group; an optionally substituted - NR1- X R2’ -HET, an optionally substituted -NR1-X R2’ -Aryl-HET or an optionally substituted - NR1- X R2’ -HET-Aryl,
  • R 1 of ULM-g through ULM-i is H or a C 1 -C 3 alkyl group (preferably H);
  • Xv of ULM-g through ULM-i is H, a halo or a C1-C3 alkyl group which is optionally
  • Alkyl of ULM-g through ULM-i is an optionally substituted C1-C 10 alkyl (preferably a C 1 -C 6 alkyl) group (in certain preferred embodiments, the alkyl group is end-capped with a halo group, often a Cl or Br);
  • Aryl of ULM-g through ULM-i is an optionally substituted phenyl or naphthyl group
  • HET of ULM-g through ULM-i is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl) or a group according to the chemical structure:
  • S c of ULM-g through ULM-i is CHR SS , NR URE , or O;
  • R HET of ULM-g through ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally
  • substituted C 1 -C 6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-Ra where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); R SS of ULM-g through ULM-i is H, CN, NO 2 , halo (preferably F or Cl), optionally
  • substituted C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted O-(C1-C6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted -C(O)(C 1 - C6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • R URE of ULM-g through ULM-i is H, a C 1 -C 6 alkyl (preferably H or C 1 -C 3 alkyl) or a– C(O)(C1-C6 alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, preferably fluorine groups, or an optionally substituted heterocycle, for example piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, pipe
  • C 1 -C 6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-R a where R a is H or a C 1 -C 6 alkyl group (preferably C 1 -C 3 alkyl);
  • R PRO of ULM-g through ULM-i is H, optionally substituted C1-C6 alkyl or an optionally substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C 1 -C 3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
  • R PRO1 and R PRO2 of ULM-g through ULM-i are each independently H, an optionally
  • each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1).
  • Each of said groups may be optionally connected to a PTM group (including a ULM’ group) via a linker group.
  • R S3’ is an optionally substituted alkyl group (C 1 -C 10 , preferably C 1 -C 6 alkyl), an optionally substituted Aryl group or a HET group; R 1’ is H or a C 1 -C 3 alkyl group (preferably H);
  • V is O, S or NR1’
  • Xv is H, a halo or a C1-C3 alkyl group which is optionally substituted with one or two
  • Alkyl is an optionally substituted C 1 -C 10 alkyl (preferably a C 1 -C 6 alkyl) group (in certain preferred embodiments, the alkyl group is end-capped with a halo group, often a Cl or Br);
  • Aryl is an optionally substituted phenyl or napthyl group (preferably, a phenyl group); and HET is an optionally substituted oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, benzofuran, indole, indolizine, azaindolizine, quinoline (when substituted, each preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), or a group according to the chemical structure:
  • S c of ULM-g through ULM-i is CHR SS , NR URE , or O;
  • R HET of ULM-g through ULM-i is H, CN, NO2, halo (preferably Cl or F), optionally
  • substituted C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-Ra where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); R SS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally
  • substituted C 1 -C 6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted O-(C1-C6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted -C(O)(C1- C 6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • R URE of ULM-g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3 alkyl) or a–
  • Y C of ULM-g through ULM-i is N or C-R YC , where R YC is H, OH, CN, NO 2 , halo
  • C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-Ra where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
  • R PRO of ULM-g through ULM-i is H, optionally substituted C 1 -C 6 alkyl or an optionally substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
  • R PRO1 and R PRO2 of ULM-g through ULM-i are each independently H, an optionally
  • each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1); each m’ of ULM-g through ULM-i is 0 or 1; and
  • each n’ of ULM-g through ULM-i is 0 or 1; wherein each of said compounds, preferably on the alkyl, Aryl or Het groups, is optionally connected to a PTM group (including a ULM’ group) via a linker group.
  • R 3 ’ of ULM-g through ULM-i is–(CH2)n-Aryl,– (CH 2 CH 2 O) n -Aryl,–(CH 2 ) n -HET or–(CH 2 CH 2 O) n -HET,
  • said Aryl of ULM-g through ULM-i is phenyl which is optionally substituted with one or two substitutents, wherein said substituent(s) is preferably selected from -(CH 2 ) n OH, C 1 -C 6 alkyl which itself is further optionally substituted with CN, halo (up to three halo groups), OH, -(CH2)nO(C1-C6)alkyl, amine, mono- or di-(C1-C6 alkyl) amine wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halo (preferably F, Cl) groups, or
  • said Aryl group of ULM-g through ULM-i is substituted with -(CH2)nOH, -(CH2)n-O-(C1- C6)alkyl, -(CH2)n-O-(CH2)n-(C1-C6)alkyl, -(CH2)n-C(O)(C0-C6) alkyl, -(CH2)n-C(O)O(C0- C 6 )alkyl, -(CH 2 ) n -OC(O)(C 0 -C 6 )alkyl, amine, mono- or di-(C 1 -C 6 alkyl) amine wherein the alkyl group on the amine is optionally substituted with 1 or 2 hydroxyl groups or up to three halo (preferably F, Cl) groups, CN, NO2, an optionally substituted -(CH2)n-(V)m’- CH 2 ) n -(V) m’ -(C 1 -C 6 )alkyl group,
  • Aryl group of ULM-g through ULM-i is optionally substituted with a heterocycle
  • heteroaryl selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, benzofuran, indole, indolizine, azaindolizine, (when substituted each preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), or a group according to the chemical structure:
  • S c of ULM-g through ULM-i is CHR SS , NR URE , or O;
  • R HET of ULM-g through ULM-i is H, CN, NO 2 , halo (preferably Cl or F), optionally
  • substituted C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-Ra where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl); R SS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally
  • substituted C 1 -C 6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted O-(C1-C6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted -C(O)(C1- C 6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • R URE of ULM-g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3 alkyl) or a–
  • Y C of ULM-g through ULM-i is N or C-R YC , where R YC is H, OH, CN, NO 2 , halo
  • C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-Ra where Ra is H or a C1-C6 alkyl group (preferably C1-C3 alkyl);
  • R PRO of ULM-g through ULM-i is H, optionally substituted C 1 -C 6 alkyl or an optionally substituted aryl (phenyl or napthyl), heteroaryl or heterocyclic group selected from the group consisting of oxazole, isoxazole, thiazole, isothiazole, imidazole, diazole, oximidazole, pyrrole, pyrollidine, furan, dihydrofuran, tetrahydrofuran, thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine;
  • R PRO1 and R PRO2 of ULM-g through ULM-i are each independently H, an optionally
  • HET of ULM-g through ULM-i is preferably oxazole, isoxazole, thiazole, isothiazole,
  • tetrahydrofuran thiene, dihydrothiene, tetrahydrothiene, pyridine, piperidine, piperazine, morpholine, quinoline, (each preferably substituted with a C1-C3 alkyl group, preferably methyl or a halo group, preferably F or Cl), benzofuran, indole, indolizine, azaindolizine, or a group according to the chemical structure:
  • S c of ULM-g through ULM-i is CHR SS , NR URE , or O;
  • R HET of ULM-g through ULM-i is H, CN, NO 2 , halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g.
  • R SS of ULM-g through ULM-i is H, CN, NO2, halo (preferably F or Cl), optionally
  • substituted C 1 -C 6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted O-(C1-C6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • optionally substituted -C(O)(C1- C 6 alkyl) preferably substituted with one or two hydroxyl groups or up to three halo groups
  • R URE of ULM-g through ULM-i is H, a C1-C6 alkyl (preferably H or C1-C3 alkyl) or a–
  • Y C of ULM-g through ULM-i is N or C-R YC , where R YC is H, OH, CN, NO 2 , halo
  • C1-C6 alkyl preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g. CF3), optionally substituted O(C1-C6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups) or an optionally substituted acetylenic group–CoC-R a where R a is H or a C 1 -C 6 alkyl group (preferably C1-C3 alkyl);
  • R PRO of ULM-g through ULM-i is H, optionally substituted C1-C6 alkyl or an optionally substituted aryl, heteroaryl or heterocyclic group;
  • R PRO1 and R PRO2 of ULM-g through ULM-i are each independently H, an optionally
  • each m’ of ULM-g through ULM-i is independently 0 or 1;
  • each n of ULM-g through ULM-i is independently 0, 1, 2, 3, 4, 5, or 6 (preferably 0 or 1), wherein each of said compounds, preferably on said Aryl or HET groups, is optionally
  • preferred compounds include those according to the chemical structure:
  • R 1’ of ULM-i is OH or a group which is metabolized in a patient or subject to OH;
  • R 2’ of ULM-i is a–NH-CH 2 -Aryl-HET (preferably, a phenyl linked directly to a methyl substituted thiazole);
  • R 3’ of ULM-i is a–CHR CR3’ -NH-C(O)-R 3P1 group or a–CHR CR3’ -R 3P2 group;
  • R CR3’ of ULM-i is a C 1 -C 4 alkyl group, preferably methyl, isopropyl or tert-butyl;
  • R 3P1 of ULM-i is C 1 -C 3 alkyl (preferably methyl), an optionally substituted oxetane group (preferably methyl substituted, a–(CH2)nOCH3 group where n is 1 or 2 (preferably 2), or
  • the ethyl ether group is preferably meta-substituted on the phenyl moiety
  • a morpholino grop (linked to the carbonyl at the 2- or 3-position; group;
  • Aryl of ULM-i is phenyl
  • HET of ULM-i is an optionally substituted thiazole or isothiazole
  • R HET of ULM-i is H or a halo group (preferably H);
  • bifunctional compounds comprising a ubiquitin E3 ligase binding moiety (ULM), wherein ULM is a group according to the chemical structure:
  • each R 5 and R 6 of ULM-j is independently OH, SH, or optionally substituted alkyl or R 5 , R 6 , and the carbon atom to which they are attached form a carbonyl;
  • R7 of ULM-j is H or optionally substituted alkyl
  • J of ULM-j is O or N-R8;
  • R8 of ULM-j is H, CN, optionally substituted alkyl or optionally substituted alkoxy;
  • M of ULM-j is optionally substituted aryl, optionally substituted heteroaryl, optionally
  • each R9 and R10 of ULM-j is independently H; optionally substituted alkyl, optionally
  • substituted cycloalkyl optionally substituted hydroxyalkyl, optionally substituted thioalkyl, a disulphide linked ULM, optionally substituted heteroaryl, or haloalkyl; or R9, R10, and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
  • R 11 of ULM-j is optionally substituted heterocyclic, optionally substituted alkoxy, optionally
  • R 12 of ULM-j is H or optionally substituted alkyl
  • R 13 of ULM-j is H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl; optionally substituted (oxoalkyl)carbamate,
  • each R14 of ULM-j is independently H, haloalkyl, optionally substituted cycloalkyl,
  • R 15 of ULM-j is H, optionally substituted heteroaryl, haloalkyl, optionally substituted aryl, optionally substituted alkoxy, or optionally substituted heterocyclyl;
  • each R16 of ULM-j is independently halo, optionally substituted alkyl, optionally substituted haloalkyl, CN, or optionally substituted haloalkoxy;
  • each R 25 of ULM-j is independently H or optionally substituted alkyl; or both R 25 groups can be taken together to form an oxo or optionally substituted cycloalkyl group;
  • R23 of ULM-j is H or OH
  • Z 1 , Z 2 , Z 3 , and Z 4 of ULM-j are independently C or N;
  • ULM-j is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt, stereoisomer, solvate or polymorph thereof.
  • J is O
  • R7 is H
  • each R14 is H
  • R 15 is optionally substituted heteroaryl
  • o is 0.
  • each R 18 is independently halo, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, or haloalkoxy; and p is 0, 1, 2, 3, or 4.
  • ULM and where present, ULM’ are each independently a group according to the chemical structure:
  • R 7 of ULM-k is H
  • each R14 of ULM-k is H;
  • R17 of ULM-k is H, halo, optionally substituted cycloalkyl, optionally substituted alkyl, optionally substituted alkenyl, and haloalkyl.
  • R 17 of ULM-k is alkyl (e.g., methyl) or cycloalkyl (e.g., cyclopropyl).
  • ULM and where present, ULM’ are each independently a group according to the chemical structure: ,
  • R 7 of ULM-k is H
  • each R14 of ULM-k is H;
  • R 15 of ULM-k is selected from the group consisting of:
  • R30 of ULM-k is H or an optionally substituted alkyl.
  • ULM and where present, ULM’ are each independently a group according to the chemical structure:
  • R 11 of ULM-k is selected from the group consisting of:
  • q of ULM-k is 1 or 2;
  • R20 of ULM-k is H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally
  • R21 of ULM-k is H or optionally substituted alkyl
  • R22 of ULM-k is H, optionally substituted alkyl, optionally substituted alkoxy, or haloalkyl.
  • R 11 of ULM-j or ULM-k is selected from the group consisting of:
  • R11 of ULM-j or ULM-k is selected from the group consisting of:
  • ULM (or when present ULM’) is a group according to the chemical structure:
  • X of ULM-l is O or S
  • Y of ULM-l is H, methyl or ethyl
  • R 17 of ULM-l is H, methyl, ethyl, hydoxymethyl or cyclopropyl;
  • M of ULM-l is is optionally substituted aryl, optionally substituted heteroaryl, or ;
  • R 9 of ULM-l is H;
  • R10 of ULM-l is H, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted hydroxyalkyl, optionally substituted thioalkyl or cycloalkyl;
  • R11 of ULM-l is optionally substituted heteroaromatic, optionally substituted heterocyclic,
  • R 12 of ULM-l is H or optionally substituted alkyl
  • R13 of ULM-l is H, optionally substituted alkyl, optionally substituted alkylcarbonyl,
  • ULM and where present, ULM’ are each independently a group according to the chemical structure:
  • Y of ULM-m is H, methyol or ethyl
  • R9 of ULM-m is H
  • R 10 is isopropyl, tert-butyl, sec-butyl, cyclopentyl, or cyclohexyl;
  • R11 of ULM-m is optionally substituted amide, optionally substituted isoindolinone,
  • ULM and where present, ULM’ are each independently a group according to the chemical structure:
  • R 17 of ULM-n is methyl, ethyl, or cyclopropyl
  • R9, R10, and R11 of ULM-n are as defined above. In other instances, R9 is H; and
  • R10 of ULM-n is H, alkyl, or or cycloalkyl (preferably, isopropyl, tert-butyl, sec-butyl,
  • the ULM (or when present, ULM’) as described herein may be a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate or polymorph thereof.
  • the ULM (or when present, ULM’) as described herein may be coupled to a PTM directly via a bond or by a chemical linker.
  • the ULM moiety is selected from the group consisting of:
  • VLM may be connected to a PTM via a linker, as described herein, at any appropriate location, including, e.g., an aryl, heteroary, phenyl, or phenyl of an indole group, optionally via any appropriate functional group, such as an amine, ester, ether, alkyl, or alkoxy.
  • a linker as described herein, at any appropriate location, including, e.g., an aryl, heteroary, phenyl, or phenyl of an indole group, optionally via any appropriate functional group, such as an amine, ester, ether, alkyl, or alkoxy.
  • the ILM can comprise an alanine- valine-proline-isoleucine (AVPI) tetrapeptide fragment or an unnatural mimetic thereof.
  • AVPI alanine- valine-proline-isoleucine
  • the ILM is selected from the group consisting of chemical structures represented by Formulas (I), (II), (III), (IV), and (V):
  • R 1 for Formulas (I), (II), (III), (IV), and (V) is selected from H or alkyl
  • R 2 for Formulas (I), (II), (III), (IV), and (V) is selected from H or alkyl
  • R 3 for Formulas (I), (II), (III), (IV), and (V) is selected from H, alkyl, cycloalkyl and heterocycloalkyl;
  • R 5 and R 6 for Formulas (I), (II), (III), (IV), and (V) are independently selected from H, alkyl, cycloalkyl, heterocycloalkyl, or more preferably, R 5 and R 6 taken together for Formulas (I), (II), (III), (IV), and (V) form a pyrrolidine or a piperidine ring further optionally fused to 1–2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings, each of which can then be further fused to another cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;
  • R 3 and R 5 for Formulas (I), (II), (III), (IV), and (V) taken together can form a 5–8-membered ring further optionally fused to 1–2 cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings;
  • R 7 for Formulas (I), (II), (III), (IV), and (V) is selected from cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aryl-C(O)-R 4 , arylalkyl, heteroaryl, heteroaryl-C(O)-R 4 , heteroaryl-R 4 , heteroaryl-naphthalene, heteroarylalkyl, or -C(O)NH– R 4 , each one further optionally substituted with 1–3 substituents selected from halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cyano
  • R 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, further optionally substituted with 1–3 substituents as described above.
  • P1, P2, P3, and P4 of Formular (II) correlate with A, V, P, and I, respectively, of the AVPI tetrapeptide fragment or an unnatural mimetic thereof.
  • each of Formulas (I) and (III) through (V) have portions correlating with A, V, P, and I of the AVPI tetrapeptide fragment or an unnatural mimetic thereof.
  • the ILM can have the structure of Formula (VI), which is a derivative of IAP antagonists described in WO Pub. No. 2008/014236, or an unnatural mimetic thereof:
  • R1 of Formula (VI) is, independently selected from H, C1-C4-alky, C1-C4-alkenyl, C1-C4- alkynyl or C3-C1O- cycloalkyl which are unsubstituted or substituted;
  • R 2 of Formula (VI) is, independently selected from H, C 1 -C 4 -aIkyl, C 1 -C 4 -alkenyl, C 1 -C 4 - alkynyI or C3-C1O- cycloalkyl which are unsubstituted or substituted;
  • R3 of Formula (VI) is, independently selected from H, -CF3, -C2H5, C1-C4-alkyl, C1-C4- alkenyl, C 1 -C 4 -alkynyl, - CH 2 -Z or any R 2 and R 3 together form a heterocyclic ring;
  • each Z of Formula (VI) is, independently selected from H, -OH, F, Cl, -CH3, -CF3, -CH2Cl, - CH2F or -CH2OH;
  • R 4 of Formula (VI) is, independently selected from C 1 -C 16 straight or branched alkyl, C 1 - C16-alkenyl, C1-C16- alkynyl, C3-C10-cycloalkyl, -(CH2)0-6-Z1, -(CH2)0-6-aryl, and -(CH2)0- 6-het, wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted;
  • R 5 of Formula (VI) is, independently selected from H, C 1-10 -alkyl, aryl, phenyl, C 3-7 - cycloalkyl, -(CH 2 ) 1 - 6 -C 3-7 - cycloalkyl, -C 1-10 -alkyl-aryl, -(CH 2 ) 0-6 -C 3-7 -cycloalkyl-(CH 2 ) 0- 6-phenyl, -(CH2)0-4-CH[(CH2)1-4- phenyl]2, indanyl, -C(O)-C1-10-alkyl, -C(O)-(CH2)1-6-C3- 7-cycloalkyl, -C(O)-(CH2)0-6-phenyl, - (CH2)0-6-C(O)-phenyl, -(CH2)0-6-het, -C(O)- (CH 2 ) 1-6 -het, or R 5 is selected from a
  • Z1 of Formula (VI) is, independently selected from -N(R10)-C(O)-C1-10-alkyl, -N(R1O)-C(O)- (CH 2 ) 0-6 -C 3-7 -cycloalkyl, -N(R 10 )-C(O)-(CH 2 ) 0-6 -phenyl, -N(R 10 )-C(O)(CH 2 ) 1-6 -het, - C(O)-N(R11)(R12), -C(O)-O-C1-10-alkyl, -C(O)-O-(CH2)1-6-C3-7-cycloalkyl, -C(O)-O- (CH2)0-6-phenyl, -C(O)-O- (CH2)1-6-het, -O-C(O)-C1-10-alkyl, -O-C(O)1-6-C3-7-cycloaIkyl
  • het of Formula (VI) is, independently selected from a 5-7 member heterocyclic ring
  • heterocyclic ring or fused ring system containing 1 -4 heteroatoms selected from N, O, and S, or an 8-12 member fused ring system including at least one 5-7 member heterocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, which heterocyclic ring or fused ring system is unsubstituted or substituted on a carbon or nitrogen atom;
  • R 10 of Formula (VI) is selected from H, -CH 3, -CF 3 , -CH 2 OH, or -CH 2 Cl;
  • R11 and R12 of Formula (VI) are independently seleted from H, C1-4-alkyl, C3-7-cycloalkyl, - (CH2)1-6-C3-7- cycloakyl, (CH2)0-6-phenyl, wherein alkyl, cycloalkyl, and phenyl are unsubstituted or substituted; or R 11 and R 12 together with the nitrogen form het, and U of Formula (VI) is, independently, as shown in Formula (VII): (VII),
  • each n of Formula (VII) is, independently selected from 0 to 5;
  • X of Formula (VII) is selected from the group -CH and N;
  • R a and R b , of Formula (VII) are independently selected from the group O, S, or N atom or C 0- 8-alkyl wherein one or more of the carbon atoms in the alkyl chain are optionally replaced by a heteroatom selected from O, S, or N, and where each alkyl is, independently, either unsubstituted or substituted;
  • R d of Formula (VII) is selected from the group Re-Q-(R f ) p (R g ) q, and Ar 1 -D-Ar 2 ;
  • Rc of Formula (VII) is selected from the group H or any Rc and Rd together form a cycloalkyl or het; where if R c and R d form a cycloalkyl or het, R 5 is attached to the formed ring at a C or N atom;
  • p and q of Formula (VII) are independently selected from 0 or 1;
  • R e of Formula (VII) is selected from the group C 1-8 -alkyl and alkylidene, and each Re is either unsubstituted or substituted;
  • Q is selected from the group N, O, S, S(O), and S(O)2;
  • Ar1 and Ar2 of Formula (VII) are independently selected from the group of substituted or unsubstituted aryl and het;
  • R f and R g of Formula (VII) are independently selected from H, -C1-10-alkyl, C 1-10 -alkylaryl, -OH, -O-C1-10-alkyl, - (CH2)0-6-C3-7-cycloalky, -O-(CH2)0-6-aryl, phenyl, aryl, phenyl– phenyl, -(CH 2 ) 1-6 -het, -O-(CH 2 ) 1-6 -het, -OR 13, -C(0)-R 13, -C(O)-N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -S-R 13, -S(O)-R 13, -S(O) 2 -R 13 , -S(O) 2 -R 13 , -S(O) 2 -NR 13 R 14, -NR 13 -S(O) 2 -R 14, -S-C t-10
  • Rh is selected from the group H, unsubstituted or substituted C1 -7-alkyl, aryl, unsubstituted or substituted -O-(C1-7-cycloalkyl), -C(O)-C1-10-aIkyl, - C(O)-C0-10-alkyl-aryl, -C-O-C01- 1 0 -alkyl, -C-O-C 0-10 -alkyl-aryl, -SO 2 -C 1-10 -alkyI, or -SO 2 -(C 0-10 - alkylaryl);
  • R6, R7, R8, and R9 of Formula (VII) are, independently, selected from the group H, -C1-10- alkyl, -C1-10-alkoxy, aryl-C1 -10- alkoxy, -OH, -O-C1-10-aIkyl, -(CH2)0-6-C3-7-cycloalkyI, - O-(CH 2 ) 0-6 -aryl, phenyl, -(CH 2 ) 1-6 -het, -O-(CH 2 ) 1-6 -het, -OR 13, -C(O)-R 13, -C(O)- N(R 13 )(R 14 ), -N(R 13 )(R 14 ), -S-R 13, -S(O)-R 13 , -S(O) 2 - R 13, -S(O) 2 -NR 13 R 14, or -NR 13 - S(O)2-R14; wherein each alkyl,
  • R 13 and R 14 of Formula (VII) are independently selected from the group H, C 1-10 -alkyl, - (CH2)0-6-C3-7-cycloalkyl, -(CH2)0-6- (CH)0-1-(aryl)1-2, -C(O)-C1-10-alkyl, -C(O)-(CH2)1-6- C3-7-cycloalkyl, -C(O)-O-(CH2)0-6-aryl, - C(O)-(CH2)0-6-O-fluorenyl, -C(O)-NH-(CH2)0-6- aryl, -C(O)-(CH 2 ) 0-6 -aryl, -C(O)-(CH 2 ) 0 .
  • the ILM can have the structure of Formula (VIII), which is based on the IAP ligrands described in Ndubaku, C., et al. Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists, ACS Chem. Biol., 557-566, 4 (7) ( 2009), or an unnatural mimetic thereof:
  • each of A1 and A2 of Formula (VIII) is independently selected from optionally substituted monocyclic, fused rings, aryls and hetoroaryls;
  • R of Formula (VIII) is selected from H or Me.
  • the linker group L is attached to A1 of Formula (VIII). In another embodiment, the linker group L is attached to A2 of Formula (VIII).
  • the ILM is selected from the group consisting of
  • the ILM can have the structure of Formula (IX), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 ( 2010), or an unnatural mimetic thereof:
  • R 1 is selected from alkyl, cycloalkyl and heterocycloalkyl and, most preferably, from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl
  • R 2 of Formula (IX) is selected from–OPh or H.
  • the ILM can have the structure of Formula (X), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 ( 2010), or an unnatural mimetic thereof:
  • R 1 of Formula (X) is selected from H,–CH 2 OH, --CH 2 CH 2 OH, --CH 2 NH 2, --CH 2 CH 2 NH 2 ;
  • X of Formula (X) is selected from S or CH2;
  • R 2 of Formula (X) is selected from:
  • R 3 and R 4 of Formula (X) are independently selected from H or Me [0192]
  • the ILM can have the structure of Formula (XI), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 ( 2010), or an unnatural mimetic thereof:
  • R 1 of Formula (XI) is selected from H or Me
  • R 2 of Formula (XI) is selected from H or
  • the ILM can have the structure of Formula (XII), which is derived from the chemotypes cross-referenced in Mannhold, R., et al. IAP antagonists: promising candidates for cancer therapy, Drug Discov. Today, 15 (5-6), 210-9 ( 2010), or an unnatural mimetic thereof:
  • R 1 of Formula (XII) is selected from: ; and R 2 of Formula (XII) is selected from:
  • the IAP E3 ubiquitin ligase binding moiety is selected from the group consisting of:
  • the ILM can have the structure of Formula (XIII), which is based on the IAP ligands summarized in Flygare, J.A., et al. Small- molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20 (2), 251-67 ( 2010), or an unnatural mimetic thereof:
  • Z of Formula (XIII) is absent or O;
  • R 1 of Formula (XIII) is selected from: ;
  • R 10 of is selected from H, alkyl, or aryl
  • X is selected from CH2 and O; and is a nitrogen-containing heteroaryl.
  • the ILM can have the structure of Formula (XIV), which is based on the IAP ligands summarized in Flygare, J.A., et al. Small- molecule pan-IAP antagonists: a patent review, Expert Opin. Ther. Pat., 20 (2), 251-67 ( 2010), or an unnatural mimetic thereof:
  • Z of Formula (XIV) is absent or O;
  • R 3 and R 4 of Formula (XIV) are independently selected from H or Me;
  • R 1 of Formula (XIV) is selected from: ;
  • the ILM is selected from the group consisting of:
  • the ILM can have the structure of Formula (XV), which was a derivative of the IAP ligand described in WO Pub. No.2008/128171, or an unnatural mimetic thereof:
  • Z of Formula (XV) is absent or O;
  • R 1 of Formula (XV) is selected from:
  • R 2 of Formula (XV) selected from H, alkyl, or acyl
  • the ILM has the following structure:
  • the ILM can have the structure of Formula (XVI), which is based on the IAP ligand described in WO Pub. No. 2006/069063, or an unnatural mimetic thereof:
  • R 2 of Formula (XVI) is selected from alkyl, cycloalkyl and heterocycloalkyl; more preferably, from isopropyl, tert-butyl, cyclohexyl and tetrahydropyranyl, most preferably from cyclohexyl;
  • Formula (XVI) is a 5- or 6-membered nitrogen-containing heteroaryl; more preferably, 5-membered nitrogen-containing heteroaryl, and most preferably thiazole; and Ar of Formula (XVI) is an aryl or a heteroaryl.
  • the ILM can have the structure of Formula (XVII), which is based on the IAP ligands described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or an unnatural mimetic thereof:
  • X of Formula (XVII) is selected from the group O or CH2.
  • the ILM can have the structure of Formula (XVIII), which is based on the IAP ligands described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or an unnatural mimetic thereof:
  • R of Formula (XVIII) is selected from alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or halogen (in variable substitution position).
  • the ILM can have the structure of Formula (XIX), which is based on the IAP ligands described in Cohen, F. et al., Antogonists of inhibitors of apoptosis proteins based on thiazole amide isosteres, Bioorg. Med. Chem. Lett., 20(7), 2229-33 (2010), or an unnatural mimetic thereof:
  • the ILM of the composition is selected from the group consisting of:
  • the ILM of the composition is selected from the group consisting of:
  • the ILM can have the structure of Formula (XX), which is based on the IAP ligands described in WO Pub. No. 2007/101347, or an unnatural mimetic thereof:
  • XX wherein X of Formula (XX) is selected from CH 2 , O, NH, or S.
  • the ILM can have the structure of Formula (XXI), which is based on the IAP ligands described in U.S. Pat. No. 7,345,081 and U.S. Pat. No.7,419,975, or an unnatural mimetic thereof:
  • R 2 of Formula (XXI) is selected from:
  • R 5 of Formula (XXI) is selected from:
  • W of Formula (XXI) is selected from CH or N;
  • the ILM of the compound is selected from the group consisting of:
  • the ILM can have the structure of Formula (XXII) or (XXIV), which are derived from the IAP ligands described in WO Pub. No. 2015/006524 and Perez HL, Discovery of potent heterodimeric antagonists of inhibitor of apoptosis proteins (IAPs) with sustained antitumor activity. J. Med. Chem. 58(3), 1556-62 (2015), or an unnatural mimetic thereof, and the chemical linker to linker group L as shown:
  • R 1 of Formula (XXII), (XXIII) or (XXIV) is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl;
  • R 2 of Formula (XXII), (XXIII) or (XXIV) is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl; or alternatively,
  • R 1 and R 2 of Formula (XXII), (XXIII) or (XXIV) are independently selected from optionally substituted thioalkyl wherein the substituents attached to the S atom of the thioalkyl are optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH 2 ) v COR 20 , -CH 2 CHR 21 COR 22 or -CH 2 R 23 ,
  • v is an integer from 1-3;
  • R 20 and R 22 of–(CH 2 ) v COR 20 and -CH 2 R 23 are independently selected from OH, NR 24 R 25 or OR 26 ;
  • R 21 of -CH2CHR 21 COR 2 is selected from NR 24 R 25 ;
  • R 23 of -CH 2 R 23 is selected from optionally substituted aryl or optionally substituted heterocyclyl, wherein the optional substituents include alkyl and halogen;
  • R 24 of NR 24 R 25 is selected from hydrogen or optionally substituted alkyl;
  • R 25 of NR 24 R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, -CH 2 (OCH 2 CH 2 O) m CH 3 , or a polyamine chain, such as spermine or spermidine;
  • R 26 of OR 26 is selected from optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH2;
  • n is an integer from 1-8;
  • R 3 and R 4 of Formula (XXII), (XXIII) or (XXIV) are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted heteroarylalkyl or optionally substituted heterocycloalkyl, wherein the substituents are alkyl, halogen or OH;
  • R 5 , R 6 , R 7 and R 8 of Formula (XXII), (XXIII) or (XXIV) are independently hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl; and/or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
  • R 7 and R 8 are selected from the H or Me
  • R 5 and R 6 are selected from the group comprising:
  • R 3 and R 4 are selected from the group comprising:
  • the ILM can have the structure of Formula (XXV), (XXVI), (XXVII), or (XXVIII), which are derived from the IAP ligands described in WO Pub. No. 2014/055461 and Kim, KS, Discovery of tetrahydroisoquinoline- based bivalent heterodimeric IAP antagonists. Bioorg. Med. Chem. Lett. 24(21), 5022-9 (2014), or an unnatural mimetic thereof, and the chemical linker to linker group L as shown:
  • R 2 of Formula (XXV) through (XXVIII) is selected from H, an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted aryl; or alternatively;
  • R 1 and R 2 of Formula (XXV) and (XXVIII) are independently selected from H, an optionally substituted thioalkyl–CR 60 R 61 SR 70 wherein R 60 and R 61 are selected from H or methyl, and R 70 is an optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted heterocyclyl, -(CH2)vCOR 20 , -CH2CHR 21 COR 22 or -CH2R 23 ;
  • v is an integer from 1-3;
  • R 20 and R 22 of–(CH 2 ) v COR 20 and -CH 2 CHR 21 COR 22 are independently selected from OH, NR 24 R 25 or OR 26 ;
  • R 21 of -CH2CHR 21 COR 22 is selected from NR 24 R 25 ;
  • R 23 of -CH 2 R 23 is selected from an optionally substituted aryl or optionally substituted heterocyclyl, where the optional substituents include alkyl and halogen;
  • R 24 of NR 24 R 25 is selected from hydrogen or optionally substituted alkyl
  • R 25 of NR 24 R 25 is selected from hydrogen, optionally substituted alkyl, optionally substituted branched alkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl, - CH2CH2(OCH2CH2)mCH3, or a polyamine chain – [CH 2 CH 2 (CH 2 )dNH]yCH 2 CH 2 (CH 2 )v r NH 2 , such as spermine or spermidine,
  • R 26 of OR 26 is an optionally substituted alkyl, wherein the optional substituents are OH, halogen or NH 2;
  • n is an integer from 1-8;
  • R 6 and R 8 of Formula (XXV) through (XXVIII) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;
  • R 31 of Formulas (XXV) through (XXVIII) is selected from alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl optionally further substituted, preferably selected form the group consisting of:
  • the ILM can have the structure of Formula (XXIX) or (XXX), which are derived from the IAP ligands described in WO Pub. No. 2013/071039, or an unnatural mimetic thereof:
  • R 43 and R 44 of Formulas (XXIX) and (XXX) are independently selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl further optionally substituted, and
  • R 6 and R 8 of Formula (XXIX) and (XXX) are independently selected from hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl.
  • each X of Formulas (XXIX) and (XXX) is independently selected from:
  • each Z of Formulas (XXIX) and (XXX) is selected from , wherein each represents a point of attachment to the compound;
  • each Y is selected from:
  • A is selected from -C(O)R 3 or
  • R 3 of -C(O)R 3 is selected from OH, NHCN, NHS0 2 R 10 , NHOR 11 or N(R 12 )(R 13 );
  • R 10 and R 11 of NHS02R 10 and NHOR 11 are independently selected from -C1-C4 alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, any of which are optionally substituted, and hydrogen;
  • each of R 12 and R 13 of N(R 12 )(R 13 ) are independently selected from hydrogen, -C1-C4 alkyl, - (C1-C4 alkylene)-NH-(C1-C4 alkyl), benzyl, -(C1-C4 alkylene)-C(O)OH,
  • R 12 and R 13 of N(R 12 )(R 13 ) are taken together with the nitrogen atom to which they are commonly bound to form a saturated heterocyclyl optionally comprising one additional heteroatom selected from N, O and S, and wherein the saturated heterocycle is optionally substituted with methyl.
  • the ILM can have the structure of Formula (XXXI), which are derived from the IAP ligands described in WO Pub. No. 2013/071039, or an unnatural mimetic thereof:
  • W 1 of Formula (XXXI) is selected from O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 of Formula (XXXI) is selected from O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 1 of Formula (XXXI) is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C 1 -C 6 alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or unsubstituted aryl), or –C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
  • X 1 is selected from O, N-R A , S, S(O), or S(O) 2 , then X 2 is C(R 2a R 2b );
  • X 1 of Formula (XXXI) is selected from CR 2c R 2d and X 2 is CR 2a R 2b , and R 2c and R 2a together form a bond;
  • X 1 and X 2 of Formula (XXXI) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring;
  • R 2a , R 2b , R 2c , R 2d of CR 2c R 2d and CR 2a R 2b are independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl- (substituted or unsubstituted C 3 - C 6 cycloalkyl), -C 1 -C 6 alkyl-(substituted or unsubstituted C2-C5heterocycloalkyl), -C1-C6alkyl- (substituted or unsubstituted aryl), -C1-
  • R D and R E of NR D R E are independently selected from H, substituted or unsubstituted C1- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 - C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl- (substituted or unsubstituted C3-C6cycloalkyl), -C1-C6alkyl- (substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or–C1-C6alkyl- (substituted or unsubstituted heteroaryl);
  • n 1 or 2;
  • R 3 of Formula (XXXI) is selected from C 1 -C 3 alkyl, or C 1 -C 3 fluoroalkyl;
  • R 4 of Formula (XXXI) is selected from -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 ;
  • each R 5 of -NHR 5 , -N(R 5 )2, -N+(R 5 )3 and -OR 5 is independently selected from H, C1-C3alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 heteroalkyl and–C 1 -C 3 alkyl-(C 3 -C 5 cycloalkyl);
  • R 3 of Formula (XXXI) is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • R 7 is selected from 0, 1 or 2;
  • R 8a , R 8b , R 8c , and R 8d of C(R 8a )(R 8b ) and C(R 8c )(R 8d ) are independently selected from H, C 1 - C6alkyl, C1-C6fluoroalkyl, C1-C6 alkoxy, C1-C6heteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • the ILM can have the structure of Formula (XXXII), which are derived from the IAP ligands described in WO Pub. No. 2013/071039, or an unnatural mimetic thereof:
  • W 1 of Formula (XXXII) is O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 of Formula (XXXII) is O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 1 of Formula (XXXII) is selected from H, C1-C6alkyl, C3-C6cycloalkyl, -C1-C6alkyl- (substituted or unsubstituted C 3 -C 6 cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or unsubstituted aryl), or –C1-C6alkyl-(substituted or unsubstituted heteroaryl);
  • X 1 of Formula (XXXII) is selected from S, S(O), or S(O)2, then X 2 is CR 2c R 2d , and X 3 is CR 2a R 2b ;
  • X 1 of Formula (XXXII) is CH 3
  • X 2 is selected from O, N-R A , S, S(O), or S(O) 2
  • X 3 is CR 2a R 2b ;
  • X 1 and X 2 of Formula (XXXII) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 is CR 2a R 2b ;
  • X 2 and X 3 of Formula (XXXII) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 of Formula (XXXII) is CR 2e R 2f ;
  • R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f of CR 2c R 2d , CR 2a R 2b and CR 2e R 2f are independently selected from H, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1- C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C 2 -C 5 heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or unsubstituted C3- C6cycloalkyl), -C1-C6alkyl- (substituted or unsubstituted C2-C5heterocycloalkyl), -C1-C6alkyl-(substit
  • R D and R E of NR D R E are independently selected from H, substituted or unsubstituted C1- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 - C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl- (substituted or unsubstituted C3-C6cycloalkyl), -C1-C6alkyl- (substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or–C1-C6alkyl- (substituted or unsubstituted heteroaryl);
  • n 1 or 2;
  • R 3 of Formula (XXXII) is selected from C1-C3alkyl, or C1-C3fluoroalkyl;
  • R 4 of Formula (XXXII) is selected from -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 ;
  • each R 5 of -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 and -OR 5 is independently selected from H, C 1 -C 3 alkyl, C1-C3haloalkyl, C1-C3heteroalkyl and–C1-C3alkyl-(C3-C5cycloalkyl);
  • R 3 of Formula (XXXII) is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • p of R 7 is selected from 0, 1 or 2;
  • R 8a , R 8b , R 8c , and R 8d of C(R 8a )(R 8b ) and C(R 8c )(R 8d ) are independently selected from H, C1- C6alkyl, C1-C6fluoroalkyl, C1-C6 alkoxy, C1-C6heteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • the ILM can have the structure of Formula (XXXIII), which is derived from the IAP ligands described in WO Pub. No. 2013/071039, or an unnatural mimetic thereof:
  • W 1 of Formula (XXXIII) is selected from O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 of Formula (XXXIII) is selected from O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • R 1 of Formula (XXXIII) is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C 1 -C 6 alkyl- (substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl-(substituted or unsubstituted aryl), or –C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl);
  • X 1 of Formula (XXXIII) is O
  • X 2 of Formula (XXXIII) is selected from O, N-R A , S, S(O), or S(O)2
  • X 3 of Formula (XXXIII) is CR 2a R 2b ; or:
  • X 1 and X 2 of Formula (XXXIII) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 of Formula (XXXIII) is CR 2a R 2b ;
  • X 2 and X 3 of Formula (XXXIII) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 1 of Formula (VLII) is CR 2e R 2f ;
  • R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f of CR 2c R 2d , CR 2a R 2b and CR 2e R 2f are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 - C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 alkyl-(substituted or unsubstituted C 3 - C 6 cycloalkyl), -C 1 -C 6 alkyl- (substituted or unsubstituted C2-C5heterocycloalkyl), -C1-C6alky
  • R D and R E of NR D R E are independently selected from H, substituted or unsubstituted C1- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 - C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl- (substituted or unsubstituted C3-C6cycloalkyl), -C1-C6alkyl- (substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or–C1-C6alkyl- (substituted or unsubstituted heteroaryl);
  • R 3 of Formula (XXXIII) is C1-C3alkyl, or C1-C3fluoroalkyl
  • R 4 of Formula (XXXIII) is -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 ;
  • each R 5 of -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 and -OR 5 is independently selected from H, C 1 -C 3 alkyl, C1-C3haloalkyl, C1-C3heteroalkyl and–C1-C3alkyl-(C3-C5cycloalkyl);
  • R 3 of Formula (XXXIII) is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • p of R 7 is 0, 1 or 2;
  • R 8a , R 8b , R 8c , and R 8d of C(R 8a )(R 8b ) and C(R 8c )(R 8d ) are independently selected from H, C1- C6alkyl, C1-C6fluoroalkyl, C1-C6 alkoxy, C1-C6heteroalkyl, and substituted or unsubstituted aryl;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together form a bond;
  • R 8a and R 8d are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8c and R 8d are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a and R 8b are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3 -7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • the ILM can have the structure of Formula (XXXIV), which is derived from the IAP ligands described in WO Pub. No. 2013/071039, or an unnatural mimetic thereof:
  • W 1 of Formula (XXXIV) is selected from O, S, N-R A , or C(R 8a )(R 8b );
  • W 2 of Formula (XXXIV) is selected from O, S, N-R A , or C(R 8c )(R 8d ); provided that W 1 and W 2 are not both O, or both S;
  • W 3 of Formula (XXXIV) is selected from O, S, N-R A , or C(R 8e )(R 8f ), providing that the ring comprising W 1 , W 2 , and W 3 does not comprise two adjacent oxygen atoms or sulfer atoms;
  • R 1 of Formula (XXXIV) is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, -C 1 -C 6 alkyl- (substituted or unsubstituted C3-C6cycloalkyl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or –C 1 -C 6 alkyl-(substituted or unsubstituted heteroaryl); when X 1 of Formula (XXXIV) is O, then X 2 of Formula (XXXIV) is selected from CR 2c R 2d and N-R A , and X 3 of Formula (XXXXIV) is CR 2a R 2b ;
  • X 1 of Formula (XXXIV) is CH 2
  • X 2 of Formula (XXIV) is selected from O, N-R A , S, S(O), or S(O)2
  • X 3 of Formula (XXXIV) is CR 2a R 2b ;
  • X 1 and X 2 of Formula (XXXIV) are independently selected from C and N, and are members of a fused substituted or unsubstituted saturated or partially saturated 3-10 membered cycloalkyl ring, a fused substituted or unsubstituted saturated or partially saturated 3-10 membered heterocycloalkyl ring, a fused substituted or unsubstituted 5-10 membered aryl ring, or a fused substituted or unsubstituted 5-10 membered heteroaryl ring, and X 3 of Formula (XXXIV) is CR 2a R 2b ;
  • R 2a , R 2b , R 2c , R 2d , R 2e , and R 2f of CR 2c R 2d , CR 2a R 2b and CR 2e R 2f are independently selected from H, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 - C6heteroalkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C 1 -C 6 alkyl-(substituted or unsubstituted C 3 - C 6 cycloalkyl), -C 1 -C 6 alkyl- (substituted or unsubstituted C2-C5heterocycloalkyl), -C1-C6alky
  • R D and R E of NR D R E are independently selected from H, substituted or unsubstituted C1- C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 - C5heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -C1-C6alkyl- (substituted or unsubstituted C3-C6cycloalkyl), -C1-C6alkyl- (substituted or unsubstituted C 2 - C 5 heterocycloalkyl), -C 1 -C 6 alkyl-(substituted or unsubstituted aryl), or–C 1 -C 6 alkyl- (substituted or unsubstituted heteroaryl);
  • n 1 or 2;
  • R 3 of Formula (XXXIV) is selected from C1-C3alkyl, or C1-C3fluoroalkyl;
  • R 4 of Formula (XXXIV) is selected from -NHR 5 , -N(R 5 )2, -N+(R 5 )3 or -OR 5 ;
  • each R 5 of -NHR 5 , -N(R 5 ) 2 , -N+(R 5 ) 3 and -OR 5 is independently selected from H, C 1 -C 3 alkyl, C1-C3haloalkyl, C1-C3heteroalkyl and–C1-C3alkyl-(C3-C5cycloalkyl);
  • R 3 of Formula (XXXIV) is bonded to a nitrogen atom of U to form a substituted or unsubstituted 5-7 membered ring;
  • p of R 7 is selected from 0, 1 or 2;
  • R 8a , R 8b , R 8c , R 8d , R 8e , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are independently selected from H, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6 alkoxy, C1-C6heteroalkyl, and substituted or unsubstituted aryl;
  • R 8a , R 8d , R 8e , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8b and R 8c together form a bond;
  • R 8a , R 8b , R 8d , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8c and R 8e together form a bond;
  • R 8a , R 8d , R 8e , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8b and R 8c together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8d , and R 8f of C(R 8a )(R 8b ), C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8c and R 8e together with the atoms to which they are attached form a substituted or unsubstituted fused 5-7 membered saturated, or partially saturated carbocyclic ring or heterocyclic ring comprising 1 -3 heteroatoms selected from S, O and N, a substituted or unsubstituted fused 5-10 membered aryl ring, or a substituted or unsubstituted fused 5-10 membered heteroaryl ring comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8c , R 8d , R 8e , and R 8f of C(R 8c )(R 8d ) and C(R 8e )(R 8f ) are as defined above, and R 8a and R 8b together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1 -3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8e , and R 8f of C(R 8a )(R 8b ) and C(R 8e )(R 8f ) are as defined above, and R 8c and R 8d together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatoms selected from S, O and N;
  • R 8a , R 8b , R 8c , and R 8d of C(R 8a )(R 8b ) and C(R 8c )(R 8d ) are as defined above, and R 8e and R 8f together with the atoms to which they are attached form a substituted or unsubstituted saturated, or partially saturated 3-7 membered spirocycle or heterospirocycle comprising 1-3 heteroatoms selected from S, O and N; or:
  • the ILM can have the structure of Formula (XXXV), (XXXVI) or (XXXVII), which is derived from the IAP ligands described in Vamos, M., et al., Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP, ACS Chem. Biol., 8(4), 725-32 (2013), or an unnatural mimetic thereof:
  • R 2 of Formulas (XXXV) and (XXXVII) are independently selected from H or ME;
  • R 3 and R 4 of Formula (XXXV) are independently selected from H or ME;
  • X of Formulas (XXXV) and (XXXVII) is independently selected from O or S;
  • R 1 of Formulas (XXXV) and (XXXVII) is selected from:
  • the ILM has a structure according to Formula (XXXVIII):
  • R 3 and R 4 of Formula (XXXVIII) are independently selected from H or ME;
  • the ILM has a structure and attached to a linker group L as shown below:
  • the ILM can have the structure of Formula (XXXIX) or (XL), which is based on the IAP ligands described in Hennessy, EJ, et al., Discovery of aminopiperidine-based Smac mimetics as IAP antagonists, Bioorg. Med. Chem. Lett., 22(4), 1960-4 (2012), or an unnatural mimetic thereof:
  • R 2 of Formulas (XXXIX) and (XL) is selected from H or Me;
  • R 3 of Formulas (XXXIX) and (XL) is selected from:

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Abstract

La présente invention concerne des composés bifonctionnels, ULM— L—PTM, qui s'avèrent utiles en tant que modulateurs du fibrosarcome rapidement accéléré (RAF, tel que c-RAF, A-RAF et/ou B-RAF ; la protéine cible). En particulier, la présente invention concerne des composés bifonctionnels, qui contiennent, au niveau d'une extrémité, un ligand de Von Hippel-Lindau, de céréblon, d'inhibiteurs de protéines d'apoptose ou d'homologue 2 double-minute de souris, qui se lie à l'ubiquitine ligase E3 respective, et, au niveau de l'autre extrémité, une fraction qui se lie à la protéine RAF cible, de sorte que la protéine cible se trouve à proximité de l'ubiquitine ligase pour effectuer la dégradation (et l'inhibition) de la protéine cible. La présente invention présente une large plage d'activités pharmacologiques associées à la dégradation/inhibition de la protéine cible. Les composés et les compositions selon la présente invention permettent de traiter ou de prévenir des maladies ou des troubles qui résultent de l'agrégation ou de l'accumulation de la protéine cible, ou de l'activation constitutive de la protéine cible.
PCT/US2019/050114 2018-09-07 2019-09-07 Composés polycycliques et méthodes pour la dégradation ciblée de polypeptides du fibrosarcome rapidement accéléré Ceased WO2020051564A1 (fr)

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CN201980073600.1A CN113164775B (zh) 2018-09-07 2019-09-07 用于迅速加速性纤维肉瘤多肽的靶向降解的多环化合物和方法
IL319737A IL319737A (en) 2018-09-07 2019-09-07 Polycyclic compounds and methods for targeted reduction of rapidly accelerating fibrosarcoma polypeptides
CA3109981A CA3109981A1 (fr) 2018-09-07 2019-09-07 Composes polycycliques et methodes pour la degradation ciblee de polypeptides du fibrosarcome rapidement accelere
CN202411258198.3A CN119192142A (zh) 2018-09-07 2019-09-07 用于迅速加速性纤维肉瘤多肽的靶向降解的多环化合物和方法
AU2019335516A AU2019335516B2 (en) 2018-09-07 2019-09-07 Polycyclic compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
CN202411258205.XA CN119101049A (zh) 2018-09-07 2019-09-07 用于迅速加速性纤维肉瘤多肽的靶向降解的多环化合物和方法
CN202411258195.XA CN119219628A (zh) 2018-09-07 2019-09-07 用于迅速加速性纤维肉瘤多肽的靶向降解的多环化合物和方法
KR1020217009937A KR102642203B1 (ko) 2018-09-07 2019-09-07 급속 진행형 섬유육종 폴리펩티드의 표적화 분해를 위한 다중 고리 화합물 및 방법
JP2021512854A JP2022500368A (ja) 2018-09-07 2019-09-07 急速進行性線維肉腫ポリペプチドの標的分解のための多環式化合物および方法
IL281188A IL281188B2 (en) 2018-09-07 2019-09-07 Polycyclic compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
EP19773614.3A EP3846907A1 (fr) 2018-09-07 2019-09-07 Composés polycycliques et méthodes pour la dégradation ciblée de polypeptides du fibrosarcome rapidement accéléré
MX2021002559A MX2021002559A (es) 2018-09-07 2019-09-07 Compuestos policiclicos y metodos para la degradacion dirigida de polipeptidos de fibrosarcoma rapidamente acelerado.
KR1020247005115A KR20240028539A (ko) 2018-09-07 2019-09-07 급속 진행형 섬유육종 폴리펩티드의 표적화 분해를 위한 다중 고리 화합물 및 방법
MX2024015414A MX2024015414A (es) 2018-09-07 2021-03-04 Compuestos policiclicos y metodos para la degradacion dirigida de polipeptidos de fibrosarcoma rapidamente acelerado
MX2024015415A MX2024015415A (es) 2018-09-07 2021-03-04 Compuestos policiclicos y metodos para la degradacion dirigida de polipeptidos de fibrosarcoma rapidamente acelerado
AU2022228150A AU2022228150B2 (en) 2018-09-07 2022-09-08 Polycyclic compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides
JP2023127233A JP2023159166A (ja) 2018-09-07 2023-08-03 急速進行性線維肉腫ポリペプチドの標的分解のための多環式化合物および方法
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US11524949B2 (en) 2017-11-16 2022-12-13 C4 Therapeutics, Inc. Degraders and Degrons for targeted protein degradation
US11753397B2 (en) 2018-03-26 2023-09-12 C4 Therapeutics, Inc. Cereblon binders for the degradation of ikaros
US11584748B2 (en) 2018-04-16 2023-02-21 C4 Therapeutics, Inc. Spirocyclic compounds
US12227504B2 (en) 2018-04-16 2025-02-18 C4 Therepeutics, Inc. Spirocyclic compounds
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