WO2019060742A1 - AGENTS FOR DEGRADING PROTEINS AND USES THEREOF - Google Patents

AGENTS FOR DEGRADING PROTEINS AND USES THEREOF Download PDF

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Publication number
WO2019060742A1
WO2019060742A1 PCT/US2018/052242 US2018052242W WO2019060742A1 WO 2019060742 A1 WO2019060742 A1 WO 2019060742A1 US 2018052242 W US2018052242 W US 2018052242W WO 2019060742 A1 WO2019060742 A1 WO 2019060742A1
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Prior art keywords
agent
nitrogen
sulfur
oxygen
membered
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PCT/US2018/052242
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English (en)
French (fr)
Inventor
Nello Mainolfi
Nan JI
Yi Zhang
Matthew M. Weiss
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Kymera Therapeutics Inc
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Kymera Therapeutics Inc
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Priority to US16/649,732 priority Critical patent/US11623932B2/en
Priority to IL273432A priority patent/IL273432B/en
Priority to AU2018338314A priority patent/AU2018338314B2/en
Priority to CA3076613A priority patent/CA3076613A1/en
Priority to EP18857581.5A priority patent/EP3684365A4/en
Priority to IL307995A priority patent/IL307995A/en
Priority to MX2020003190A priority patent/MX2020003190A/es
Priority to IL322809A priority patent/IL322809A/en
Priority to EP25195747.8A priority patent/EP4624467A3/en
Priority to IL295603A priority patent/IL295603B2/en
Application filed by Kymera Therapeutics Inc filed Critical Kymera Therapeutics Inc
Priority to JP2020538753A priority patent/JP7366031B2/ja
Publication of WO2019060742A1 publication Critical patent/WO2019060742A1/en
Anticipated expiration legal-status Critical
Priority to US17/837,449 priority patent/US20230115184A1/en
Priority to JP2023175302A priority patent/JP7818560B2/ja
Priority to AU2025201796A priority patent/AU2025201796A1/en
Priority to US19/304,052 priority patent/US20260085075A1/en
Priority to JP2025136973A priority patent/JP2025170324A/ja
Ceased legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and methods useful for the modulation of targeted ubiquitination, especially with respect to a variety of polypeptides and other proteins, which are degraded and/or otherwise inhibited by compounds according to the present invention.
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • UPP Ubiquitin-Proteasome Pathway
  • E3 ubiquitin ligases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity.
  • Cereblon interacts with damaged DNA binding protein 1 and forms an E3 ubiquitin ligase complex with Cullin 4 where it functions as a substrate receptor in which the proteins recognized by CRBN might be ubiquitinated and degraded by proteasomes.
  • CRBN Proteasome-mediated degradation of unneeded or damaged proteins plays a very important role in maintaining regular function of a cell, such as cell survival, proliferation and growth.
  • a new role for CRBN has been identified; i.e., the binding of immunomodulatory drugs (EVIiDs), e.g. thalidomide, to CRBN has now been associated with teratogenicity and also the cytotoxicity of EVIiDs, including lenalidomide, which are widely used to treat multiple myeloma patients.
  • EVIiDs immunomodulatory drugs
  • thalidomide e.g. thalidomide
  • CRBN is likely a key player in the binding, ubiquitination and degradation of factors involved in maintaining function of myeloma cells.
  • UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
  • the pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman's syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting.
  • the UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation.
  • Bifunctional compounds composed of a target protein- binding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression.
  • Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40-46).
  • the present application relates novel bifunctional compounds, which function to recruit targeted proteins to E3 Ubiquitin Ligase for degradation, and methods of preparation and uses thereof.
  • the present disclosure provides bifunctional 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., multiple myeloma.
  • the present application further relates to targeted degradation of proteins through the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds the targeted protein.
  • the present application also relates to a bifunctional compound having the following structure:
  • TBM is a target binding moiety capable of binding to the targeted protein(s);
  • L is a bivalent moiety that connects TBM to UBM
  • UBM is a ubiquitin binding moiety capable of binding to a ubiquitin ligase such as an E3 Ubiquitin Ligase (e.g., cereblon).
  • a ubiquitin ligase such as an E3 Ubiquitin Ligase (e.g., cereblon).
  • Compounds provided by this invention are also useful for the study of CRBN and targeted proteins in biological and pathological phenomena; the study of CRBN and targeted proteins occurring in bodily tissues; and the comparative evaluation of new CRBN or targeted protein ligands or other regulators of CRBN or targeted proteins in vitro or in vivo.
  • binding As defined herein, the terms “binder,” “modulator,” and “ligand” are used interchangeably and describe a compound that binds to, modulates or is a ligand for CRBN or a targeted protein.
  • the present invention provides a compound of formula I:
  • X 1 a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-,
  • R is hydrogen, deuterium, halogen, -CN, OR, SR, -S(0)R, -S(0) 2 R, -NR 2 , or an optionally substituted Ci-4 aliphatic; each R 2 is independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 R 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
  • R 3 is selected from hydrogen, halogen, -OR, -N(R) 2 , or -SR;
  • each R 4 is independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • R 5 is hydrogen, C1-4 aliphatic, or -CN
  • each R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, -S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -N(R)C(0)-,
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen
  • TBM is a target binding moiety
  • n 0, 1, 2, 3 or 4;
  • each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula I':
  • X 1 is a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-, or
  • R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, -NR 2 , or an optionally substituted Ci-4 aliphatic;
  • each R 2 is independently hydrogen, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring A is a bi- or tricy wherein Ring B is other than imidazo or benzo, ein Ring B is other than benzo, wherein Ring B is other than benz
  • Ring B is other than benzo
  • Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
  • R 3 is selected from hydrogen, halogen, -OR, -N(R) 2 , or -SR;
  • each R 4 is independently hydrogen, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • R 5 is hydrogen, Ci-4 aliphatic, or -CN;
  • each R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen,
  • TBM is a target binding moiety
  • n 0, 1, 2, 3 or 4;
  • each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula I":
  • X 1 is a bivalent moiet selected from a covalent bond, -C(R) 2 - -C(O)-, -C(S)-, -P(0)(OR)-, -
  • X 2 is a carbon atom or silicon atom
  • X 3 is a bivalent moiety selected from -C(R) 2 - -N(R)-, -CF 2 - -CHF-, -S-, or -0-;
  • X 4 is a bivalent moiety selected from a covalent bond or -C(R) 2 -;
  • — is a single bond or double bond
  • R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, - R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, -P(0)( R 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , an optionally substituted C 1-4 aliphatic, or:
  • R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur; each R 2 is independently hydrogen, deuterium, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N
  • Ring B is a fused ring selected from 6-membered aryl containing 0-3 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5 -membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
  • R 3 is selected from hydrogen, deuterium, halogen, -CN, -N0 2 , -OR, - R 2 , -SR, -S(0) 2 R, -S(0) 2 R 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0) R(OR), -OC(0)R, -OC(0) R 2 , -OP(0)(OR) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)(OR) R 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 NR 2 , -N(R)P(0)(OR) 2 , -N(R)P(0)(OR) R 2 , -P(0)(OR)
  • each R 4 is independently hydrogen, deuterium, -R 6 , halogen, -S(0) 2 R, -S(0) 2 R 2; -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -P(0)(OR) 2 , -P(0)( R 2 )OR, or -P(0)( R 2 ) 2 ;
  • R 5 is hydrogen, deuterium, an optionally substituted C1-4 aliphatic, or -CN;
  • each R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)- , -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - -P(0)(OR)-, -P(0)(R)-, -P(0)( R 2 )-, -S-, - OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - -N(R)S(0) 2 - -S(0) 2 N(R)-,
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently
  • TBM is a target binding moiety
  • n 0, 1, 2, 3 or 4;
  • each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • Ring B where a point of attachment of is depicted on Ring B, it is intended, and one of ordinary skill in the art would appreciate, that the point of attachment of may be on Ring A and may also be at any available carbon or nitrogen atom on
  • Ring A including the ring to which Ring B is fused. Where is attached to a nitrogen atom bound to R 4 or R 5 R 4 or R 5 is absent and takes the lace of the
  • Ring A when is attached to Ring B, Ring A is when is attached to Ring A, Ring A is when d to a nitrogen atom bound to R 4 , Ring A is
  • Ring A is
  • the present invention provides a compound of Formula II-A:
  • a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-,
  • each R 2 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , or -N(R)S(0) 2 R;
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, C 1-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N( -, -S(0) 2 N(R -, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaryl enyl having 1-4 heteroatoms independently selected from nitrogen
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula II'-A:
  • X 1 a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-,
  • R is hydrogen, deuterium, halogen, -CN, OR, SR, -S(0)R, -S(0) 2 R, -NR 2 , or an optionally substituted Ci-4 aliphatic; Ring - or bicyclic ring selected from
  • each R 2 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , or -N(R)S(0) 2 R;
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, C 1-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N( -, -S(0) 2 N(R -, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaryl enyl having 1-4 heteroatoms independently selected from nitrogen
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of Formula II"-A:
  • X 1 is ivalent moiety selected from a covalent bond, -C(R) 2 - -C(O)-, -C(S)-, -P(0)(OR)-, -
  • X 2 is a carbon atom or silicon atom
  • X 3 is a bivalent moiety selected from -C(R) 2 - -N(R)-, -CF 2 - -CHF-, -S-, or -0-;
  • X 4 is a bivalent moiety selected from a covalent bond or -C(R) 2 -;
  • — is a single bond or double bond
  • R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, - R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, -P(0)( R 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , an optionally substituted Ci-4 aliphatic, or: R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;
  • each R 2 is independently hydrogen, deuterium, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, - R 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , -S(0) 2 R, -S(0) 2 R 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, or -P(0)( R 2 ) 2 ;
  • Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur; each R 3 is selected from hydrogen, deuterium, halogen, -CN, -NO2, -OR, - R 2 , -SR, -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0) R(OR), -OC(0)R, -OC(0) R 2 , -OP(0)(OR) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)(OR) R 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0) R 2 , -N(R)S
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, deuterium, an optionally substituted C1-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)- , -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - -P(0)(OR)-, -P(0)(R)-, -P(0)(NR 2 )-, -S-, - OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - -N(R) - -S(0) 2 N(R)- -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-1 1 membered saturated or partially unsaturated spiro carbocyclylenyl, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 6-1 1 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatom
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of Formula II-B:
  • a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-,
  • Ring A is a mono- or bicyclic ring selected from
  • each R 2 is independently hydrogen, -R 4 , halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , or -N(R)S(0) 2 R;
  • Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, C1-4 aliphatic, or -CN
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N( -, -S(0) 2 N(R -, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaryl enyl having 1-4 heteroatoms independently selected from nitrogen,
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula II'-B:
  • Ci-4 aliphatic is hydrogen, deuterium, halogen, -CN, -C OR, SR, -S(0)R, -S(0) 2 R, -NR 2 , or an optionally substituted Ci-4 aliphatic; Ring
  • each R 2 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , or -N(R)S(0) 2 R;
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, C1-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N( -, -S(0) 2 N(R -, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of Formula II"-B:
  • X 1 is ivalent moiety selected from a covalent bond, -C(R) 2 - -C(O)-, -C(S)-, -P(0)(OR)-, -
  • X 2 is a carbon atom or silicon atom
  • X 3 is a bivalent moiety selected from -C(R) 2 - -N(R)-, -CF 2 - -CHF-, -S-, or -0-;
  • X 4 is a bivalent moiety selected from a covalent bond or -C(R) 2 -;
  • — is a single bond or double bond
  • R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, - R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, -P(0)( R 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , an optionally substituted Ci-4 aliphatic, or:
  • R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;
  • each R 2 is independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, - R2, -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, or -P(0)( R 2
  • Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is selected from hydrogen, deuterium, halogen, -CN, -N0 2 , -OR, -NR 2 , -SR, -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)NR(OR), -OC(0)R, -OC(0)NR 2 , -OP(0)(OR) 2 , -OP(0)(NR 2 ) 2 , -OP(0)(NR 2 ) 2 , -OP(0)(OR)NR 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)NR 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 NR 2
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, deuterium, an optionally substituted Ci-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)- , -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - -P(0)(OR)-, -P(0)(R)-, -P(0)( R 2 )-, -S-, - OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - -N(R) - -S(0) 2 N(R)- -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of Formula III- A, III-B, or III-C:
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms.
  • aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limitation to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cy cl oalkyl) alkenyl .
  • bridged bicyclic refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a "bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a "bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:
  • lower alkyl refers to a C 1-4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), H (as in pyrrolidinyl) or R + (as in N-substituted pyrrolidinyl)).
  • Ci -8 saturated or unsaturated, straight or branched, hydrocarbon chain
  • bivalent Ci -8 or Ci-6) saturated or unsaturated, straight or branched, hydrocarbon chain
  • alkenylene or alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An "alkylene chain” is a polymethylene group, i.e., -(CH 2 )n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • cyclopropylenyl refers to a bivalent cyclopropyl group of
  • halogen means F, CI, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one.
  • heteroaryl group may be mono- or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4-dihydro- 2H-pyrrolyl), H (as in pyrrolidinyl), or + R (as in N-substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain "optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o- 2 R*, -(haloR"), -(CH 2 )o- 2 OH, -(CH 2 ) 0 - 2 OR", -(CH 2 ) 0 - 2 CH(OR") 2 ; -O(haloR'), -CN, -N 3 , -(CH 2 ) 0 - 2 C(0)R', -(CH 2 )o- 2 C(0)OH, -(CH 2 )o- 2 C(0)OR', -(CH 2 ) 0 - 2 SR', -(CH 2 ) 0 - 2 SH, -(CH 2 ) 0 - 2 NH 2 , - (CH 2 )o- 2 NHR e , -(CH 2 )o- 2 NR' 2
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an "optionally substituted” group include: -0(CR * 2 ) 2 - 3O-, wherein each independent occurrence of R * is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, -R", -(haloR"), -OH, -OR', -O(haloR'), -CN, -C(0)OH, -C(0)OR', - H 2 , -NHR", -NR' 2 , or -NO2, wherein each R" is unsubstituted or where preceded by "halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R ⁇ , - R ⁇ 2 , -C(0)R ⁇ , -C(0)OR ⁇ , -C(0)C(0)R ⁇ , -C(0)CH 2 C(0)R ⁇ , -S(0) 2 R ⁇ , -S(0) 2 R ⁇ 2 , -C(S) R ⁇ 2 , -C( H) R ⁇ 2 , or -N(R ⁇ )S(0) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, Ci- 6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R ⁇ , taken together with their intervening atom(
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, -R', -(haloR*), -OH, -OR', -O(haloR'), -CN, -C(0)OH, -C(0)OR', -NH 2 , -NHR', -NR' 2 , or -NO2, wherein each R* is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH 2 Ph, -0(CH 2 )o-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • a provided compound may be substituted with one or more deuterium atoms.
  • the term "binder” or “inhibitor” is defined as a compound that binds to CRBN and binds to or inhibits a targeted protein with measurable affinity.
  • an inhibitor has an IC50 and/or binding constant of less than about 50 ⁇ , less than about 1 ⁇ , less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.
  • a compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents.
  • a detectable moiety may be attached to a provided compound via a suitable substituent.
  • suitable substituent refers to a moiety that is capable of covalent attachment to a detectable moiety.
  • moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few.
  • moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain.
  • such moieties may be attached via click chemistry.
  • such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst.
  • Methods of using click chemistry are known in the art and include those described by Rostovtsev et al, Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.
  • detectable moiety is used interchangeably with the term “label” and relates to any moiety capable of being detected, e.g., primary labels and secondary labels.
  • Primary labels such as radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications.
  • Detectable moieties also include luminescent and phosphorescent groups.
  • secondary label refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal.
  • the secondary intermediate may include streptavidin-enzyme conjugates.
  • antigen labels secondary intermediates may include antibody-enzyme conjugates.
  • fluorescent label refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength.
  • fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy
  • mass-tag refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques.
  • mass-tags include electrophore release tags such as N-[3-[4'-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4'-[2,3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives.
  • mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition.
  • nucleotides dideoxynucleotides
  • oligonucleotides of varying length and base composition oligopeptides, oligosaccharides
  • other synthetic polymers of varying length and monomer composition.
  • a large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.
  • measurable affinity and “measurably modulate,” as used herein, means a measurable change in a CRBN activity between a sample comprising a compound of the present invention, or composition thereof, and CRBN, and an equivalent sample comprising CRBN, in the absence of said compound, or composition thereof.
  • the present invention provides a compound of formula I:
  • X 1 a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-,
  • R is hydrogen, deuterium, halogen, -CN, OR, SR, -S(0)R, -S(0) 2 R, -NR 2 , or an optionally substituted Ci-4 aliphatic; each R 2 is independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 R 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
  • R 3 is selected from hydrogen, halogen, -OR, -N(R) 2 , or -SR;
  • each R 4 is independently hydrogen, -R 6 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • R 5 is hydrogen, C1-4 aliphatic, or -CN
  • each R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen
  • TBM is a target binding moiety
  • n 0, 1, 2, 3 or 4;
  • each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula I':
  • X 1 is a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-, or
  • R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, -NR 2 , or an optionally substituted Ci-4 aliphatic;
  • each R 2 is independently hydrogen, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring A is a bi- or tricy wherein Ring B is other than imidazo or benzo, ein Ring B is other than benzo, wherein Ring B is other than benz
  • Ring B is other than benzo
  • Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5- membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;
  • R 3 is selected from hydrogen, halogen, -OR, -N(R) 2 , or -SR;
  • each R 4 is independently hydrogen, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • R 5 is hydrogen, Ci-4 aliphatic, or -CN;
  • each R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen,
  • TBM is a target binding moiety
  • n 0, 1, 2, 3 or 4;
  • each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula I":
  • X 1 is a bivalent moiet selected from a covalent bond, -C(R) 2 - -C(O)-, -C(S)-, -P(0)(OR)-, -
  • X 2 is a carbon atom or silicon atom
  • X 3 is a bivalent moiety selected from -C(R) 2 - -N(R)-, -CF 2 - -CHF-, -S-, or -0-;
  • X 4 is a bivalent moiety selected from a covalent bond or -C(R) 2 -;
  • — is a single bond or double bond
  • R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, - R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, -P(0)( R 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , an optionally substituted C 1-4 aliphatic, or:
  • R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur; each R 2 is independently hydrogen, deuterium, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, -N(R) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR,
  • Ring A i - or tricyclic ring selected from
  • Ring B is a fused ring selected from 6-membered aryl containing 0-3 nitrogen atoms, 5 to 7- membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5 -membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
  • R 3 is selected from hydrogen, deuterium, halogen, -CN, -N0 2 , -OR, - R 2 , -SR, -S(0) 2 R, -S(0) 2 R 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0) R(OR), -OC(0)R, -OC(0) R 2 , -OP(0)(OR) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)(OR) R 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 NR 2 , -N(R)P(0)(OR) 2 , -N(R)P(0)(OR) R 2 , -P(0)(OR)
  • each R 4 is independently hydrogen, deuterium, -R 6 , halogen, -S(0) 2 R, -S(0) 2 R 2; -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -P(0)(OR) 2 , -P(0)( R 2 )OR, or -P(0)( R 2 ) 2 ;
  • R 5 is hydrogen, deuterium, an optionally substituted C1-4 aliphatic, or -CN;
  • each R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)- , -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - -C(H)(CF 3 )-, -P(0)(OR)-, -P(0)(R)-, -P(0)( R 2 )- , -S-, -OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - -N(R)S(0) 2 - - -, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-1 1 membered saturated or partially unsaturated spiro carbocyclylenyl, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 6-1 1 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatom
  • TBM is a target binding moiety
  • n 0, 1, 2, 3 or 4;
  • each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula II-A:
  • X 1 is a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-, or is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, -NR 2 , or an optionally substituted C 1-4 aliphatic;
  • each R 2 is independently hydrogen, -R 4 , halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , or -N(R)S(0) 2 R;
  • Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is independently hydrogen, -R 4 , halogen, -CN, -N0 2 , -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, Ci-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N( -, -S(0) 2 N(R -, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaryl enyl having 1-4 heteroatoms independently selected from nitrogen
  • TBM is a target binding moiety
  • m is 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula II'-A:
  • a bivalent moiety selected from a covalent bond, -CH 2 - -C(O)-, -C(S)-,
  • Ci-4 aliphatic is hydrogen, deuterium, halogen, -CN, OR, SR, -S(0)R, -S(0) 2 R, -NR 2 , or an optionally substituted Ci-4 aliphatic; Ring - or bicyclic ring selected from
  • each R 2 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , or -N(R)S(0) 2 R;
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, C 1-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N( -, -S(0) 2 N(R -, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroaryl enyl having 1-4 heteroatoms independently selected from nitrogen
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of Formula II"-A:
  • X 1 is ivalent moiety selected from a covalent bond, -C(R) 2 - -C(O)-, -C(S)-, -P(0)(OR)-, -
  • X 2 is a carbon atom or silicon atom
  • X 3 is a bivalent moiety selected from -C(R) 2 - -N(R)-, -CF 2 - -CHF-, -S-, or -0-;
  • X 4 is a bivalent moiety selected from a covalent bond or -C(R) 2 -;
  • — is a single bond or double bond
  • R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, - R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, -P(0)( R 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , an optionally substituted Ci-4 aliphatic, or: R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;
  • each R 2 is independently hydrogen, deuterium, -R 4 , halogen, -CN, -N0 2 , -OR, -SR, -N(R) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , -S(0) 2 R, -S(0) 2 R 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, or -P(0)( R 2 ) 2 ;
  • Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur; each R 3 is selected from hydrogen, deuterium, -R 4 , halogen, -CN, -NO2, -OR, -NR 2 , -SR, -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0) R(OR), -OC(0)R, -OC(0) R 2 , -OP(0)(OR) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)(OR) R 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0) R 2 ,
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, deuterium, an optionally substituted C1-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)- , -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - -P(0)(OR)-, -P(0)(R)-, -P(0)(NR 2 )-, -S-, - OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - -N(R) - -S(0) 2 N(R)- -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1 -4 heteroatoms
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula II-B:
  • X 1 is a bivalent moiety selected from a covalent bond, -CH 2 - R 1 is hydrogen, deuterium, halogen,
  • each R 2 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , or -N(R)S(0) 2 R;
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, C1-4 aliphatic, or -CN
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of formula II'-
  • a bivalent moiety selected from a covalent bond, -CH 2 - is hydrogen, deuterium, halogen,
  • each R 2 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , or -N(R)S(0) 2 R;
  • Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R 3 is independently hydrogen, -R 4 , halogen, -CN, -NO2, -OR, -SR, -NR 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)N(R)OR, -OC(0)R, -OC(0)NR 2 , -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)NR 2 , or -N(R)S(0) 2 R;
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, C1-4 aliphatic, or -CN
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)-, - S-, -OC(O)-, -C(0)0-, -C(O)-, -S(O)-, -S(0) 2 -, -N(R)S(0) 2 -, -S(0) 2 N(R)-, -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, or an optionally substituted group selected from Ci aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • the present invention provides a compound of Formula II"-B:
  • X 1 is a bivalent moiety selected from a covalent bond -C(R) 2 - -C(O)-, -C(S)-, -P(0)(OR)-, -
  • X 2 is a carbon atom or silicon atom
  • X 3 is a bivalent moiety selected from -C(R) 2 - -N(R)-, -CF 2 - -CHF-, -S-, or -0-;
  • X 4 is a bivalent moiety selected from a covalent bond or -C(R) 2 -;
  • — is a single bond or double bond
  • R 1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(0)R, -S(0) 2 R, - R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, -P(0)( R 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , an optionally substituted C1-4 aliphatic, or:
  • R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur;
  • each R 2 is independently hydrogen, deuterium, -R 6 , halogen, -CN, -NO2, -OR, -SR, - R2, -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, or -P(0)( R 2
  • Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur;
  • each R 3 is selected from hydrogen, deuterium, -R 4 , halogen, -CN, -NO2, -OR, -NR 2 , -SR, -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0)NR 2 , -C(0)NR(OR), -OC(0)R, -OC(0)NR 2 , -OP(0)(OR) 2 , -OP(0)(NR 2 ) 2 , -OP(0)(NR 2 ) 2 , -OP(0)(OR)NR 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)NR 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 NR 2 , -N(R)P(0)(OR) 2 , -N(R)P(0)(OR) R 2 , -N(R)P(0)(OR) R 2
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4- 7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 5 is hydrogen, deuterium, an optionally substituted Ci-4 aliphatic, or -CN;
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -0-, -N(R)- , -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - -P(0)(OR)-, -P(0)(R)-, -P(0)( R 2 )-, -S-, - OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - -N(R) - -S(0) 2 N(R)- -N(R)C(0)-, -
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently
  • TBM is a target binding moiety
  • n 0, 1, or 2;
  • n 0, 1, 2, 3, or 4;
  • p is 0 or 1;
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
  • X 1 is a bivalent moiety selected from a covalent bond -CH 2 - -C(R) 2 - -C(O)-, -C(S)-, -CH(R)-, -CH(CF 3 )-, -P(0)(OR)-, -P(0)(R)-, -
  • X 1 is a covalent bond. In some embodiments, X 1 is -CH 2 - In some embodiments, X 1 is -C(R) 2 - In some embodiments, X 1 is -C(O)-. In some embodiments, X 1 is -C(S)-. In some embodiments, X 1 is -CH(R)-. In some embodiments, X 1 is -CH(CF 3 )-. In some embodiments, X 1 is -P(0)(OR)-. In some embodiments, X 1 is -P(0)(R)-. In some embodiments, X 1 is -P(0)( R 2 )-. In som mbodiments, X 1 is -S(O)-. In some embodiments, X 1 is -S(O)-. In some embodiments, X 1
  • X 1 i is [0080] In some embodiments, X 1 is selected from those depicted in Table 1, below.
  • X 2 is a carbon atom or silicon atom.
  • X 2 is a carbon atom. In some embodiments, X 2 is a silicon atom.
  • X 2 is selected from those depicted in Table 1, below.
  • X 3 is a bivalent moiety selected from -CH 2 -
  • X 3 is -CH 2 - In some embodiments, X 1 is -C(R) 2 - In some embodiments, X 3 is -N(R)-. In some embodiments, X 3 is -CF 2 - In some embodiments, X 3 is - CHF-. In some embodiments, X 3 is -S-. In some embodiments, X 3 is -CH(R)-. In some embodiments, X 3 is -0-.
  • X 3 is selected from those depicted in Table 1, below.
  • X 4 is a bivalent moiety selected from a covalent bond, -CH 2 - or -C(R) 2 -.
  • X 4 is a covalent bond. In some embodiments, X 4 is -CH 2 - In some embodiments, X 4 is -C(R) 2 -
  • X 4 is selected from those depicted in Table 1, below.
  • R 1 is hydrogen, deuterium, halogen, -CN, - OR, -SR, -S(0)R, -S(0) 2 R, - R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, -P(0)( R 2 ) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , an optionally substituted Ci-4 aliphatic, or R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1-3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.
  • R 1 is hydrogen. In some embodiments, R 1 is deuterium. In some embodiments, R 1 is halogen. In some embodiments, R 1 is -CN. In some embodiments, R 1 is -OR. In some embodiments, R 1 is -SR. In some embodiments, R 1 is -S(0)R. In some embodiments, R 1 is -S(0) 2 R. In some embodiments, R 1 is -NR 2 . In some embodiments, R 1 is - P(0)(OR) 2 . In some embodiments, R 1 is -P(0)(NR 2 )OR. In some embodiments, R 1 is - P(0)(NR 2 ) 2 . In some embodiments, R 1 is -Si(OH) 2 R.
  • R 1 is -Si(OH)(R) 2 . In some embodiments, R 1 is -Si(R) 3 . In some embodiments, R 1 is an optionally substituted Ci-4 aliphatic. In some embodiments, R 1 and X 1 or X 4 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, carbocyclic ring or heterocyclic ring having 1 -3 heteroatoms, independently selected from nitrogen, oxygen, or sulfur.
  • R 1 is selected from those depicted in Table 1, below.
  • each R 2 is independently hydrogen, deuterium, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, -N(R) 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , -S(0) 2 R, - S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , - N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 R 2 , -P(0)(OR) 2 , - P(0)( R 2 )OR, or -P(0)( R 2 ) 2 .
  • R 2 is hydrogen. In some embodiments, R 2 is deuterium. In some embodiments, R 2 is -R 6 . In some embodiments, R 2 is halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -N0 2 . In some embodiments, R 2 is -OR. In some embodiments, R 2 is -Si(OH) 2 R. In some embodiments, R 2 is -Si(OH)(R) 2 . In some embodiments, R 2 is -SR. In some embodiments, R 2 is -NR 2 . In some embodiments, R 2 is -Si(R) 3 . In some embodiments, R 2 is -S(0) 2 R.
  • R 2 is -S(0) 2 NR 2 . In some embodiments, R 2 is -S(0)R. In some embodiments, R 2 is -C(0)R. In some embodiments, R 2 is -C(0)OR. In some embodiments, R 2 is -C(0)NR 2 . In some embodiments, R 2 is -C(0)N(R)OR. In some embodiments, R 2 is -OC(0)R. In some embodiments, R 2 is -OC(0)NR 2 . In some embodiments, R 2 is -N(R)C(0)OR. In some embodiments, R 2 is -N(R)C(0)R. In some embodiments, R 2 is -N(R)C(0)NR 2 .
  • R 2 is -N(R)S(0) 2 R. In some embodiments, R 2 is -P(0)(OR) 2 . In some embodiments, R 2 is -P(0)(NR 2 )OR. In some embodiments, R 2 is -P(0)(NR 2 ) 2 .
  • R 2 is selected from those depicted in Table 1, below.
  • Ring A is a bi- or tricyclic ring selected from
  • Ring A is embodiments, Ring A is me embodiments, Ring A is . In some embodiments, Ring A is some embodiments, Ring A is odiments, Ring A is NR°
  • Ring A is . In some embodiments, Ring A is ome embodiments, Rin
  • Ring A is In some embodiments,
  • Ring A is . i n some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is .
  • Ring A is . In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments Rin A is In some embodiments, Ring A is T Inn s soommee e emmbbooddii .mmeennttss R Rii.nngcr A A i i.ss . In some embodiments,
  • Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments,
  • Ring A is In some embodiments, Ring A is
  • Ring A is embodiments, Ring A is
  • Ring A is ome embodiments, Ring ome embodiments, Ring A is . In some embodiments,
  • Ring A is selected from those depicted in Table 1, below.
  • Ring B is a fused ring selected from 6- membered aryl containing 0-3 nitrogen atoms, 5 to 7-membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.
  • Ring B is a 6-membered aryl containing 0-3 nitrogen atoms.
  • Ring B is a 5 to 7-membered partially saturated carbocyclyl.
  • Ring B is 5 to 7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, Ring B is 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. ome embodiments, Ring B is some embodiments, Ring B is In some embodiments, Ring
  • each Ring B is In some embodiments, each
  • Ring B is some embodiments, Ring B is In some embodiments, Ring B In some embodiments, Ring B In some embodiments, Ring B is . In some embodiments, Ring B is n some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is some embodiments, Ring B is . In some embodiments, Ring B is In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is
  • Ring B is selected from those depicted in Table 1, below.
  • — is a single bond. In some embodiments,— is a double bond.
  • — is selected from those depicted in Table 1, below.
  • R 3 is hydrogen, deuterium, halogen, -CN, - N0 2 , -OR, - R 2 , -SR, -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0) R(OR), -OC(0)R, -OC(0) R 2 , -OP(0)(OR) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)(OR) R 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 NR 2 , -N(R)P(0)(OR) 2 , -N(R)P(0)(OR) R 2 , -P(0)(OR) R
  • R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -N0 2 . In some embodiments, R 3 is -OR. In some embodiments, R 3 is -NR 2 . In some embodiments, R 3 is -SR. In some embodiments, R 3 is -S(0) 2 R. In some embodiments, R 3 is - S(0) 2 NR 2 . In some embodiments, R 3 is -S(0)R. In some embodiments, R 3 is -C(0)R. In some embodiments, R 3 is -C(0)OR.
  • R 3 is -C(0)NR 2 . In some embodiments, R 3 is -C(0)NR(OR). In some embodiments, R 3 is -OC(0)R. In some embodiments, R 3 is -OC(0)NR 2 . In some embodiments, R 3 is -OP(0)(OR) 2 . In some embodiments, R 3 is -OP(0)(NR 2 ) 2 . In some embodiments, R 3 is -OP(0)(OR)NR 2 . In some embodiments, R 3 is -N(R)C(0)R. In some embodiments, R 3 is -N(R)C(0)OR. In some embodiments, R 3 is -N(R)C(0)NR 2 .
  • R 3 is -N(R)S(0) 2 R. In some embodiments, R 3 is -N(R)S(0) 2 NR 2 . In some embodiments, R 3 is -N(R)P(0)(OR) 2 . In some embodiments, R 3 is -N(R)P(0)(OR) R 2 . In some embodiments, R 3 is -P(0)(OR) 2 . In some embodiments, R 3 is -P(0)( R 2 )OR. In some embodiments, R 3 is -P(0)(NR 2 ) 2 . In some embodiments, R 3 is -Si(OH) 2 R. In some embodiments, R 3 is -Si(OH)(R) 2 . In some embodiments, R 3 is -Si(R) 3 .
  • R 3 is methyl. In some embodiments, R 3 is -OCH 3 . In some embodiments, R 3 is chloro.
  • R 3 is selected from those depicted in Table 1, below.
  • each R 4 is independently hydrogen, deuterium, -R 6 , halogen, -CN, -N0 2 , -OR, -SR, - R 2 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -P(0)(OR) 2 , -P(0)( R 2 )OR, or -P(0)( R 2 ) 2 .
  • R 4 is hydrogen. In some embodiments, R 4 is -R 6 . In some embodiments, R 4 is halogen. In some embodiments, R 4 is -CN. In some embodiments, R 4 is - N0 2 . In some embodiments, R 4 is -OR. In some embodiments, R 4 is -SR. In some embodiments, R 4 is -NR 2 . In some embodiments, R 4 is -S(0) 2 R. In some embodiments, R 4 is -S(0) 2 NR 2 . In some embodiments, R 4 is -S(0)R. In some embodiments, R 4 is -C(0)R. In some embodiments, R 4 is -C(0)OR.
  • R 4 is -C(0)NR 2 . In some embodiments, R 4 is - C(0)N(R)OR. In some embodiments, R 4 is -OC(0)R. In some embodiments, R 4 is -OC(0)NR 2 . In some embodiments, R 4 is -N(R)C(0)OR. In some embodiments, R 4 is -N(R)C(0)R. In some embodiments, R 4 is -N(R)C(0)NR 2 . In some embodiments, R 4 is -N(R)S(0) 2 R. In some embodiments, R 4 is -P(0)(OR) 2 . In some embodiments, R 4 is -P(0)(NR 2 )OR. In some embodiments, R 4 is -P(0)(NR 2 ) 2 .
  • R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is cyclopropyl.
  • R 4 is selected from those depicted in Table 1, below.
  • R 5 is hydrogen, deuterium, an optionally substitute C 1-4 aliphatic, or -CN.
  • R 5 is hydrogen. In some embodiments, R 5 is deuterium. In some embodiments, R 5 is an optionally substituted C 1-4 aliphatic. In some embodiments, R 5 is - CN.
  • R 5 is selected from those depicted in Table 1, below.
  • each R 6 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • R 6 is an optionally substituted Ci-6 aliphatic. In some embodiments, R 6 is an optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R 6 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • R 6 is selected from those depicted in Table 1, below.
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy- -0-, -N(R)-, -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - -P(0)(OR)-, -P(0)(R)-, -P(0)( R 2 )-, -S-, -OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - - - - - -
  • L is a covalent bond.
  • L is a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy- -0-, -N(R)-, -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - , -P(0)(OR)-, -P(0)(R)-, -P(0)( R 2 )-, -S-, -OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - - N(R)S(0) 2 - -S(0) 2 N(R)-, -N(R)C(0)-, -C(0)N(R)-, -OC(0)N(R)-, -N(R)C(0)0-,
  • L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some
  • L is embodiments, L is s [00129] In some embodiments, L is In some embodiments, L is In some embodiments, L
  • L is some embodiments
  • L is In some embodiments, L is In some embodiments, L is In some embodiments, L is
  • L is selected from those depicted in Table 1, below.
  • each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 3-8 membered saturated or partially unsaturated carbocyclylenyl, a 6-11 membered saturated or partially unsaturated spiro carbocyclylenyl, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-10 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, a 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclyl,
  • -Cy- is an optionally substituted bivalent ring selected from phenylenyl. In some embodiments, -Cy- is an optionally substituted 8-10 membered bicyclic arylenyl. In some embodiments, -Cy- is an optionally substituted 3-8 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, -Cy- is an optionally substituted 6- 11 membered saturated or partially unsaturated spiro carbocyclylenyl. In some embodiments, - Cy- is an optionally substituted 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated carbocyclylenyl.
  • -Cy- is an optionally substituted 4- 10 membered saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur.
  • -Cy- is an optionally substituted 6-11 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur.
  • -Cy- is an optionally substituted 5-12 membered bridged or unbridged bicyclic saturated or partially unsaturated heterocyclylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur.
  • -Cy- is an optionally substituted 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, phosphorus, or sulfur.
  • -Cy- is selected from those depicted in Table 1, below.
  • TBM is a target binding moiety.
  • TBM is a target binding moiety.
  • TBM binds to a protein selected from those listed in paragraph
  • TBM is selected from one of the drugs listed in Table 2, wherein
  • the drug is attached to at any modifiable carbon, oxygen, sulfur or nitrogen atom.
  • TBM is selected from one of the drugs listed in Table 2, wherein
  • TBM is selected from one of the dru s listed in Table 2, wherein
  • the drug is attached to at any modifiable carbon, oxygen, sulfur or nitrogen atom.
  • TBM is selected from one of the drugs listed in Table 2, wherein
  • the drug is attached to at any modifiable carbon, oxygen, sulfur or nitrogen atom.
  • TBM In some embodiments, TBM
  • TBM is In some embodiments, TBM is . In some
  • TBM is selected from those depicted in Table 1, below.
  • n 0, 1, 2, 3 or 4.
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.
  • m is selected from those depicted in Table 1, below.
  • each n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.
  • n is selected from those depicted in Table 1, below.
  • each R is independently hydrogen, deuterium, or an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, or two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • R is hydrogen. In some embodiments, R is deuterium. In some embodiments, R is optionally substituted Ci- 6 aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R is optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • R is selected from those depicted in Table 1, below.
  • the present invention provides a compound of formula II-A or II-B, wherein X 1 , R 1 , R 5 , R, -Cy- and TBM are recited as for formula I as above and herein, and Ring A, Ring B, R 2 , R 3 , R 4 , L, m, n, p, and q are recited as for formula II-A and II-B as below and herein.
  • Ring A is a mono- or bicyclic ring selected
  • Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is In some embodiments, Ring embodiments, Ring A is In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is .
  • Ring A is e embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring
  • Ring A is . In some embodiments, Ring A is O In some embodiments, Ring A is in some embodiments, Ring A is 00156] In some embodiments, Ring A is . In some embodiments, Ring A is ome embodiments, Ring . In some embodiments, Ring A is . In some embodiments,
  • Ring A is . In some embodiments, Ring A is In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, Ring A is .
  • Ring A is in some embodiments, Ring A is . In some embodiments, Ring A is . In some embodiments, embodiment , Ring A is .
  • Ring A is a mono- or bicyclic ring selected from
  • Ring A is selected from those depicted in Table 1, below.
  • each R 2 is independently hydrogen, deuterium, -R 4 , halogen, -CN, -N0 2 , -OR, -SR, - R 2 , -Si(OH) 2 R, -Si(OH)(R) 2 , -Si(R) 3 , -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, -C(0) R 2 , -C(0)N(R)OR, -OC(0)R, -OC(0) R 2 , -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0)R, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 R 2 , -P(0)(OR) 2 , -P(0)( R 2 )OR, or -P(0)( R 2 ) 2
  • R 2 is hydrogen. In some embodiments, R 2 is deuterium. In some embodiments, R 2 is -R 4 . In some embodiments, R 2 is halogen. In some embodiments, R 2 is -CN. In some embodiments, R 2 is -N0 2 . In some embodiments, R 2 is -OR. In some embodiments, R 2 is -Si(OH) 2 R. In some embodiments, R 2 is -Si(OH)(R) 2 . In some embodiments, R 2 is -SR. In some embodiments, R 2 is -NR 2 . In some embodiments, R 2 is -Si(R) 3 . In some embodiments, R 2 is -S(0) 2 R.
  • R 2 is -S(0) 2 NR 2 . In some embodiments, R 2 is -S(0)R. In some embodiments, R 2 is -C(0)R. In some embodiments, R 2 is -C(0)OR. In some embodiments, R 2 is -C(0)NR 2 . In some embodiments, R 2 is -C(0)N(R)OR. In some embodiments, R 2 is -OC(0)R. In some embodiments, R 2 is -OC(0)NR 2 . In some embodiments, R 2 is -N(R)C(0)OR. In some embodiments, R 2 is -N(R)C(0)R. In some embodiments, R 2 is -N(R)C(0)NR 2 .
  • R 2 is -N(R)S(0) 2 R. In some embodiments, R 2 is -P(0)(OR) 2 . In some embodiments, R 2 is -P(0)( R 2 )OR. In some embodiments, R 2 is -P(0)( R 2 ) 2 .
  • R 2 is methyl
  • R 2 is selected from those depicted in Table 1, below.
  • Ring B is selected from a 6-membered aryl containing 0-3 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • Ring B is a 6-membered aryl containing 0-3 nitrogen atoms. In some embodiments, Ring B is a 5-membered heteroaryl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • Ring B is selected from those depicted in Table 1, below.
  • each R 3 is independently hydrogen, deuterium, halogen, -CN, -N0 2 , -OR, - R 2 , -SR, -S(0) 2 R, -S(0) 2 NR 2 , -S(0)R, -C(0)R, -C(0)OR, - C(0) R 2 , -C(0) R(OR), -OC(0)R, -OC(0) R 2 , -OP(0)(OR) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)( R 2 ) 2 , -OP(0)(OR) R 2 , -N(R)C(0)R, -N(R)C(0)OR, -N(R)C(0) R 2 , -N(R)S(0) 2 R, -N(R)S(0) 2 NR 2 , -N(R)P(0)(OR) 2 , -N(R)P(0)(OR) R 2 , -P(0)(OR
  • R 3 is hydrogen. In some embodiments, R 3 is deuterium. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -CN. In some embodiments, R 3 is -N0 2 . In some embodiments, R 3 is -OR. In some embodiments, R 3 is -NR 2 . In some embodiments, R 3 is -SR. In some embodiments, R 3 is -S(0) 2 R. In some embodiments, R 3 is - S(0) 2 NR 2 . In some embodiments, R 3 is -S(0)R. In some embodiments, R 3 is -C(0)R. In some embodiments, R 3 is -C(0)OR.
  • R 3 is -C(0)NR 2 . In some embodiments, R 3 is -C(0)NR(OR). In some embodiments, R 3 is -OC(0)R. In some embodiments, R 3 is -OC(0)NR 2 . In some embodiments, R 3 is -OP(0)(OR) 2 . In some embodiments, R 3 is -OP(0)(NR 2 ) 2 . In some embodiments, R 3 is -OP(0)(OR)NR 2 . In some embodiments, R 3 is -N(R)C(0)R. In some embodiments, R 3 is -N(R)C(0)OR. In some embodiments, R 3 is -N(R)C(0)NR 2 .
  • R 3 is -N(R)S(0) 2 R. In some embodiments, R 3 is -N(R)S(0) 2 NR 2 . In some embodiments, R 3 is -N(R)P(0)(OR) 2 . In some embodiments, R 3 is -N(R)P(0)(OR)NR 2 . In some embodiments, R 3 is -P(0)(OR) 2 . In some embodiments, R 3 is -P(0)( R2)OR. In some embodiments, R 3 is -P(0)(NR 2 ) 2 . In some embodiments, R 3 is - Si(OH)2R. In some embodiments, R 3 is -Si(OH)(R)2. In some embodiments, R 3 is -Si(R) 3 .
  • R 3 is selected from those depicted in Table 1, below.
  • each R 4 is independently an optionally substituted group selected from Ci- 6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • R 4 is an optionally substituted Ci-6 aliphatic. In some embodiments, R 4 is an optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, R 4 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.
  • R 4 is methyl
  • R 4 is selected from those depicted in Table 1, below.
  • L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy- -0-, -N(R)-, -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - -P(0)(OR)-, -P(0)(R)-, -P(0)( R 2 )-, -S-, -OC(O)-, -C(0)0- -C(O)-, -S(O)-, -S(0) 2 - -N(R)S(0) 2 - - -
  • L is a covalent bond.
  • L is a bivalent, saturated or unsaturated, straight or branched Ci-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy- -0-, -N(R)-, -Si(R) 2 - -Si(OH)(R)-, -Si(OH) 2 - , -P(0)(OR)-, -P(0)(R)-, -P(0)( R 2 )-, -S- C(0)0- -C(O)-, -S(O)-, -S(0) 2 - - N(R)S(0) 2 - -S(0) 2 N(R)-, -N - : OC(0)N(R)-, N(R)C(0)0-
  • L is selected from those depicted in Table 1, below.
  • n 0, 1, or 2.
  • m is 0. In some embodiments, m is 1. In some embodiments, m is 2.
  • m is selected from those depicted in Table 1, below.
  • n 0, 1, 2, 3, or 4.
  • n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
  • n is selected from those depicted in Table 1, below.
  • p is 0. In some embodiments, p is 1. In some embodiments, p
  • p is selected from those depicted in Table 1, below.
  • each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6. In some embodiments, q is 7. In some embodiments, q is 8. In some embodiments, q is 9. In some embodiments, q is 10.
  • the TBM group is a group, which binds to target proteins.
  • Targets of the TBM group are numerous in kind and are selected from proteins that are expressed in a cell such that at least a portion of the sequences is found in the cell and may bind to a TBM group.
  • the term"protein” includes oligopeptides and polypeptide sequences of sufficient length that they can bind to a TBM group according to the present invention. Any protein in a eukaryotic system, as described herein, are targets for ubiquitination mediated by the compounds according to the present invention.
  • TBM groups according to the present invention include, for example, include any moiety which binds to a protein specifically (binds to a target protein) and includes the following non-limiting examples of small molecule target protein moieties: Hsp90 inhibitors, kinase inhibitors, HDM2 & MDM2 inhibitors, compounds targeting Human BET Bromodomain- containing proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR), among numerous others.
  • the compositions described below exemplify some of the members of these nine types of small molecule target protein binding moieties.
  • Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs of these compositions, as well as other small molecules that may target a protein of interest.
  • These binding moieties are linked to the ubiquitin ligase binding moiety preferably through a linker in order to present a target protein (to which the protein target moiety is bound) in proximity to the ubiquitin ligase for ubiquitination and degradation.
  • target proteins may include, for example, structural proteins, receptors, enzymes, cell surface proteins, proteins pertinent to the integrated function of a cell, including proteins involved in catalytic activity, aromatase activity, motor activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transducer activity, structural molecule activity, binding activity (protein, lipid carbohydrate), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, response to stimulus, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport
  • Proteins of interest can include proteins from eurkaryotes and prokaryotes including humans as targets for drug therapy, other animals, including domesticated animals, microbials for the determination of targets for antibiotics and other antimicrobials and plants, and even viruses, among numerous others.
  • TBM (or target binding moiety) is a small molecule which is capable of binding to or binds to a target protein of interest.
  • TBMs which include but are not limited to Hsp90 inhibitors, kinase inhibitors, MDM2 inhibitors, compounds targeting Human BET Bromodomain-containing proteins, compounds targeting cytosolic signaling protein FKBP12, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (AHR).
  • TBM is a BRD ligand selected from
  • TBM is a glucocorticoid receptor ligand selected from
  • TBM is a RasG12C ligand selected from
  • TBM is a Bcl-2/Bcl-XL ligand selected from
  • TBM is an Abl, KRAS, SHP2, cRAF, MerTK or PRMT5 ligand that are selected from the following non-limiting examples:
  • a TBM moiety is selected from PTM moieties as recited in WO 2016/197032 the entirety of which is incorporated herein by reference. In some embodiments, a TBM moiety is selected from such inhibitors as described in WO 2016/197032 at paragraphs [00116] through [00173] wherein the recitation of a "Linker" moiety in WO 2016/197032 corresponds to the -L- group as defined and described herein.
  • the method employs a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a compound of formula I, wherein the compound is not any of compounds depicted in Table A-1, below.
  • the present invention provides a compound of formula II-A, wherein the compound is not any of compounds depicted in Table A-2, below.
  • ADX10059 antimigraine agent for treatment of GRM5 gastroesophageal reflux disease
  • succinobucol antiatherosclerosis agent VCAM1 succinobucol antiatherosclerosis agent
  • AGN-214868 analgesic,neuralgia ADRA1A
  • AGN-214868 analgesic,neuralgia ADRA1B
  • AGN-214868 analgesic,neuralgia ADRA1D
  • AGN-214868 analgesic,neuralgia ADRA2A
  • AGN-214868 analgesic,neuralgia ADRA2B
  • AGN-214868 analgesic,neuralgia ADRA2C Drug Name Indication(s) Gene agomelatine antidepressant MTNR1B agomelatine antidepressant HTR2B agomelatine antidepressant HTR2C agomelatine antidepressant MTNR1A hydroxychloroquine antirheumatic agent TLR7 hydroxychloroquine antirheumatic agent TLR9 paclitaxel antineoplastic agent BCL2 paclitaxel antineoplastic agent TUBB1
  • buprenorphine antidepressant for OPRD1 treatment of opioid addiction
  • buprenorphine antidepressant for OPRK1 treatment of opioid addiction
  • altropane diagnostic agent for parkinson's SLC6A3 disease and ADHD
  • ADRB3 amifostine radiation-protective agent ALPPL2 amiodarone antiarrhytmic agent ADRA1A amiodarone antiarrhytmic agent ADRB1 amiodarone antiarrhytmic agent KC H2 amisulpride antipsychotic agent DRD2 amisulpride antipsychotic agent DRD3 amitriptyline analgesic SLC6A2 amitriptyline analgesic SLC6A4 ketamine analgesic GRIN3A amlodipine antihypertensive agent, CACNA1C cardiovascular agent
  • amlodipine antihypertensive agent CACNA1D cardiovascular agent Drug Name Indication(s) Gene amlodipine antihypertensive agent, CACNA1 S cardiovascular agent
  • amlodipine antihypertensive agent CACNA2D1 cardiovascular agent
  • amlodipine antihypertensive agent CACNB2 cardiovascular agent
  • Anacetrapib for treatment of dyslipidemia CETP anamorelin appetite stimulating agent GHSR anastrozole antineoplastic agent CYP19A1 anatibant for treatment of traumatic brain BDKRB2 injury
  • ARRY-614 for treatment of myelodysplastic ABLl syndrome
  • ARRY-614 for treatment of myelodysplastic KDR syndrome
  • ARRY-614 for treatment of myelodysplastic MAPK11 syndrome Drug Name Indication(s) Gene
  • ARRY-614 for treatment of myelodysplastic MAPK12 syndrome
  • ARRY-614 for treatment of myelodysplastic MAPK13 syndrome
  • ARRY-614 for treatment of myelodysplastic MAPK14 syndrome
  • arverapamil for treatment of irritable bowel CACNA1 S syndrome Drug Name Indication(s) Gene arverapamil for treatment of irritable bowel CAC B1 syndrome
  • Arzoxifene antineoplastic agent antiosteoporotic ESR1 agent

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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EP18857581.5A EP3684365A4 (en) 2017-09-22 2018-09-21 PROTEIN DEGRADATION AGENTS AND USES OF SUCH
IL307995A IL307995A (en) 2017-09-22 2018-09-21 Protein compounds and their uses
MX2020003190A MX2020003190A (es) 2017-09-22 2018-09-21 Degradadores de proteinas y usos de los mismos.
IL322809A IL322809A (en) 2017-09-22 2018-09-21 Protein Decomposers and Their Uses
IL295603A IL295603B2 (en) 2017-09-22 2018-09-21 Protein degraders and uses thereof
EP25195747.8A EP4624467A3 (en) 2017-09-22 2018-09-21 Protein degraders and uses thereof
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US17/837,449 US20230115184A1 (en) 2017-09-22 2022-06-10 Protein degraders and uses thereof
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AU2025201796A AU2025201796A1 (en) 2017-09-22 2025-03-12 Protein degraders and uses thereof
US19/304,052 US20260085075A1 (en) 2017-09-22 2025-08-19 Protein degraders and uses thereof
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