WO2021126974A1 - Bifunctional agents for protein recruitment and/or degradation - Google Patents

Bifunctional agents for protein recruitment and/or degradation Download PDF

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Publication number
WO2021126974A1
WO2021126974A1 PCT/US2020/065304 US2020065304W WO2021126974A1 WO 2021126974 A1 WO2021126974 A1 WO 2021126974A1 US 2020065304 W US2020065304 W US 2020065304W WO 2021126974 A1 WO2021126974 A1 WO 2021126974A1
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Prior art keywords
cio
inhibitor
groups
aryl
valence
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PCT/US2020/065304
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French (fr)
Inventor
Nikolai Kley
Riccardo Sabatini
Edward Suh
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Orionis Biosciences, Inc.
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Priority to US17/786,162 priority Critical patent/US20230099031A1/en
Priority to EP20903863.7A priority patent/EP4076530A4/en
Priority to CA3162266A priority patent/CA3162266A1/en
Priority to CN202080096815.8A priority patent/CN115348872A/en
Priority to JP2022537441A priority patent/JP2023508891A/en
Priority to AU2020408333A priority patent/AU2020408333A1/en
Publication of WO2021126974A1 publication Critical patent/WO2021126974A1/en

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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, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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
    • A61K47/545—Heterocyclic compounds
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 invention provides new compounds, including bifunctional compounds, for the degradation of a target protein by the ubiquitin proteasome pathway for therapeutic applications as described further herein.
  • Protein degradation is a highly regulated and essential process that maintains cellular homeostasis.
  • the selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP).
  • UPP ubiquitin-proteasome pathway
  • Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins.
  • Thalidomide and its analogues have been found to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (Ito, T. et al., Science, 2010, 327: 1345). Cereblon forms part of an E3 ubiquitin ligase complex which interacts with damaged DNA binding protein, forming an E3 ubiquitin ligase complex with Cullin 4 and the E2 -binding protein ROC1 (known as RBX1) where it functions as a substrate receptor to select proteins for ubiquitination.
  • ROC1 the E2 -binding protein
  • the present invention relates to new compounds and their uses and manufacture thereof.
  • the compounds have general formula (A)k-Li or (A)k-L-Q.
  • Moiety A of the compounds binds to cereblon.
  • L or Li is a linker.
  • Moiety Q is a moiety that binds to a target protein which is sequestered to the E3 ubiquitin ligase and/or degraded upon interaction with the E3 ubiquitin ligase.
  • the present invention relates to a compound having the general formula (A)k-Li, or a salt, enantiomer, stereoisomer, polymorph, orN-oxide thereof, wherein:
  • A is a moiety that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
  • Li is a linker; each A is covalently linked to the Li as allowed by valence;
  • R 1 is aryl, -N(R 5 )-X-R 6 , -SO2R 5 , or -0(CH2)mR 5 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 2 is aryl, -NH-(C3-CIO) heteroaryl, or -N(R 5 )-(CH2)m-X-(CH2) n -R 6 , any of which may be optionally substituted with 1 or more R" groups as allowed by valence;
  • R 3 is cyano, aryl, -NH-(C i-Cm) heteroaryl, (C3-Cio)heterocyclo, or -N(R 5 )-(CH2)m-X- (CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 4 is halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n- ary 1. -(CkkVheteroaryl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroarvl. or R 5 and R 6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 7 is H, (Ci-C3)alkyl, or R 7 and R 26 taken together with the carbons they are attached to forming a carbon carbon double bond;
  • R 8 , R 9 , R 10 , R 11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 12 , R 13 , R 14 , R 15 each is independently H, NH2, (Ci-C3)alkyl, -N(R 5 )-(CH2)m-N(R 5 )- X-R 6 , with proviso that no more than three substituents out of R 12 , R 13 , R 14 , and R 15 are H, any of which may be optionally substituted with 1 or more R" groups as allowed by valence;
  • R 16 is NH2 or -N(R 5 )-(CH2) m -X-(CH 2 )n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 17 is cyano, heteroaryl, -(CH2)m-C(0)0-R 6 , or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 18 , R 19 , R 20 , R 21 each independently is H, halo, (Ci-C: alkyl, (Ci-C3)alkoxy, or - N(R 5 )-X-R 6 , with the proviso that no more than two substituents of R 18 , R 19 , R 20 , R 21 are H; or
  • R 25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R w at each occurrence is independently H, halo, cyano, nitro, oxo, alky l, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH
  • X is a bond, -S0 2 -, -(CH 2 )nC(0)(CH 2 ) m -, -C(0)NH-, -C(0)N(R w )-, -NHC(0)NH-, or -(CH 2 )n-;
  • Yi is -NHR 25 , -NHC(0)R 25 , or -CHR 25 R 26 ; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
  • H is hydrogen
  • Lb is selected from the group consisting of:
  • t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the present invention relates to a compound of the general formula (A)k-L-Q, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, wherein:
  • A is a compound that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
  • Q is a moiety that binds to a target protein which is sequestered to the E3 ubiquitin ligase and/or degraded upon interaction with the E3 ubiquitin ligase;
  • L is a linker; each A is covalently linked to the L as allowed by valence;
  • R 1 is aryl, -N(R 5 )-X-R 6 , -SO2R 5 , or -0(CH2)mR 5 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 2 is aryl, -NH-(C3-CIO) heteroaryl, or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 3 is cyano, aryl, -NH-(C3-CIO) heteroaryl, (C3-Cio)heterocyclo, or -N(R 5 )-(CH2)m-X- (CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 4 is halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CFhV aryl, -(CH2)n-heteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl. or R 5 and R 6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 7 is H, (Ci-C3)alkyl, or R 7 and R 26 taken together with the carbons they are attached to forming a carbon carbon double bond;
  • R 8 , R 9 , R 10 , R 11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 12 , R 13 , R 14 , R 15 each is independently H, NH2, (Ci-C3)alkyl, -N(R 5 )-(CH2)m-N(R 5 )- X-R 6 , with proviso that no more than three substituents out of R 12 , R 13 , R 14 , and R 15 are H, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 16 is NH2 or -N(R 5 )-(CH2) m -X-(CH 2 )n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 17 is cyano, heteroaryl, -(CH2)m-C(0)0-R 6 , or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 18 , R 19 , R 20 , R 21 each independently is H, halo, (Ci-C3)alkyl, (Ci-C3)alkoxy, or - N(R 5 )-X-R 6 , with the proviso that no more than two substituents of R 18 , R 19 , R 20 , R 21 are H; or
  • R 25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R w at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl.
  • cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, -(CPhL-heteroaryl. aryl, and heteroaryl;
  • X is a bond, -SO2-, -(CH2)nC(0)(CH 2 )m-, -C(0)NH-, -C(0)N(R">. -NHC(0)NH-, or -(CH 2 )n-;
  • Yi is -NHR 25 , -NHC(0)R 25 , or-CHR 25 R 26 ; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
  • Lb is selected from the group consisting of: t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. [0014] In an embodiment, L is -(CfhCLhy, -(CLLO or -(CfhCfhC t-.
  • moiety A is selected from the group consisting of:
  • Q is a moiety that binds to a target protein, wherein said target protein is selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, Bel, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, Squalene-hopene cyclase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase.
  • target protein is selected from the group consisting
  • Q is a moiety that is an Hsp90 inhibitor, a kinase inhibitor, a phosphatase inhibitor, an HDM2/MDM2 inhibitor, a human BET Bromodomain inhibitor, an HD AC inhibitor, a human lysine methyltransferase inhibitor, a RAF receptor inhibitor, a FKBP inhibitor, an angiogenesis inhibitor, an aryl hydrocarbon receptor inhibitor, an androgen receptor inhibitor, an estrogen receptor inhibitor, a thyroid hormone receptor inhibitor, an HIV protease inhibitor, an HIV integrase inhibitor, an acyl protein thioesterase 1 inhibitor, or an acyl protein thioesterase 2 inhibitor.
  • Q is a moiety that is a TANK-binding kinase 1 (TBK1) inhibitor, an estrogen receptor a (ERa) inhibitor, a bromodomain-containing protein 4 (BRD4) inhibitor, an androgen receptor (AR) inhibitor, a platelet-derived growth factor receptor inhibitor, a p38 MAPK inhibitor, aBcr-Abl tyrosine-kinase inhibitor, an Her2 inhibitor, an EGFR inhibitor, an MDM2 inhibitor, a bromodomain-containing protein 2 (BRD2) inhibitor, an HD AC inhibitor, a DHFR inhibitor, or a c-Myc inhibitor.
  • Q is a moiety selected from the group consisting of trimethoprim, vorinostat, tamoxifen, JQ1, Nutlin 3, afatinib, chloroalkane, dasatinib, BIRB796, FK-506, simvastatin, rapamycin, and sorafenib.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula (A)k-L-Q or (A)k-Li and a pharmaceutically acceptable carrier, additive, and/or excipient.
  • the composition is a bivalent inducer of protein degradation (also known as a proteolysis-targeting chimera (PROTAC)).
  • the composition is a CLIckable Proteolysis TArgeting Chimeras (CLIPTACs).
  • Such CLIPTAC includes (a) a first portion comprising a ligand for a target protein; (b) a second portion comprising a ligand for an E3 ubiquitin ligase; and (c) a linker portion covalently coupling the first and second portions; wherein the linker comprises a covalent bond produced by a bioorthogonal click reaction between a compatible pair of reactive moieties.
  • the composition is an in-cell click-formed proteolysis targeting chimera (CLIPTAC).
  • the present invention relates to a method for treating a disease in a subject, said method compnsing administering an effective amount of a compound having Formula (A)k-L-Q or (A)k-Li
  • the present invention relates to a method for treating a disease in a subject wherein dysregulated protein activity is responsible for said disease, said method comprising administering an effective amount of a compound having Formula (A)k-L-Q or (A)k-Li.
  • the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, renal cell carcinomas, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemias, lymphomas, Burkitt's lymphoma, Non-Hodgkin's lymphoma, melanomas, myeloproliferative diseases, multiple myeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendroglio
  • the present invention relates to a method of treating or preventing one or more autoimmune diseases or disorders comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject in need thereof.
  • the autoimmune disease or disorder is selected from, such as multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, Fibromyalgia, Menier's syndrome; transplantation rejection (e g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren’s syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome,
  • the subject is a human.
  • FIG. 1 illustrates the HNMR of the intermediate compound 53 in Example 5.
  • FIG. 2 illustrates the LCMS data of Trimethoprim-lenalidomide (TMP-LEN).
  • FIG. 3 illustrates TMP-LEN hybrid ligand-induced binding between CRBN and DHFR detected with a MAPPIT-like assay.
  • a hybrid molecule consisting of the DHFR ligand trimethoprim (TMP) fused to the CRBN ligand lenalidomide through a PEG linker was used to induce DHFR recruitment to CRBN bait in the MAPPIT assay.
  • TMP trimethoprim
  • the present invention provides such compounds having general formula (A)k-Li or (A)k-L-Q, wherein A is a moiety binding to the E3 ubiquitin ligase protein; L or Li is a linker; Q is a moiety binding to the target protein.
  • compounds disclosed herein, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof can be used to treat a disorder mediated by one or more of cereblon, IKZF1, SALL4, and ASS1, e g. various cancers and autoimmune diseases or disorders.
  • ⁇ denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
  • alkyl is used, either alone or within other terms such as “haloalkyl” or “alkylamino", it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms.
  • alkylenyl or “alkylene” embraces bridging divalent alkyl radicals such as methylenyl or ethyl enyl.
  • lower alkyl substituted with R 2 does not include an acetal moiety.
  • alkyl further includes alkyl radicals wherein one or more carbon atoms in the chain is substituted with a heteroatom selected from oxygen, nitrogen, or sulfur.
  • alkenyl embraces linear or branched radicals having at least one carbon- carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • alkenyl and “lower alkenyl” embrace radicals having "cis” and “trans” orientations, or alternatively, "E” and "Z” orientations.
  • alkynyl denotes linear or branched radicals having at least one carbon- carbon triple bond and having two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl” radicals having two to about six carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, and butynyl, and the like.
  • Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, ammo, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo and the like.
  • halo means halogens such as fluorine, chlorine, bromine or iodine atoms.
  • haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl.
  • a monohaloalkyl radical for example, may have either an iodo, bromo, chloro or fluoro atom within the radical.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
  • “Lower haloalkyl” embraces radicals having 1 to 6 carbon atoms.
  • haloalkyl radicals having one to three carbon atoms.
  • haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • perfluoroalkyl means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
  • hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl” radicals having one to six carbon atoms and one or more hy droxyl radicals. Examples of such radicals include hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
  • alkoxy embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy propoxy, butoxy and tert- butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one or two rings, wherein such nngs may be attached together in a fused manner.
  • aryl embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl.
  • An "aryl” group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino, and the like. Phenyl substituted with -O-CH2-O- forms the aryl benzodioxolyl substituent.
  • heterocyclyl (or heterocyclo ) embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing -O-O-, -O-S- or -S-S- portions.
  • the "heterocyclyl” group may have 1 to 4 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino.
  • saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocychc groups containing 1 to 4 nitrogen atoms [e g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocychc group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl] ; saturated 3 to 6-membered heteromonocychc group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
  • heteroaryl radicals examples include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-
  • heterocyclyl also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isomdolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazmyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
  • heterocyclic radicals include five to ten membered fused or unfused radicals.
  • heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl.
  • Other preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, py ridyl, piperidinyl and pyrazinyl.
  • non-nitrogen containing heteroary l include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, and benzothienyl, and the like.
  • Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2, 3, 4, 4a, 9,9a- hexahydro-lH-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinoly
  • heterocyclo thus encompasses the following ring systems:
  • sulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-.
  • sulfamyl denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO2NH2).
  • alkylaminosulfonyl includes "N-alkylaminosulfonyl” where sulfamyl radicals are independently substituted with one or two alkyl radical(s). More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl” radicals having one to six carbon atoms.
  • lower alkylaminosulfonyl radicals having one to three carbon atoms.
  • Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl.
  • N-alkylaminocarbonyl and N,N-dialkylaminocarbonyl denote aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to an aminocarbonyl radical.
  • N-arylaminocarbonyl and "N-alkyl-N-arylammocarbonyl” denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical.
  • heterocyclylalkylenyl and “heterocyclylalkyl” embrace heterocyclic- substituted alkyl radicals. More preferred heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl” radicals having alkyl portions of one to six carbon atoms and a 5- or 6- membered heteroaryl radical. Even more preferred are lower heteroarylalkylenyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridylmethyl and thienylmethyl.
  • aralkyl embraces aryl-substituted alkyl radicals.
  • Preferable aralkyl radicals are "lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are “phenylalkylenyl” attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl.
  • the aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy. halkoalkyl and haloalkoxy.
  • alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms.
  • An example of “alkylthio” is methylthio, (CEES-).
  • haloalkylthio embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalky lthio radicals having one to three carbon atoms. An example of “haloalkylthio” is trifluoromethylthio.
  • alkylamino embraces “N-alkylamino” and “N,N-dialkylamino” where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom.
  • Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N- ethylamino, N,N-dimethylamino, and N,N-diethylammo, and the like.
  • arylamino denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino.
  • the ary lamino radicals may be further substituted on the aryl ring portion of the radical.
  • heteroarylamino denotes amino groups, which have been substituted with one or two heteroaryl radicals, such as N-thienylamino.
  • heteroarylamino radicals may be further substituted on the heteroaryl ring portion of the radical.
  • aralkylamino denotes amino groups, which have been substituted with one or two aralkyl radicals. More preferred are phenyl -Ci-CT-alkylamino radicals, such as N- benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion.
  • N-alkyl-N-arylamino and “N-aralkyl-N-alkylamino” denote amino groups, which have been independently substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.
  • aminoalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl” radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and ammohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.
  • alkylammoalkyl embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl” radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl, and N,N-diethylaminomethyl, and the like.
  • alkylaminoalkoxy embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy” radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N- methylaminoethoxy, N,N-dimethylaminoethoxy, and N,N-diethylaminoethoxy, and the like.
  • alkylammoalkoxyalkoxy embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylammoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylammoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms.
  • Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N,N- dimethylaminoethoxyethoxy, and N,N-diethylaminomethoxymethoxy, and the like.
  • carboxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl” radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, and carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CEk groups.
  • halosulfonyl embraces sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl.
  • arylthio embraces aryl radicals of six to ten carbon atoms, atached to a divalent sulfur atom. An example of “arylthio” is phenylthio.
  • aralkylthio embraces aralkyl radicals as described above, atached to a divalent sulfur atom. More preferred are phenyl-Ci-C3-alkylthio radicals. An example of “aralkylthio” is benzylthio.
  • aryloxy embraces optionally substituted ary l radicals, as defined above, atached to an oxygen atom. Examples of such radicals include phenoxy.
  • aralkoxy embraces oxy-contammg aralkyl radicals atached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy” radicals having optionally substituted phenyl radicals atached to lower alkoxy radical as described above.
  • heteroaryloxy embraces optionally substituted heteroaryl radicals, as defined above, atached to an oxygen atom.
  • heteroarylalkoxy embraces oxy- containing heteroarylalkyl radicals atached through an oxygen atom to other radicals. More preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy” radicals having optionally substituted heteroaryl radicals atached to lower alkoxy radical as described above.
  • cycloalkyl includes saturated carbocyclic groups.
  • Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl.
  • cycloalkylalkyl embraces cycloalkyl-substituted alkyl radicals.
  • Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl” radicals having cycloalkyl radicals atached to alkyl radicals having one to six carbon atoms. Even more preferred are "5 to 6-membered cycloalkylalkyl” atached to alkyl portions having one to three carbon atoms. Examples of such radicals include cyclohexylmethyl.
  • the cy cloalkyl in said radicals may be additionally substituted with halo, alkyl, alkoxy and hydroxy.
  • cycloalkenyl includes carbocyclic groups having one or more carbon- carbon double bonds including " cycloalky ldienyl” compounds.
  • Preferred cycloalkenyl groups include Ci-Ce rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.
  • the term “comprising” is meant to be open ended, including the indicated component but not excluding other elements.
  • a group or atom that replaces a hydrogen atom is also called a substituent.
  • Any particular molecule or group can have one or more substituent depending on the number of hydrogen atoms that can be replaced.
  • the symbol represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group.
  • the symbol is commonly used to represent a methyl group in a molecule.
  • terapéuticaally effective amount means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.
  • patient and “subj ect” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals. The term patient includes males and females.
  • pharmaceutically acceptable means that the referenced substance, such as a compound of Formula I, or a salt of a compound of Formula I, or a formulation containing a compound of Formula I, or a particular excipient, are suitable for administration to a patient.
  • treating include preventative (e.g., prophylactic) and palliative treatment.
  • excipient means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient.
  • API active pharmaceutical ingredient
  • cancer means a physiological condition in mammals that is characterized by unregulated cell growth.
  • General classes of cancers include carcinomas, lymphomas, sarcomas, and blastomas.
  • compositions are administered to a patient in a therapeutically effective amount.
  • the compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation.
  • the compounds or compositions can be admimstered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.
  • the compounds of the present invention can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) mtracistemally, mtravaginally, mtrapentoneally, mtravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • a coating such as lecithin
  • surfactants for example, water, alcohol, alcohol, and the like.
  • compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Solid dosage forms for oral administration include capsules, tablets, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, mannitol, and silicic acid;
  • binders as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia;
  • humectants as for example, glycerol;
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • solution retarders as for example, paraffin;
  • absorption accelerators as for example, quaternary' ammonium compounds;
  • compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well know n in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are poly meric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing
  • the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administration are preferable suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
  • Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants.
  • the active compound or fit compounds are admixed under sterile condition with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required.
  • Opthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient.
  • the specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill in the art.
  • the compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodmgs.
  • salts refers to inorganic and organic salts of compounds of the present invention.
  • the salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • the salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19 (1977).
  • esters of the compounds of the present invention include Ci-Cs alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl. C1-C4 alkyl esters are commonly used. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.
  • Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary Ci-Cx alkyl amines, and secondary Ci-Cs dialkyl amines.
  • the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom.
  • Amides derived from ammonia, C1-C3 primary alkyl amines and C1-C2 dialkyl secondary amines are commonly used.
  • Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.
  • prodrug means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • a discussion of the use of prodrugs is provided by T Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-Ce alkyl, (C2-Ci2)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, l-methyl-l-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthali
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C6)alkanoyloxy methyl, l-(( Ci-C6)alkanoyloxy)ethyl, 1- methyl-l-(( Ci-C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxy methyl, N-( Ci- C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C6)alkanoyl, a-amino(Ci-C4)alkanoyl, arylacyl and a-aminoacyl, or a-ammoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(0)(0H)2, - P(0)(0(Ci-C6)
  • the compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated as S and E, respectively), as well as mixtures, are contemplated.
  • stereoisomers such as diastereomeric mixtures
  • Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e g., an alcohol
  • separating the diastereomers converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • some compounds may be atropisomers (e.g., substituted biaryls).
  • the compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like.
  • compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the tetrazole moiety are included in this invention Also, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention.
  • the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.
  • the present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nrtrogen, oxygen, phosphorous, fluonne and chlonne, such as 2 H, ⁇ , 13 C, 14 C, 15 N, 16 0, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F, and 36 C1.
  • the present invention relates to compounds wherein one or more hydrogen atom is replaced with deuterium ( 2 H) atoms.
  • Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically- labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detection.
  • Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds of the present invention may exist in vanous solid states including crystalline states and as an amorphous state.
  • the different crystalline states, also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.
  • the present invention relates to a compound having the general formula (A)k-Li, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, wherein:
  • A is a moiety that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
  • Li is a linker; each A is covalently linked to the Li as allowed by valence;
  • R 1 is aryl, -N(R 5 )-X-R 6 , -SO2R 5 , or -0(CH2)mR 5 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 2 is aryl, -NH-(C3-CIO) heteroaryl, or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 3 is cyano, aryl, -NH-(C3-CIO) heteroaryl, (C3-Cio)heterocyclo, or -N(R 5 )-(CH2)m-X- (CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 4 is halo, cyano, aryl, OR 5 , or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n- aiyl. -(CH2)n-heteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryd, or R 5 and R 6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic nng, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 7 is H, (Ci-C3)alkyl, or R 7 and R 26 taken together with the carbons they are attached to forming a carbon carbon double bond;
  • R 8 , R 9 , R 10 , R 11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 12 , R 13 , R 14 , R 15 each is independently H, NH2, (Ci-C3)alkyl, -N(R 5 )-(CH2)m-N(R 5 )- X-R 6 , with proviso that no more than three substituents out of R 12 , R 13 , R 14 , and R 15 are H, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 16 is NH2 or -N(R 5 )-(CH2) m -X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 17 is cyano, heteroaryl, -(CH2)m-C(0)0-R 6 , or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 18 , R 19 , R 20 , R 21 each independently is H, halo, (Ci-C3)alkyl, (Ci-C3)alkoxy, or - N(R 5 )-X-R 6 , with the proviso that no more than two substituents of R 18 , R 19 , R 20 , R 21 are H; or R 18 , R 19 taken together with the carbons they are attached to forming a (C3- Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R 19 , R 20 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a
  • R 25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R w at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n
  • X is a bond, -SO2-, -(CH2)nC(0)(CH 2 )m-, -C(0)NH-, -C(0)N(R w )-, -NHC(0)NH-, or -(CH 2 )n-;
  • Yi is -NHR 25 , -NHC(0)R 25 , or-CHR 25 R 26 ; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
  • H is hydrogen
  • Lb is selected from the group consisting of:
  • t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • moiety A is selected from the compounds listed in Table 6 in Example 6.
  • the present invention relates to a compound of the general formula (A)k-L-Q, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, wherein:
  • A is a compound that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
  • Q is a moiety that binds to a target protein which is sequestered to the E3 ubiquitin ligase and/or degraded upon interaction with the E3 ubiquitin ligase;
  • L is a linker; each A is covalently linked to the L as allowed by valence;
  • R 1 is aryl, -N(R 5 )-X-R 6 , -SO2R 5 , or -0(CH2)mR 5 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 2 is aryl, -NH-(C3-CIO) heteroaryl or -N(R 5 )-(CH2)m-X-(CH2)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 3 is cyano, aryl, -NH-(C3-CIO) heteroaryl, (O-Cio)heterocyclo. or -N(R 5 )-(CH2)m-X- (CEh)n-R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 5 at each occurrence is independently H, (Cr-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cro) cycloalkyl, -(CH2)n-(C3-Cro)heterocyclo, -(CEhy aryl, -(CEbVheteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R 5 and R 6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more R w groups as allowed by valence; R 7 is H, (Ci-C3)alkyl, or R 7 and R 26 taken together with the carbons they are attached to forming a carbon carbon double bond;
  • R 8 , R 9 , R 10 , R 11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 12 , R 13 , R 14 , R 15 each is independently H, NH2, (Ci-C3)alkyl, -N(R 5 )-(CH 2 )m-N(R 5 )- X-R 6 , with proviso that no more than three substituents out of R 12 , R 13 , R 14 , and R 15 are H, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 16 is NH2 or -N(R 5 )-(CH 2 ) m -X-(CH 2 ) n -R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 17 is cyano, heteroaryl, -(CH 2 )m-C(0)0-R 6 , or -N(R 5 )-(CH 2 ) m -X-(CH 2 ) n -R 6 , any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 18 , R 19 , R 20 , R 21 each independently is H, halo, (Ci-C: alkyl, (Ci-C3)alkoxy, or - N(R 5 )-X-R 6 , with the proviso that no more than two substituents of R 18 , R 19 , R 20 , R 21 are H; or
  • R 25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R w at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl. cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH 2
  • X is a bond, -SO2-, -(CH2)nC(0)(CH 2 )m-, -C(0)NH-, -C(0)N(R w )-, -NHC(0)NH-, or -(CH 2 )n-;
  • Yi is -NHR 25 , -NHC(0)R 25 , or-CHR 25 R 26 ; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
  • Lb is selected from the group consisting of:
  • L is -(CH 2 CH2)t-, -(CH20)t- or -(CH 2 CH 2 0)t-.
  • A is a moiety of Formula XI or a pharmaceutically acceptable salt thereof, wherein:
  • R 22 is H, halo, OH, -NR 5 R 5 , (Ci-C3)alkyl, (Ci-C3)alkoxy, (hydroxy)(Ci-C3)alkyl, cyano, -N(R 5 )-X-R 6 , -N(R 5 )-(CH 2 )m-N(R 5 )-X-R 6 , aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 23 is H, halo, OH, -NR 5 R 5 , -(CH 2 )n-NR 5 R 5 , (Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, - C(0)NR 5 R 6 , (hydroxy)(Ci-C3)alkyl, cyano, -N(R 5 )-X-R 6 , -N(R 5 )-(CHR 5 ) m -X-R 6 , - N(R 5 )-(CH2)m-N(R 5 )-X-R 6 , aryl, heteroaryl, or R 22 and R 23 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl ring or a (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R 24 is H, halo, OH, -NR 5 R 5 , -(CH2)n-NR 5 R 5 , (Ci-C 3 )alkyl, (Ci-C3)alkoxy, (halo)(Ci- C 3 )alkyl, (hydroxy)(Ci-C 3 )alkyl, cyano, -NO2, -N(R 5 )-X-R 6 , -N(R 5 )-(CH 2 )m-N(R 5 )- X-R 6 , aryl, heteroaryl, or R 23 and R 24 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl ring or a (C3-Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more R w groups as allowed by valence; R 5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)he
  • R 6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryd, or R 5 and R 6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic nng, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R w at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alky ny l.
  • cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, and heteroaryl;
  • X is a bond, -SO2-, -(CH2)nC(0)(CH 2 )m-, -C(0)NH-, -C(0)N(R">, -NHC(0)NH-, or -(CH 2 )n-; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4.
  • R 22 is H; R 23 is H; R 24 is halo.
  • A is a moiety of Formula XII, XIII, XIV, XV, XVI, XVII, or XVIII,
  • R 28 , R 29 , R 30 , R 31 is independently H, halo, OH, -NR 5 R 5 , -(CH2)n-NR 5 R 5 , (Ci-C3)alkyl, (Ci-C3)alkoxy, (halo)(Ci-C3)alkyl, (hydroxy)(Ci-C3)alkyl, cyano, -NO2, -N(R 5 )-X-R 6 , -N(R 5 )-(CH2)m-N(R 5 )-X-R 6 , aryl, heteroaryl, or R 28 , R 29 taken together with the carbons to which they are attached to form a (C3-Cio)cycloalkyl or a (C3- Cio)heterocyclo, or R 30 , R 31 taken together with the carbons to which they are attached to form a (C3-Cio)cycloalkyl or a (C 3
  • R 6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH 2 )n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R 5 and R 6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more R w groups as allowed by valence;
  • R w at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, ary lalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)
  • X is a bond, -SO2-, -(CH 2 )nC(0)(CH 2 )m-, -C(0)NH-, -C(0)N(R w )-, -NHC(0)NH-, or - (CH 2 )n-; m is 0, 1, 2, 3, or 4; ms 0, 1, 2, 3, or 4.
  • Linker Li and L
  • the linker Li and L each is independently covalently bound to the E3 ubiquitin ligase binding moiety A.
  • the linker L is also independently covalently bound to the target protein binding moiety Q.
  • the covalent bond of linking is preferably through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, each of which groups may be inserted anywhere on A moiety or Q moiety as allowed by valence, including any substituent or functional group in A moiety or Q moiety.
  • the linker may be optionally substituted with (Ci-C6)alkyl, (Ci-C6)alkylene, (C i-G,) alkyne, aryl, heteroaryl, (C3-C8)cycloalkyl, or (C3-Cs)heterocyclo.
  • the linker Li or L is linked to A moiety via R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 ,
  • Li is -Lb-(L a )t-H, wherein H is hydrogen.
  • L is -Lb-(L a )t-.
  • t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • L a is selected from the group consisting of
  • Lb is selected from the group consisting of: t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
  • the compound having general formula A-Li is selected from the compounds listed in Table 1.
  • the compound having general formula (A)k-L-Q is selected from the compounds listed in Table 2, Table 3, or Table 4.
  • the compounds of the present invention have the general formula A-Lb-L -Q, wherein the moiety A, Lb, and L a -Q are independently selected from Table 4. Any combination of the A, Lb, and L a -Q listed in Table 4 are contemplated as the compound of the present invention.
  • Lb is connected to the moiety A via a covalent bond at any position of A as allowed by valence.
  • L a 1.0-6 includes seven L a l moieties, wherein T is 0, 1, 2, 3, 4, 5, or 6 respectively.
  • L a 2.0-5 includes six L a 2 moieties, wherein T is 0, 1, 2, 3, 4, or 5 respectively;
  • Lb6.1-3 includes three Lb6 moieties, having 1, 2, or 3 methylene chain respectively;
  • Lb7.0-5 includes six Lb7 moieties, having 0, 1, 2, 3, 4, or 5 methylene chain respectively;
  • Lb8.1-4 includes four Lb8 moieties, having 1, 2, 3, or 4 methylene chain respectively.
  • R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , and R 105 are each independently selected from the group consisting of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl, wherein said alkyl, haloalk l, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalky l, cycloalky lalkyl, and heterocycloalkyl
  • the compound has the structure of 4.001- L b l- Lal.0-6, 4.001- L b l- L a 2.0-5, 4.002- L b l- Lal.0-6, 4.002- L b l- L a 2.0-5, 4.003- L b l- L a 1.0-6, 4.003- L b l- La2.0-5, 4.004- L b l- Lal.0-6, 4.004- L b l- L a 2.0-5, 4.005- L b l- Lal.0-6, 4.005- L b l- La2.0-5, 4.006- L b l- L a l.0-6, 4.006- L b l- L a 2.0-5, 4.007- L b l- L a l.0-6, 4.007- L b l- L a 2.0-5, 4.008- l- L a l.0-6, 4.008- L b b b a 2.0
  • the compound has the structure of 4.001- L b 2- Lal.0-6, 4.001- L b 2- L a 2.0-5, 4.002- L b 2- L a 1.0-6, 4.002- L b 2- L a 2.0-5, 4.003- L b 2- L a l.0-6, 4.003- L b 2- L a 2.0-5, 4.004- L b 2- L a l.0-6, 4.004- L b 2- L a 2.0-5, 4.005- L b 2- L a l.0-6, 4.005- L b 2- L a 2.0-5, 4.006- L b 2- Lal.0-6, 4.006- L b 2- La2.0-5, 4.007- L b 2- Lal.0-6, 4.007- L b 2- L a 2.0-5, 4.008- L b 2- L a l.0-6, 4.008- L b 2- L a 2.0-5, 4.009- L b 2- L a 1.0-6,
  • the compound has the structure of 4.001- L b 3 - Lal.0-6, 4.001- L b 3 - La2.0-5, 4.002- L b 3 - Lal.0-6, 4.002- L b 3 - L a 2.0-5, 4.003- L b 3 - Lal.0-6, 4.003- L b 3 - L a 2.0-5, 4.004- L b 3 - L a l.0-6, 4.004- L b 3 - L a 2.0-5, 4.005- L b 3 - L a l.0-6, 4.005- L b 3 - L a 2.0- 5, 4.006- L 3 - L a l.0-6, 4.006- L b 3 - L a 2.0-5, 4007- L b 3 - L.l.0-6, 4.007- L b 3 - L a 2.0-5, 4.008- L b 3 - Lal.0-6, 4.008- L a 2.0-5, 4007-
  • the compound has the structure of 4.001- L b 4 - Lal.0-6, 4.001- L b 4 - L a 2.0-5, 4.002- L b 4 - L a 1.0-6, 4.002- L b 4 - L a 2.0-5, 4.003- L b 4 - L a 1.0-6, 4.003- L b 4 - L a 2.0-5, 4.004- L 4 - L a 1.0-6, 4.004- L b 4 - L a 2.0-5, 4.005- L b 4 - L a 1.0-6, 4.005- L b 4 - L a 2.0- 5, 4.006- L b 4 - L a l.0-6, 4.006- L b 4 - L a 2.0-5, 4007- L b 4 - L a l.0-6, 4.007- L b 4 - L a 2.0-5, 4.008- L b 4 - L a l
  • the compound has the structure of 4.001- L b 5 - L a l.0-6, 4.001- L b 5 - L a 2.0-5, 4.002- L b 5 - Lal.0-6, 4.002- L b 5 - L a 2.0-5, 4.003- L b 5 - L a 1.0-6, 4.003- L b 5 - L a 2.0-5, 4.004- L b 5 - LJ.0-6, 4.004- L b 5 - L a 2.0-5, 4.005- L b 5 - Lal.0-6, 4.005- L b 5 - La2.0- 5, 4.006- L b 5 - L a l.0-6, 4.006- L b 5 - L a 2.0-5, 4007- L b 5 - L a l.0-6, 4.007- L b 5 - L a 2.0-5, 4.008- L b 5 - Lal.0-6, 4.008
  • the compound has the structure of 4.001- L b 6 - Lal.0-6, 4.001- L b 6 - L a 2.0-5, 4.002- L b 6 - LJ.0-6, 4.002- L b 6 - L a 2.0-5, 4.003- L b 6 - L a 1.0-6, 4.003- L b 6 - L a 2.0-5, 4.004- L b 6 - L a l.0-6, 4.004- L b 6 - L a 2.0-5, 4.005- L b 6 - L a l.0-6, 4.005- L b 6 - L a 2.0- 5, 4.006- L b 6 - Lal.0-6, 4.006- L b 6 - L a 2.0-5, 4007- L b 6 - Lal.0-6, 4.007- L b 6 - L a 2.0-5, 4.008- L b 6 - L a l.0-6,
  • the compound has the structure of 4.001- L b 7 - Lal.0-6, 4.001- L b 7 - L a 2.0-5, 4.002- L b 7 - LJ.0-6, 4.002- L b 7 - L a 2.0-5, 4.003- L b 7 - Lal.0-6, 4.003- L b 7 - L a 2.0-5, 4.004- L b 7 - L a l.0-6, 4.004- L b 7 - L a 2.0-5, 4.005- L b 7 - L a l.0-6, 4.005- L b 7 - L a 2.0- 5, 4.006- L b 7 - L a l.0-6, 4.006- L b 7 - L a 2.0-5, 4007- L b 7 - L a l.0-6, 4.007- L b 7 - L a 2.0-5, 4.008- L b 7 - Lal.0-6,
  • the compound has the structure of 4.001- L b 8 - Lal.0-6, 4.001- L b 8 - L a 2.0-5, 4.002- L b 8 - LJ.0-6, 4.002- L b 8 - L a 2.0-5, 4.003- L b 8 - LJ.0-6, 4.003- L b 8 - L a 2.0-5, 4.004- L b 8 - L a l.0-6, 4.004- L b 8 - L a 2.0-5, 4.005- L b 8 - L a l.0-6, 4.005- L b 8 - L a 2.0- 5, 4.006- L b 8 - Lal.0-6, 4.006- L b 8 - L a 2.0-5, 4007- L b 8 - Lal.0-6, 4.007- L b 8 - L a 2.0-5, 4.008- L b 8 - LJ.0-6, 4.008- L L a 2.0-5, 4007
  • the compound has the structure of 4.001- L b 9 - Lal.0-6, 4.001- L b 9 - La2.0-5, 4.002- L b 9 - LJ.0-6, 4.002- L b 9 - L a 2.0-5, 4.003- L b 9 - Lal.0-6, 4.003- L b 9 - L a 2.0-5, 4.004- L b 9 - L a 1.0-6, 4.004- L b 9 - L a 2.0-5, 4.005- L b 9 - L a l.0-6, 4.005- L b 9 - L a 2.0- 5, 4.006- L b 9 - L a l.0-6, 4.006- L b 9 - L a 2.0-5, 4007- L b 9 - L a l.0-6, 4.007- L b 9 - L a 2.0-5, 4.008- L b 9 - Lal.0-6, 4.008
  • the compound has the structure of 4.001- LblO - Lal.0-6, 4.001- L b lO - L a 2.0-5, 4.002- L b lO - L a l.0-6, 4.002- L b 10 - L a 2.0-5, 4.003- L b lO - L a 1.0-6, 4.003- L b lO - L a 2.0-5, 4.004- L b lO - L a l.0-6, 4.004- L b 10 - L a 2.0-5, 4.005- L b 10 - L a 1.0-6, 4.005- L b lO - L a 2.0-5, 4.006- L b lO - L a l.0-6, 4.006- L b 10 - L a 2.0-5, 4.007- L b 10 - L a 1.0-6, 4.007- L b lO - L - L - L
  • the compound has the structure of 4.001- L b ll - LJ.0-6, 4.001- Lbl l - La2.0-5, 4.002- Lbll - Lal.0-6, 4.002- Lbll - L a 2.0-5, 4.003- Lbll - Lai.0-6, 4.003- L b l l - L a 2.0-5, 4.004- L b ll - L a l.0-6, 4.004- L b ll - L a 2.0-5, 4.005- L b ll - LJ.0-6, 4.005-
  • the compound has the structure of 4.001- L b 12 - LJ.0-6, 4.001- L b 12 - L a 2.0-5, 4.002- L b 12 - L a l.0-6, 4.002- L b 12 - L a 2.0-5, 4.003- L b 12 - LJ.O-6, 4.003- L b 12 - L a 2.0-5, 4.004- L b 12 - Lal.0-6, 4.004- L b 12 - L a 2.0-5, 4.005- L b 12 - L a 1.0-6, 4.005- L b 12 - L a 2.0-5, 4.006- L b 12 - L a l.0-6, 4.006- L b 12 - L a 2.0-5, 4.007- L b 12 - L a 1.0-6, 4.007- L b 12 - L a 2.0-5, 4.008- L b 12 - L a l
  • the compound has the structure of 4.001- L b 13 - LJ.O-6, 4.001- L b 13 - L a 2.0-5, 4.002- L b 13 - L a l.0-6, 4.002- L b 13 - L a 2.0-5, 4.003- L b 13 - L a 1.0-6, 4.003- L b 13 - L a 2.0-5, 4.004- L b 13 - L a l.0-6, 4.004- L b 13 - L a 2.0-5, 4.005- L b 13 - LJ.O-6, 4.005- L b 13 - L a 2.0-5, 4.006- 13 - L a l.0-6, 4.006- U13 - L a 2.0-5, 4.007- U13 - L a l.0-6, 4.007- 13 - La2.0-5, 4.008- 13 - Lal.0-6, 4.008- L b 13
  • the compound has the structure of 4.001- Lbl4 - Lal.0-6, 4.001- L b 14 - L a 2.0-5, 4.002- L b 14 - L a l.0-6, 4.002- L b 14 - L a 2.0-5, 4.003- L b 14 - L a l.0-6, 4.003-
  • moiety A is selected from the compounds listed in Table 6 in Example 6.
  • moiety A is selected from the group consisting of:
  • the target proteins to be bound by moiety Q 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.
  • the term “protein” includes oligopeptides and polypeptide sequences of sufficient length that they can bind to a Q moiety according to the present invention. Any protein in a eukary otic system or a microbial system, including a virus, bacteria or fungus, as otherwise described herein, are targets for ubiquitmation mediated by the compounds according to the present invention.
  • the target protein is a eukaryotic protein.
  • the Q moiety according to the present invention include, for example, includes 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-containmg 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.
  • Hsp90 inhibitors Hsp90 inhibitors, kinase inhibitors, HDM2 & MDM2 inhibitors, compounds targeting Human BET Bromodomain-containmg proteins, HDAC inhibitors, human lysine methyltransferase inhibitors, angiogenesis inhibitors, nuclear hormone receptor compounds, immunosuppressive compounds, and compounds targeting the aryl hydrocarbon receptor (A
  • Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs thereof These binding moieties are linked to the ubiquitin ligase binding moiety 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.
  • the ubiquitin ligase is cereblon.
  • 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 catrabolism), 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 transporter activity, nuclear transport
  • Proteins of interest can include proteins from eurkaryotes and prokaiyotes 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.
  • the target protein is selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, Bel, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, Squalene-hopene cyclase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphoi lase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokme receptors, JAW/STAT
  • CD5 IL-2 receptor, IL-1 receptor, TNF-alpha, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, Ras/Raf/ME/ERK pathway, interleukin- 1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, c-Kit, TORb activated kinase 1, mammalian target of rapamycin, SHP
  • Q is a moiety that is an Hsp90 inhibitor, a kinase inhibitor, a phosphatase inhibitor, an HDM2/MDM2 inhibitor, a human BET Bromodomain inhibitor, an HD AC inhibitor, a human lysine methyltransferase inhibitor, a RAF receptor inhibitor, a FKBP inhibitor, an angiogenesis inhibitor, an aryl hydrocarbon receptor inhibitor, an androgen receptor inhibitor, an estrogen receptor inhibitor, a thyroid hormone receptor inhibitor, an HIV protease inhibitor, an HIV integrase inhibitor, an acyl protein thioesterase 1 inhibitor, or an acyl protein thioesterase 2 inhibitor.
  • Q is a moiety that is a TANK-binding kinase 1 (TBK1) inhibitor, an estrogen receptor a (ERa) inhibitor, a bromodomain-containing protein 4 (BRD4) inhibitor, an androgen receptor (AR) inhibitor, a platelet-derived growth factor receptor inhibitor, a p38 MAPK inhibitor, aBcr-Abl tyrosine-kinase inhibitor, an Her2 inhibitor, an EGFR inhibitor, an MDM2 inhibitor, a bromodomain-containing protein 2 (BRD2) inhibitor, an HD AC inhibitor, a DHFR inhibitor, or a c-Myc inhibitor.
  • Q is a moiety selected from the group consisting of trimethoprim, vorinostat, tamoxifen, JQ1, Nutlin 3, afatinib, chloroalkane, dasatinib, BIRB796, FK-506, simvastatin, rapamycin, and sorafenib.
  • Q is a moiety binding to a target protein.
  • target protein can be degraded or sequestrated by an E3 ubiquitin ligase, wherein the E3 ubiquitin ligase is selected from cereblon (CRBN), damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), regulator of cullins 1 (ROC1), and Yon Hippel Lindau (VHL).
  • E3 ubiquitin ligase is selected from cereblon (CRBN), damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), regulator of cullins 1 (ROC1), and Yon Hippel Lindau (VHL).
  • the E3 ubiquitin ligase is CRBN.
  • the compound having the general formula (A)k-Li or (A)k-L-Q described herein is capable of simultaneously binding to the target protein and the E3 ubiquitin ligase.
  • the binding causes ubiquitination of the target protein by the E3 ubiquitin ligase.
  • the binding causes degradation of the target protein by the proteasome.
  • the linker L can be covalently connected to Q moiety at any position allowed by valence.
  • the linker L is covalently connected to Q moiety via the specific position indicated as : shown in the table below.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula (A)k-L-Q or (A)k-Li and a pharmaceutically acceptable carrier, additive, and/or excipient.
  • the present invention relates to a method for treating a disease in a subject, said method comprising administering an effective amount of a compound having Formula (A)k-L-Q or (A)k-Li
  • the present invention relates to a method for treating a disease in a subject wherein dysregulated protein activity is responsible for said disease, said method comprising administering an effective amount of a compound having Formula (A)k-L-Q or (A)k-Li.
  • the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, renal cell carcinomas, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovanan cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemias, lymphomas, Burkit s lymphoma, Non-Hodgkin's lymphoma, melanomas, myeloproliferative diseases, multiple myeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendroglio
  • the present invention relates to a method of treating or preventing one or more autoimmune diseases or disorders comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject in need thereof.
  • the autoimmune disease or disorder is selected from, such as multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, Fibromyalgia, Menier's syndrome; transplantation rejection (e.g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome,
  • the subject is a human.
  • the present invention relates to a method of modulating cereblon comprising administering the composition comprising the compounds having the general formula (A)k-Li or (A)k-L-Q described herein, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, to a subject in need thereof.
  • the present invention relates to a method of modulating proteasomal degradation of a protein comprising administering the composition comprising the compounds having the general formula (A)k-Li or (A)k-L-Q described herein, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, to a subject in need thereof.
  • the present invention relates to a method of modulating sequestration of a protein to the proteasome comprising administering the composition comprising the compounds having the general formula (A)k-Li or (A)k-L-Q described herein, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, to a subject in need thereof.
  • CRBN binding is assessed with a MAPPIT-like assay by determining the ability of test compounds to compete with a trimethoprim-lenalidomide hybrid ligand for binding to CRBN in cells.
  • the traditional MAPPIT assay as described for example in Lemmens, et al “MAPPIT, a mammalian two-hybrid method for in-cell detection of protein-protein interactions,” Methods Mol Biol. 2015;1278:447-55, has been used to monitor protein-protein interactions.
  • a bait protein (protein A) is expressed as a fusion protein in which it is genetically fused to an engineered intracellular receptor domain of the leptin receptor, which is itself fused to the extracellular domain of the erythropoietin (Epo) receptor. Binding of Epo ligand to the EpoR component results in activation of receptor-associated intracellular JAK2.
  • activated JAK2 cannot activate the leptin receptor to trigger STAT3 binding and its phosphorylation because its tyrosine residues, normally phosphorylated by activated JAK2, have been mutated.
  • Reconstitution of a JAK2 phosphorylatable STAT3 docking site is instead created through interaction of a protein B with protein A, whereby protein B is fused to a cytoplasmic domain of the gpl30 receptor (which now harbors appropriate tyrosine resides recognized by the activated JAK2 kinase).
  • physical interaction of protein A with protein B reconstitutes and Epo triggers JAK2-STAT3 signaling pathway activation.
  • Activation of STAT3 can be monitored by introduction of a STAT3-responsive reporter gene, including a luciferase-encoding gene or a gene encoding a fluorescent marker such as GFP or some other type of fluorescent protein (EGF etc ).
  • the MAPPIT assay provides a versatile assay to assess such recombinant protein-protein interactions, or compound- or hybrid ligand-induced protein-protem interactions, in intact cells.
  • HEK293 cells transfected with the appropriate cDNAs encoding transgenes are used to generate a positive assay signal as a result of ternary protein/compound complex formation, including a DHFR-fusion protein, a tnmethopnm(TMP)-lenalidomide hybrid ligand (TMP is a ligand for DHFR), and a CRBN-gpl30 fusion protein (CRBN binds the ligand lenalidomide) - thus, a DHFR-TMP-LEN-CRBN complex formation.
  • TMP tnmethopnm(TMP)-lenalidomide hybrid ligand
  • CRBN-gpl30 fusion protein CRBN binds the ligand lenalidomide
  • Formation of the complex results in activation of a STAT-responsive luciferase reporter gene. That signal is set to 100% luciferase activity.
  • cells are prepared in the same manner but, in addition, coincubated with a test compound whose interaction with CRBN is investigated. Binding to the CRBN fusion protein competes with binding of the hybrid ligand to the same CRBN protein, hence inhibiting the assay signal due to prevention of ternary' complex formation, which is required to generate an assay signal. Increasing concentrations of test compound are assessed to determine CRBN binding efficiency as determined in this type of ligand competition experiment in living cells.
  • test compound effect is assessed for inhibition of signal generated by a control gpl30 fusion protein (CTRL) that directly binds to the DHFR-fusion protein in the absence of hybrid ligand (i.e. a direct interaction of the proteins).
  • CTL control gpl30 fusion protein
  • HEK293T cells are cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal calf serum, incubated at 37 °C, 8% CO2. Cells are transfected with a plasmid encoding E.
  • DHFR coli Dihydrofolate Reductase fused to the tails of the cytoplasmic domain of a mutated leptin receptor (pCLG-eDHFR), a plasmid encoding a CRBN prey fused to gpl30 cytoplasmic domain (pMGl-CRBN ) or a plasmid encoding a REM2 control prey that can directly interact with the leptin receptor of the DHFR fusion protein (pMGl-REM2), and the STAT3 responsive pXP2d2-rPAPI-luciferase reporter plasmid - using a standard transfection method, as described (Li evens, etal.
  • Array MAPPIT high-throughput interactome analysis in mammalian cells. Journal of Proteome Research 8.2 (2009): 877-886). Cells are treated with leptin to activate the leptin receptor fusion protein and supplemented with 300 nM trimethoprim-lenalidomide fusion compound (hybrid ligand, where trimethoprim interacts with DHFR and lenalidomide with CRBN) without or w ith the indicated dose of test compound at 24 hours after transfection.
  • trimethoprim-lenalidomide fusion compound hybrid ligand, where trimethoprim interacts with DHFR and lenalidomide with CRBN
  • Luciferase activity induced by formation of the ternary complex including DHFR-trimethoprim-lenalidomide-CRBN, and consequential activation of STAT3 signaling, is measured 24 hours after compound treatment using the Luciferase Assay System kit (PROMEGA, Madison, WI) with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA).
  • Data points represent the average luciferase activity of triplicate samples derived from cells treated with leptin + test compound for the REM2 control (CTRL) or cells treated with leptin + hybrid ligand + test compound (CRBN) relative to leptin (CTRL) or leptin + hybrid ligand (CRBN) only treated samples (the signals obtained in absence of added test compound for both cases is set at 100% of luciferase activity on y-axis). Error bars represent standard deviations. Curves are fit using 4-parameter nonlinear regression in GRAPHPAD PRISM software
  • Example 2 a similar MAPPIT-like assay is applied as described in Example 1 to determine test compound-induced binding of a particular substrate protein of interest to CRBN.
  • cells are transfected with a construct encoding a CRBN- fusion protein and another one encoding a substrate-fusion protein.
  • Test compound activity is assessed with increasing concentrations of test compounds (dose-response studies) to monitor the ability to promote CRBN-ligand-induced protein interaction.
  • HEK293T cells are transfected with a plasmid encoding the MAPPIT receptor fusion wherein the protein of interest (CRBN or substrate protein) is genetically linked to a cytoplasmic domain of the leptin receptor, which itself is fused to the extracellular domain of the erythropoietin (Epo) receptor (pSEL-X, where X represents either CRBN or any of the tested substrate proteins of interest) or to the extracellular domain of the leptin receptor (pCLG-X, where X represents either CRBN or any of the tested substrate proteins of mterst), a plasmid encoding the MAPPIT gpl30 fusion (pMGl-Y, Y being either any of the tested substrate proteins or CRBN) and a STAT3-responsive luciferase-encoding reporter plasmid (pXP2d2-rPAPI-luciferase reporter plasmid), as described (Lievens, e
  • IKZF1 recruitment pSEL-CRBN + pMGl-IKZFl (isoform 7); ASS1 recruitment: pSEL-CRBN + pMGl-ASSl; SALL4 recruitment: pSEL-SALL4 + pMGl-CRBN; DHFR recruitment: pCLG-DHFR + pMGl-CRBN; ESR1 recruitment: pSEL-CRBN + pMGl-ESRl; BRD4 recruitment: pSEL- CRBN + pMGl-BRD4(isoform 3).
  • Luciferase activity is measured 24 hours after test compound treatment using the Luciferase Assay System kit (PROMEGA, Madison, WI) with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA).
  • Data points depict fold induction of the average luciferase activity of triplicate samples from Epo or leptin + test compound treated cells versus Epo or leptin only treated cells. Error bars represent standard deviations. Curves are fit using 4-parameter nonlinear regression in GRAPHPAD PRISM software.
  • TANK-binding kinase 1 TNK1
  • ERa estrogen receptor a
  • BBD4 bromodomain-containing protein 4
  • AR androgen receptor
  • Panc02.13 cells were purchased from ATCC and cultured in RPMI-1640 (Gibco), supplemented with 15% FBS (ATCC) and 10 Units/mL human recombinant insulin (Gibco).
  • DMSO control and compound treatments (0.1 mM, 0.3 mM, and 1 mM) were carried out in 12- well plates for 16 h.
  • TLR3 agonist Poly I:C (Invivogen; tlrl-pic) was added for the final 3 h.
  • Cells were harvested, and lysed in RIPA buffer (50 mM Tris pHB, 150 mM NaCl, 1% Tx- 100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 16,000 g for 10 minutes, and supernatants were separated by SDS-PAGE. Immunoblotting was performed using standard protocols. The antibodies used were TBK1 (Cell Signaling #3504), pIRF3 (abeam #ab76493), and GAPDH (Cell Signaling #5174). Bands were quantified using a Biorad ChemiDoc MP imaging system.
  • NAMALWA cells were cultured in RPMI-1640 (Life Technologies) supplemented with 15% FBS (Life Technologies). DMSO controls and compound incubations (0.1 mM, 0.3 mM, and 1 mM) were carried out in 24-well plates for 16 h. Cells were harvested and lysed with cell lysis buffer (Cell Signaling Technologies) containing protease inhibitors (Thermo Scientific). Lysates were clarified at 16,000 g for 10 minutes, and supernatants were separated by SDS-PAGE. Immunoblotting was performed using standard protocols. The antibodies used were ERRa (Cell Signaling #8644) and GAPDH (Cell Signaling #5174). Bands were quantified using a Bio-Rad ChemiDoc MP imaging system. 3. BRD4 Western Protocol
  • VCaP cells were purchased from ATCC and cultured in Dulbecco's Modified Eagle's Medium (ATCC), supplemented with 10% FBS (ATCC) and Penicillin/Streptomycin (Life Technologies). DMSO control and compound treatments (0.003 mM, 0.01 mM, 0.03 mM and 0.1 mM) were performed in 12-well plates for 16 h. Cells were harvested, and lysed in RIPA buffer (50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 16,000 g for 10 minutes, and protein concentration was determined.
  • RIPA buffer 50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate
  • Equal amount of protein (20 mg) was subjected to SDS-PAGE analysis and followed by immunoblotting according to standard protocols.
  • the antibodies used were BRD4 (Cell Signaling #13440), and Actin (Sigma #5441). Detection reagents were Clarity Western ECL substrate (Bio-rad #170-5060).
  • VCaP cells were purchased from ATCC and cultured in Dulbecco's Modified Eagle's Medium (ATCC), supplemented with 10% FBS (ATCC) and Penicillin/Streptomycin (Life Technologies). DMSO control and compound treatments (0.0001 mM-1 mM) were performed in 96-well plates for 16 h.
  • Cells were harvested, and lysed with Cell Lysis Buffer (Catalog#9803) (20 mM Tns-HCL (pH 7.5), 150 mM NaCl, 1 mM Na 2 EDTA, 1 mM EGTA, 1% Tnton, 2.5 mM sodium pyrophosphate, 1 mM B-glycerophosphate, 1 mM NaiVCL, 1 ug/ml leupeptin. Lysates were clarified at 16,000 g for 10 minutes, and loaded into the PathScan AR ELISA (Cell Signaling Catalog# 12850).
  • Cell Lysis Buffer (Catalog#9803) (20 mM Tns-HCL (pH 7.5), 150 mM NaCl, 1 mM Na 2 EDTA, 1 mM EGTA, 1% Tnton, 2.5 mM sodium pyrophosphate, 1 mM B-glycerophosphate, 1 mM NaiVCL, 1 ug/m
  • the PathScan® Total Androgen Receptor Sandwich ELISA Kit is a solid phase sandwich enzyme-linked immunosorbent assay (ELISA) that detects endogenous levels of total androgen receptor protein.
  • ELISA enzyme-linked immunosorbent assay
  • An Androgen Receptor Rabbit mAb has been coated onto the microwells. After incubation with cell lysates, androgen receptor protein is captured by the coated antibody. Following extensive washing, an Androgen Receptor Mouse Detection mAb is added to detect the captured androgen receptor protein. Anti-mouse IgG, HRP-lmked Antibody is then used to recognize the bound detection antibody. HRP substrate, TMB, is added to develop color. The magnitude of absorbance for the developed color is proportional to the quantity of total androgen receptor protein.
  • 22RV-1 cells were purchased from ATCC and cultured in RPMI+10% FBS media.
  • Cells were harvested using trypsin (Gibco #25200-114), counted and seeded at 30,000 cells/well at a volume of 75 pL/well in RPMI+10% FBS media in 96-well plates. The cells were dosed with compounds diluted in 0.1% DMSO, incubated for 18 h then washed and lysed in 50 uL RIPA buffer (50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. The lysates were clarified at 4000 rpm at 4° C.
  • the compounds of the present invention can be prepared by methods well known in the art of organic chemistry. See, for example, J. March, ‘Advanced Organic Chemistry’ 4th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those descnbed in T.W.
  • the protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.
  • the products of the reactions are optionally isolated and purified, if desired, using conventional techniques, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials are optionally characterized using conventional means, including physical constants and spectral data.
  • LG generally refer to groups that are displaceable by a nucleophile.
  • Such leaving groups are known in the art
  • Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e g., mesylate, tosylate), sulfides (e.g., SCH3), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like.
  • nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e g , alkoxides, amides, carbanions) and the like.
  • TMP-LEN was made according to the reaction scheme below.
  • Example 2 A similar MAPPIT-like assay as described in Example 1 was applied to evaluate binding between CRBN and DHFR (dihydrofolate reductase) induced by a hybrid molecule consisting of the DHFR ligand trimethoprim (TMP) fused to the CRBN ligand lenahdomide (LEN) through a PEG linker.
  • TMP trimethoprim
  • LN CRBN ligand lenahdomide
  • HEK293T cells were co-transfected with a plasmid encoding a fusion construct of the (E.
  • DHFR anchor protein fused to the chimeric MAPPIT receptor containing the leptin receptor extracellular domain linked to an engineered intracellular domain of the leptin receptor (pCLG-DHFR) and a gpl30-CRBN bait fusion construct, together with the STAT3 -responsive luciferase- encodmg reporter plasmid (pXP2d2-rPAPI-luciferase reporter plasmid), as described (Lievens, et al. "Array MAPPIT: high-throughput interactome analysis in mammalian cells.” Journal of Proteome Research 8.2 (2009): 877-886).
  • luciferase Assay System kit PROMEGA, Madison, WI
  • Ensight plate reader PERKIN ELMER LIFE SCIENCES, Waltham, MA
  • the dose-response curve shown in Figure 3 represents the fold induction of the average luciferase activity of triplicate samples from leptin + test compound treated cells versus leptin only treated cells. Error bars represent standard deviations and curves were fit using 4-parameter nonlinear regression in GRAPHPAD PRISM software.
  • This example shows that the MAPPIT assay presented here can be applied to assess binding between two proteins induced by a hybrid ligand.
  • IC50 Competition values were determined using the protocol and reagents described in Example 1.
  • EC50 values for recruitment of IKZF1, AS SI and SALL4 were determined using the protocols and reagents described in Example 2.
  • NA represents instances where no substrate recruitment was observed at any tested concentration
  • » represents instances were an EC50 curve could not be calculated as values did not reach a plateau over the measured concentration range
  • « represents instances where an EC50 could not be calculated because a value was read above 50% of control at the first concentration tested for the compound (13.7 nM).
  • IC50 Competition values were determined using the protocol and reagents described in Example 1.
  • EC50 values for recruitment of the indicated target proteins were determined using the protocols and reagents described in Example 2.
  • NA represents instances where no substrate recruitment was observed at any tested concentration
  • » represents instances were an EC50 curve could not be calculated as values did not reach a plateau over the measured concentration range
  • « represents instances where an EC50 could not be calculated because a value was read above 50% of control at the first concentration tested for the compound (13.7 nM).
  • Example 7 Evaluation of CRBN binding and/or substrate recruitment of bifunctional compounds

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Abstract

The disclosure relates to new compounds, including bifunctional compounds, to be used as modulators of ubiquitination for targeted protein degradation.

Description

BIFUNCTIONAL AGENTS FOR PROTEIN RECRUITMENT AND/OR
DEGRADATION
FIELD OF THE INVENTION
[0001] The invention provides new compounds, including bifunctional compounds, for the degradation of a target protein by the ubiquitin proteasome pathway for therapeutic applications as described further herein.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0002] This application claims the benefit of U.S. Provisional Application No. 62/949,028, filed on December 17, 2019, the entire contents of which are incorporated herein.
BACKGROUND OF THE INVENTION
[0003] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is essential to the regulation of almost all cellular processes.
[0004] Covalent attachment of multiple ubiquitin molecules by an E3 ubiquitin ligase to a terminal lysine residue marks the protein for proteasome degradation, where the protein is digested into small peptides and eventually into its constituent amino acids that serve as building blocks for new proteins.
[0005] Thalidomide and its analogues have been found to bind to the ubiquitin ligase cereblon and redirect its ubiquitination activity (Ito, T. et al., Science, 2010, 327: 1345). Cereblon forms part of an E3 ubiquitin ligase complex which interacts with damaged DNA binding protein, forming an E3 ubiquitin ligase complex with Cullin 4 and the E2 -binding protein ROC1 (known as RBX1) where it functions as a substrate receptor to select proteins for ubiquitination. The binding of lenalidomide to cereblon facilitates subsequent binding of cereblon to Ikaros and Aiolos, leading to their ubiquitination and degradation by the proteasome (Lu, G. et al., Science, 2014, 343:305-309; Kronke, J. et al., Science, 2014, 343:301-305). [0006] It is an object of the present invention to provide new compounds binding to cereblon and the use thereof for the treatment of various diseases and disorders, e.g. by modulating protein degradation.
SUMMARY OF THE INVENTION
[0007] The present invention relates to new compounds and their uses and manufacture thereof. The compounds have general formula (A)k-Li or (A)k-L-Q. Moiety A of the compounds binds to cereblon. L or Li is a linker. Moiety Q is a moiety that binds to a target protein which is sequestered to the E3 ubiquitin ligase and/or degraded upon interaction with the E3 ubiquitin ligase.
[0008] In one aspect, the present invention relates to a compound having the general formula (A)k-Li, or a salt, enantiomer, stereoisomer, polymorph, orN-oxide thereof, wherein:
[0009] A is a moiety that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
Figure imgf000004_0001
III IV
Figure imgf000005_0001
Li is a linker; each A is covalently linked to the Li as allowed by valence;
R1 is aryl, -N(R5)-X-R6, -SO2R5, or -0(CH2)mR5, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R2 is aryl, -NH-(C3-CIO) heteroaryl, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more R" groups as allowed by valence;
R3 is cyano, aryl, -NH-(C i-Cm) heteroaryl, (C3-Cio)heterocyclo, or -N(R5)-(CH2)m-X- (CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R4 is halo, cyano, aryl, OR5, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n- ary 1. -(CkkVheteroaryl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroarvl. or R5 and R6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R7 is H, (Ci-C3)alkyl, or R7 and R26 taken together with the carbons they are attached to forming a carbon carbon double bond;
R8, R9, R10, R11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R12, R13, R14, R15 each is independently H, NH2, (Ci-C3)alkyl, -N(R5)-(CH2)m-N(R5)- X-R6, with proviso that no more than three substituents out of R12, R13, R14, and R15 are H, any of which may be optionally substituted with 1 or more R" groups as allowed by valence;
R16 is NH2 or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R17 is cyano, heteroaryl, -(CH2)m-C(0)0-R6, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R18, R19, R20, R21 each independently is H, halo, (Ci-C: alkyl, (Ci-C3)alkoxy, or - N(R5)-X-R6, with the proviso that no more than two substituents of R18, R19, R20, R21 are H; or
R18, R19 taken together with the carbons they are attached to forming a (C3- Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R19, R20 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R20, R21 taken together with the carbons they are attached to forming a (Ch-Cio)cycloalkyl or a (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Rw at each occurrence is independently H, halo, cyano, nitro, oxo, alky l, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, and heteroaryl;
X is a bond, -S02-, -(CH2)nC(0)(CH2)m-, -C(0)NH-, -C(0)N(Rw)-, -NHC(0)NH-, or -(CH2)n-;
Yi is -NHR25, -NHC(0)R25, or -CHR25R26; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
[0010] In an embodiment, Li is -Lt>-(La)t-H; wherein La at each occurrence is independently selected from the group consisting of a bond, CR5R6, C(R5R6)0, C(R5R6)C(R5R6)0, SCh, NR5, C(R5R6)NR5, SChNR5, SONR5, C0NR5, NR5C0NR6, NR5S02NR6, CO, CR5=CR6, CºC, SiR5R6, P(0)R5, P(0)OR5, NR5C(=NCN)NR6, NR5C(=NCN), and NR5C(=CNCb)NR6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
H is hydrogen.
Lb is selected from the group consisting of:
Figure imgf000007_0001
Figure imgf000008_0001
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[0011] In one aspect, the present invention relates to a compound of the general formula (A)k-L-Q, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, wherein:
[0012] A is a compound that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
II
I
Figure imgf000009_0001
IX X
Q is a moiety that binds to a target protein which is sequestered to the E3 ubiquitin ligase and/or degraded upon interaction with the E3 ubiquitin ligase;
L is a linker; each A is covalently linked to the L as allowed by valence;
R1 is aryl, -N(R5)-X-R6, -SO2R5, or -0(CH2)mR5, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R2 is aryl, -NH-(C3-CIO) heteroaryl, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R3 is cyano, aryl, -NH-(C3-CIO) heteroaryl, (C3-Cio)heterocyclo, or -N(R5)-(CH2)m-X- (CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R4 is halo, cyano, aryl, OR5, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CFhV aryl, -(CH2)n-heteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl. or R5 and R6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R7 is H, (Ci-C3)alkyl, or R7 and R26 taken together with the carbons they are attached to forming a carbon carbon double bond;
R8, R9, R10, R11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R12, R13, R14, R15 each is independently H, NH2, (Ci-C3)alkyl, -N(R5)-(CH2)m-N(R5)- X-R6, with proviso that no more than three substituents out of R12, R13, R14, and R15 are H, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R16 is NH2 or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R17 is cyano, heteroaryl, -(CH2)m-C(0)0-R6, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R18, R19, R20, R21 each independently is H, halo, (Ci-C3)alkyl, (Ci-C3)alkoxy, or - N(R5)-X-R6, with the proviso that no more than two substituents of R18, R19, R20, R21 are H; or
R18, R19 taken together with the carbons they are attached to forming a (C3- Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R19, R20 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R20, R21 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Rw at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl. cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, -(CPhL-heteroaryl. aryl, and heteroaryl;
X is a bond, -SO2-, -(CH2)nC(0)(CH2)m-, -C(0)NH-, -C(0)N(R">. -NHC(0)NH-, or -(CH2)n-;
Yi is -NHR25, -NHC(0)R25, or-CHR25R26; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
[0013] In an embodiment, L is -Lb-(La)t-; wherein La at each occurrence is independently- selected from the group consisting of a bond, CR5R6, C(R5R6)0, C(R5R6)C(R5R6)0, SO2, NR5, C(R5R6) NR5, SO2NR5, SONR5, CONR5, NR5CONR6, NR5S02NR6, CO, CR5=CR6, CºC, SiR5R6, P(0)R5, P(0)OR5, NR5C(=NCN)NR6, NR5C(=NCN), and NR5C(=CN02)NR6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Lb is selected from the group consisting of:
Figure imgf000012_0001
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. [0014] In an embodiment, L is -(CfhCLhy, -(CLLO or -(CfhCfhC t-.
[0015] In one aspect, moiety A is selected from the group consisting of:
3- [ 1 -oxo-5 -(quinazolin-4-ylamino)isoindolin-2-yl] piperidine-2,6-dione; 3-[5-[(4-aminothieno[2,3-d]pyrimidin-2-yl)amino]-l-oxo-isoindolin-2-yl]piperidine- 2,6-dione;
N-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]acetamide;
3-[5-[(2-aminopyrimidin-4-yl)amino]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione; 6-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolm-5-yl]amino]pyridazine-3-carbonitrile; 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5- yl] amino] acetyl] amino]benzamide;
2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolm-5-yl]amino]acetic acid; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]quinoline-2-carboxamide;
3- [6- [ [2-(2-methyl- 1 -piperi dyl)-2-oxo-ethyl] amino] - 1 -oxo-isoindolin-2-yl] piperidine- 2, 6-dione;
3- [6- [(2-isoindolin-2-y l-2-oxo-ethyl)amino] - 1 -oxo-isoindolin-2-yl]piperi dine-2, 6- dione;
N-(cyclopropylmethyl)-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-
N-methyl-acetamide; acetic acid;3-[l-oxo-6-(quinazolin-4-ylamino)isoindolin-2-yl]piperidine-2, 6-dione;
3- [6- [ [2-(3 -methyl- 1 -piperi dyl)-2-oxo-ethyl] amino] - 1 -oxo-isoindolin-2-yl] piperi dine- 2,6-dione;
3-[6-[(4-methyl-3-oxo-pyrazin-2-yl)amino]-l-oxo-isoindolin-2-yl]piperidine-2,6- dione;
3- [l-oxo-6-(quinoxalin-2-ylamino)isoindolin-2-yl] piperidine-2, 6-dione; 3-[6-[(l-methylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-l-oxo-isoindolin-2- yl] piperidine-2, 6-dione;
3-[6-(5,7-dihydrofuro[3,4-d]pyrimidin-2-ylamino)-l-oxo-isoindolin-2-yl]piperidme-
2,6-dione;
3-[6-[(6-methylpyrimidin-4-yl)amino]-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione;
2-[[2-(2,6-dioxo-3-pipendyl)-3-oxo-isoindolin-5-yl]ammo]-N-phenyl-acetamide;
3-[6-[[2-(2,4-dimethylpiperazin-l-yl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl] piperi dine-2, 6-dione;
3-[6-(dimethylammo)-l-oxo-isoindolin-2-yl]piperidme-2,6-dione; 3-(l-oxo-6-phenyl-isoindolin-2-yl)piperi dine-2, 6-dione;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N,N-dimethyl-acetamide;
3-[6-[[2-(2-methylmorpholin-4-yl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl] piperi dine-2, 6-dione;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-methyl-N-[(l- methylpyrazol-4-yl)methyl]acetamide; N-benzyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide; 6-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-5-yl]amino]pyridazine-3-carbonitrile; 3- [6- [(6-methylpyrrolo[3,2-d]py rimidin-4-yl)amino] - 1 -oxo-isoindolm-2- yl] pipendine-2,6-dione;
2-(dimethylamino)-N-[2-(2,6-dioxo-3-piperidy[)-3-oxo-isoindolin-5-yl]acetainide; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-5H-pyrrolo[2,3-b]pyridine-4- carboxamide;
N-cyclopropyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide;
3-[l-oxo-6-(2-oxoimidazolidin-l-yl)isoindolin-2-yl]piperidine-2,6-dione; 2-(2:6-dioxo-3-piperidyl)-3-oxo-isoindoline-5-carbonitrile; 2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-5-yl]amino]propanoic acid; 2-acetamido-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-5-yl]amino]acetamide;
3-[6-[[2-(3-methyl-5-oxo-piperazin-l-yl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl]pipendme-2,6-dione;
N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide;
3-[6-[[2-(4-methyl-3-oxo-piperazin-l-yl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl]piperidine-2,6-dione;
N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-3H-imidazo[4,5-b]pyridine-6- carboxamide;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-5-yl]amino]-N-tetrahydropyran-4-yl- acetamide;
2-[[2-(2,6-dioxo-3-pipendyl)-3-oxo-isoindolin-5-yl]ammo]acetic acid;
3-[l-oxo-6-[[2-oxo-2-(l-piperidyl)ethyl]amino]isoindolin-2-yl]piperidine-2,6-dione; 3-(l-oxo-7-phenyl-isoindolin-2-yl)piperidine-2,6-dione; 2-(2.6-dioxo-3-piperidyl)-3-oxo-isoindoline-4-carbomtnle;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-4-yl]amino]acetic acid;
3-(7-fluoro-l-oxo-isoindolin-2-yl)piperidine-2,6-dione; 3-(5-amino-l-oxo-3,4-dihydroisoquinolin-2-yl)piperidine-2,6-dione; t-bulyl 2-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-l-yl]acetate; 3-[l-(2H-indol-3-yl)-3-oxo-isomdolin-2-yl]piperidine-2,6-dione; 2-(2:6-dioxo-3-pipendyl)-3-oxo-isoindoline-l-carbonitrile; 3-[l-(dimethylamino)-3-oxo-isoindolin-2-yl]pipendine-2,6-dione;
3-(2-oxopyrrolidin-l-yl)piperidine-2,6-dione;
3-(quinazolin-2-ylamino)piperidine-2,6-dione;
(3Z)-3-benzylidenepiperidine-2,6-dione;
3-(quinoxalin-2-ylamino)piperidine-2,6-dione;
3-(py n mid i n-2-ylami no)piperidi ne-2.6-d ione:
N-(2,6-dioxo-3-piperidyl)-2-oxo-3H-pyridine-6-carboxamide;
3-(4-methyl- 1 , 1 ,3-trioxo- 1 ,2-benzothiazol-2-y l)piperidine-2,6-dione;
3-(8-amino-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione;
3-(5-amino-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione;
3-(4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione;
3-(5-methyl-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione;
3-(6-methyl-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione; and
3-(8-methyl-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione.
[0016] In an embodiment, Q is a moiety that binds to a target protein, wherein said target protein is selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, Bel, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, Squalene-hopene cyclase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase. carbonic anhydrase, chemokine receptors, JAW/STAT, retinoid X receptor, HIV 1 protease, HIV 1 mtegrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, protein P-glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine kinase p56 lek, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha, ICAM1, Cat+ channels, VCAM, VLA-4 integnn, selectms, CD40/CD40L, newokmms and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, Ras/Raf/ME/ERK pathway, interleukin-1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, c-Kit, TGFp activated kinase 1, mammalian target of rapamycin, SHP2, androgen receptor, oxytocin receptor, microsomal transfer protein inhibitor, 5 alpha reductase, angiotensin II, glycine receptor, noradrenaline reuptake receptor, estrogen receptor, estrogen related receptors, focal adhesion kinase, Src, endothehn receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), famesyltransferases, geranylgeranyl transferase, TrkA a receptor forNGF, beta- amyloid, tyrosine kinase Flk-1, vitronectin receptor, integrin receptor, Her-2/neu, telomerase, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium channel protein, and chloride channel protein, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.
[0017] In an embodiment, Q is a moiety that is an Hsp90 inhibitor, a kinase inhibitor, a phosphatase inhibitor, an HDM2/MDM2 inhibitor, a human BET Bromodomain inhibitor, an HD AC inhibitor, a human lysine methyltransferase inhibitor, a RAF receptor inhibitor, a FKBP inhibitor, an angiogenesis inhibitor, an aryl hydrocarbon receptor inhibitor, an androgen receptor inhibitor, an estrogen receptor inhibitor, a thyroid hormone receptor inhibitor, an HIV protease inhibitor, an HIV integrase inhibitor, an acyl protein thioesterase 1 inhibitor, or an acyl protein thioesterase 2 inhibitor.
[0018] In an embodiment, Q is a moiety that is a TANK-binding kinase 1 (TBK1) inhibitor, an estrogen receptor a (ERa) inhibitor, a bromodomain-containing protein 4 (BRD4) inhibitor, an androgen receptor (AR) inhibitor, a platelet-derived growth factor receptor inhibitor, a p38 MAPK inhibitor, aBcr-Abl tyrosine-kinase inhibitor, an Her2 inhibitor, an EGFR inhibitor, an MDM2 inhibitor, a bromodomain-containing protein 2 (BRD2) inhibitor, an HD AC inhibitor, a DHFR inhibitor, or a c-Myc inhibitor.
[0019] In an embodiment, Q is a moiety selected from the group consisting of trimethoprim, vorinostat, tamoxifen, JQ1, Nutlin 3, afatinib, chloroalkane, dasatinib, BIRB796, FK-506, simvastatin, rapamycin, and sorafenib.
[0020] In one aspect, the present invention relates to a pharmaceutical composition comprising the compound of Formula (A)k-L-Q or (A)k-Li and a pharmaceutically acceptable carrier, additive, and/or excipient. [0021] In embodiments, the composition is a bivalent inducer of protein degradation (also known as a proteolysis-targeting chimera (PROTAC)). In embodiments, the composition is a CLIckable Proteolysis TArgeting Chimeras (CLIPTACs). Such CLIPTAC, in embodiments, includes (a) a first portion comprising a ligand for a target protein; (b) a second portion comprising a ligand for an E3 ubiquitin ligase; and (c) a linker portion covalently coupling the first and second portions; wherein the linker comprises a covalent bond produced by a bioorthogonal click reaction between a compatible pair of reactive moieties. In embodiments, the composition is an in-cell click-formed proteolysis targeting chimera (CLIPTAC).
[0022] In one aspect, the present invention relates to a method for treating a disease in a subject, said method compnsing administering an effective amount of a compound having Formula (A)k-L-Q or (A)k-Li
[0023] In one aspect, the present invention relates to a method for treating a disease in a subject wherein dysregulated protein activity is responsible for said disease, said method comprising administering an effective amount of a compound having Formula (A)k-L-Q or (A)k-Li.
[0024] In an embodiment, the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, renal cell carcinomas, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemias, lymphomas, Burkitt's lymphoma, Non-Hodgkin's lymphoma, melanomas, myeloproliferative diseases, multiple myeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, Schwannomas, testicular cancer, thyroid cancer, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratocarcmomas.
[0025] In another aspect, the present invention relates to a method of treating or preventing one or more autoimmune diseases or disorders comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject in need thereof. In an embodiment, the autoimmune disease or disorder is selected from, such as multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, Fibromyalgia, Menier's syndrome; transplantation rejection (e g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren’s syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Grave's disease, and other autoimmune diseases or disorders.
[0026] In an embodiment, the subject is a human.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings.
[0028] FIG. 1 illustrates the HNMR of the intermediate compound 53 in Example 5.
[0029] FIG. 2 illustrates the LCMS data of Trimethoprim-lenalidomide (TMP-LEN).
[0030] FIG. 3 illustrates TMP-LEN hybrid ligand-induced binding between CRBN and DHFR detected with a MAPPIT-like assay. A hybrid molecule consisting of the DHFR ligand trimethoprim (TMP) fused to the CRBN ligand lenalidomide through a PEG linker was used to induce DHFR recruitment to CRBN bait in the MAPPIT assay. As shown, with CRBN expressed as a gpl30 fusion and DHFR linked to the MAPPIT chimeric membrane receptor, a TMP-LEN dose-dependent signal can be observed.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The following is a detailed description of the present invention. Those of ordinary skill in the art may make modifications and variations in the embodiments described herein without departing from the spirit or scope of the present disclosure. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety. [0032] Presently described are novel compounds, including bifunctional compounds, compositions and methods that relate to the surprising and unexpected discovery that an E3 ubiquitin ligase protein, e.g., cereblon, ubiquitinates a target protein once it and the target protein are placed in proximity by a bifunctional or chimeric construct that binds the E3 ubiquitin ligase protein and the target protein. Accordingly the present invention provides such compounds having general formula (A)k-Li or (A)k-L-Q, wherein A is a moiety binding to the E3 ubiquitin ligase protein; L or Li is a linker; Q is a moiety binding to the target protein.
[0033] In an embodiment, compounds disclosed herein, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof can be used to treat a disorder mediated by one or more of cereblon, IKZF1, SALL4, and ASS1, e g. various cancers and autoimmune diseases or disorders.
[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the invention.
[0035] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise (such as in the case of a group containing a number of carbon atoms in which case each carbon atom number falling within the range is provided), between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
[0036] The following terms are used to describe the present invention In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present invention.
Definition [0037] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.
[0038] '/ ” indicates the double bond in E or Z configuration.
[0039] The term Ή" denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.
[0040] Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" or "alkylamino", it embraces linear or branched radicals having one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isoamyl, hexyl and the like. Even more preferred are lower alkyl radicals having one or two carbon atoms. The term “alkylenyl” or “alkylene” embraces bridging divalent alkyl radicals such as methylenyl or ethyl enyl. The term "lower alkyl substituted with R2" does not include an acetal moiety. The term “alkyl” further includes alkyl radicals wherein one or more carbon atoms in the chain is substituted with a heteroatom selected from oxygen, nitrogen, or sulfur.
[0041] The term "alkenyl" embraces linear or branched radicals having at least one carbon- carbon double bond of two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms. Most preferred lower alkenyl radicals are radicals having two to about four carbon atoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.
[0042] The term "alkynyl" denotes linear or branched radicals having at least one carbon- carbon triple bond and having two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about six carbon atoms. Most preferred are lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include propargyl, and butynyl, and the like. [0043] Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be optionally substituted with one or more functional groups such as halo, hydroxy, nitro, ammo, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo and the like.
[0044] The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
[0045] The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl. A monohaloalkyl radical, for example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" embraces radicals having 1 to 6 carbon atoms.
Even more preferred are lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
[0046] The term "perfluoroalkyl" means alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.
[0047] The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hy droxyl radicals. Examples of such radicals include hydroxymethyl, hydroxy ethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having one to three carbon atoms.
[0048] The term "alkoxy" embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy propoxy, butoxy and tert- butoxy. Even more preferred are lower alkoxy radicals having one to three carbon atoms. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals. Even more preferred are lower haloalkoxy radicals having one to three carbon atoms. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.
[0049] The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings, wherein such nngs may be attached together in a fused manner. The term "aryl" embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl. An "aryl" group may have 1 or more substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino, and the like. Phenyl substituted with -O-CH2-O- forms the aryl benzodioxolyl substituent.
[0050] The term "heterocyclyl" (or heterocyclo ) embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. It does not include rings containing -O-O-, -O-S- or -S-S- portions. The "heterocyclyl" group may have 1 to 4 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino.
[0051] Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocychc groups containing 1 to 4 nitrogen atoms [e g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocychc group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl] ; saturated 3 to 6-membered heteromonocychc group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.
[0052] Examples of unsaturated heterocyclic radicals, also termed "heteroaryl" radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-
1.2.3-tnazolyl]; unsaturated 5- to 6-membered heteromonocychc group containing an oxygen atom, for example, pyranyl, 2-fury 1, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocychc group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocychc group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,
1.3.4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocychc group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]
[0053] The term heterocyclyl, (or heterocyclo) also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isomdolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [l,5-b]pyridazmyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[l,4]dioxinyl and dihydrobenzofuryl]. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl. Other preferred heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, py ridyl, piperidinyl and pyrazinyl.
[0054] Particular examples of non-nitrogen containing heteroary l include pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, and benzothienyl, and the like.
[0055] Particular examples of partially saturated and saturated heterocyclyl include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2- dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2, 3, 4, 4a, 9,9a- hexahydro-lH-3-aza-fluorenyl, 5,6,7-trihydro-l,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro- 2H-benzo[ 1 ,4] oxazinyl, benzo[ 1 ,4] dioxanyl, 2,3 -dihydro-lH- Il'-benzo [d]isothiazol-6-y 1, dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the like.
[0056] The term “heterocyclo” thus encompasses the following ring systems:
Figure imgf000024_0001
Figure imgf000025_0001
[0057] The term "sulfonyl", whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals -SO2-.
[0058] The terms "sulfamyl," "aminosulfonyl" and "sulfonamidyl," denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (-SO2NH2). [0059] The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" where sulfamyl radicals are independently substituted with one or two alkyl radical(s). More preferred alkylaminosulfonyl radicals are "lower alkylaminosulfonyl" radicals having one to six carbon atoms. Even more preferred are lower alkylaminosulfonyl radicals having one to three carbon atoms. Examples of such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl, and N-ethylaminosulfonyl.
[0060] The terms "carboxy" or "carboxyl," whether used alone or with other terms, such as "carboxyalkyl," denotes -CO2H.
[0061] The term "carbonyl," whether used alone or with other terms, such as "aminocarbonyl," denotes -(C=0)-.
[0062] The term "aminocarbonyl" denotes an amide group of the formula C(=0)NH2.
[0063] The terms "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" denote aminocarbonyl radicals independently substituted with one or two alkyl radicals, respectively. More preferred are "lower alkylaminocarbonyl" having lower alkyl radicals as described above attached to an aminocarbonyl radical.
[0064] The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylammocarbonyl" denote aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical.
[0065] The terms "heterocyclylalkylenyl" and "heterocyclylalkyl" embrace heterocyclic- substituted alkyl radicals. More preferred heterocyclylalkyl radicals are "5- or 6-membered heteroarylalkyl" radicals having alkyl portions of one to six carbon atoms and a 5- or 6- membered heteroaryl radical. Even more preferred are lower heteroarylalkylenyl radicals having alkyl portions of one to three carbon atoms. Examples include such radicals as pyridylmethyl and thienylmethyl.
[0066] The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are "lower aralkyl" radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Even more preferred are "phenylalkylenyl" attached to alkyl portions having one to three carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy. halkoalkyl and haloalkoxy. [0067] The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower alkylthio radicals having one to three carbon atoms. An example of "alkylthio" is methylthio, (CEES-).
[0068] The term "haloalkylthio" embraces radicals containing a haloalkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. Even more preferred are lower haloalky lthio radicals having one to three carbon atoms. An example of "haloalkylthio" is trifluoromethylthio.
[0069] The term "alkylamino" embraces "N-alkylamino" and "N,N-dialkylamino" where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. More preferred alkylamino radicals are "lower alkylamino" radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom.
Even more preferred are lower alkylamino radicals having one to three carbon atoms.
Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N- ethylamino, N,N-dimethylamino, and N,N-diethylammo, and the like.
[0070] The term "arylamino" denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamino. The ary lamino radicals may be further substituted on the aryl ring portion of the radical.
[0071] The term "heteroarylamino" denotes amino groups, which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The "heteroarylamino" radicals may be further substituted on the heteroaryl ring portion of the radical.
[0072] The term "aralkylamino" denotes amino groups, which have been substituted with one or two aralkyl radicals. More preferred are phenyl -Ci-CT-alkylamino radicals, such as N- benzylamino. The aralkylamino radicals may be further substituted on the aryl ring portion.
[0073] The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" denote amino groups, which have been independently substituted with one aralkyl and one alkyl radical, or one aryl and one alkyl radical, respectively, to an amino group.
[0074] The term "aminoalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more amino radicals. More preferred aminoalkyl radicals are "lower aminoalkyl" radicals having one to six carbon atoms and one or more amino radicals. Examples of such radicals include aminomethyl, aminoethyl, aminopropyl, aminobutyl and ammohexyl. Even more preferred are lower aminoalkyl radicals having one to three carbon atoms.
[0075] The term "alkylammoalkyl" embraces alkyl radicals substituted with alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower alkylaminoalkyl" radicals having alkyl radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkyl radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl radicals may be mono or dialkyl substituted, such as N-methylaminomethyl, N,N-dimethyl-aminoethyl, and N,N-diethylaminomethyl, and the like.
[0076] The term "alkylaminoalkoxy" embraces alkoxy radicals substituted with alkylamino radicals. More preferred alkylaminoalkoxy radicals are "lower alkylaminoalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N- methylaminoethoxy, N,N-dimethylaminoethoxy, and N,N-diethylaminoethoxy, and the like.
[0077] The term "alkylammoalkoxyalkoxy" embraces alkoxy radicals substituted with alkylaminoalkoxy radicals. More preferred alkylammoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy" radicals having alkoxy radicals of one to six carbon atoms. Even more preferred are lower alkylammoalkoxyalkoxy radicals having alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono or dialkyl substituted, such as N-methylaminomethoxyethoxy, N-methylaminoethoxyethoxy, N,N- dimethylaminoethoxyethoxy, and N,N-diethylaminomethoxymethoxy, and the like.
[0078] The term "carboxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more carboxy radicals. More preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals having one to six carbon atoms and one carboxy radical. Examples of such radicals include carboxymethyl, and carboxypropyl, and the like. Even more preferred are lower carboxyalkyl radicals having one to three CEk groups.
[0079] The term "halosulfonyl" embraces sulfonyl radicals substituted with a halogen radical. Examples of such halosulfonyl radicals include chlorosulfonyl and fluorosulfonyl. [0080] The term "arylthio" embraces aryl radicals of six to ten carbon atoms, atached to a divalent sulfur atom. An example of "arylthio" is phenylthio.
[0081] The term "aralkylthio" embraces aralkyl radicals as described above, atached to a divalent sulfur atom. More preferred are phenyl-Ci-C3-alkylthio radicals. An example of "aralkylthio" is benzylthio.
[0082] The term "aryloxy" embraces optionally substituted ary l radicals, as defined above, atached to an oxygen atom. Examples of such radicals include phenoxy.
[0083] The term "aralkoxy" embraces oxy-contammg aralkyl radicals atached through an oxygen atom to other radicals. More preferred aralkoxy radicals are "lower aralkoxy" radicals having optionally substituted phenyl radicals atached to lower alkoxy radical as described above.
[0084] The term "heteroaryloxy" embraces optionally substituted heteroaryl radicals, as defined above, atached to an oxygen atom.
[0085] The term "heteroarylalkoxy" embraces oxy- containing heteroarylalkyl radicals atached through an oxygen atom to other radicals. More preferred heteroarylalkoxy radicals are "lower heteroarylalkoxy" radicals having optionally substituted heteroaryl radicals atached to lower alkoxy radical as described above.
[0086] The term "cycloalkyl" includes saturated carbocyclic groups. Preferred cycloalkyl groups include C3-C6 rings. More preferred compounds include, cyclopentyl, cyclopropyl, and cyclohexyl.
[0087] The term “cycloalkylalkyl" embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals having cycloalkyl radicals atached to alkyl radicals having one to six carbon atoms. Even more preferred are "5 to 6-membered cycloalkylalkyl" atached to alkyl portions having one to three carbon atoms. Examples of such radicals include cyclohexylmethyl. The cy cloalkyl in said radicals may be additionally substituted with halo, alkyl, alkoxy and hydroxy.
[0088] The term "cycloalkenyl" includes carbocyclic groups having one or more carbon- carbon double bonds including " cycloalky ldienyl" compounds. Preferred cycloalkenyl groups include Ci-Ce rings. More preferred compounds include, for example, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl. [0089] The term "comprising" is meant to be open ended, including the indicated component but not excluding other elements.
[0090] A group or atom that replaces a hydrogen atom is also called a substituent.
[0091] Any particular molecule or group can have one or more substituent depending on the number of hydrogen atoms that can be replaced.
[0092] The symbol
Figure imgf000030_0001
represents a covalent bond and can also be used in a radical group to indicate the point of attachment to another group. In chemical structures, the symbol is commonly used to represent a methyl group in a molecule.
[0093] The term "therapeutically effective amount" means an amount of a compound that ameliorates, attenuates or eliminates one or more symptom of a particular disease or condition, or prevents or delays the onset of one of more symptom of a particular disease or condition.
[0094] The terms "patient" and “subj ect” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals. The term patient includes males and females.
[0095] The term "pharmaceutically acceptable" means that the referenced substance, such as a compound of Formula I, or a salt of a compound of Formula I, or a formulation containing a compound of Formula I, or a particular excipient, are suitable for administration to a patient.
[0096] The terms "treating", "treat" or "treatment" and the like include preventative (e.g., prophylactic) and palliative treatment.
[0097] The term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient.
[0098] The term "cancer" means a physiological condition in mammals that is characterized by unregulated cell growth. General classes of cancers include carcinomas, lymphomas, sarcomas, and blastomas.
Composition [0099] The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions can be admimstered all at once, as for example, by a bolus injection, multiple times, such as by a series of tablets, or delivered substantially uniformly over a period of time, as for example, using transdermal delivery. It is also noted that the dose of the compound can be varied over time.
[0100] The compounds of the present invention, if desired, can be administered to a patient either orally, rectally, parenterally, (for example, intravenously, intramuscularly, or subcutaneously) mtracistemally, mtravaginally, mtrapentoneally, mtravesically, locally (for example, powders, ointments or drops), or as a buccal or nasal spray. All methods that are used by those skilled in the art to administer a pharmaceutically active agent are contemplated.
[0101] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0102] These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[0103] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, as for example, paraffin; (i) absorption accelerators, as for example, quaternary' ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (1) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage forms may also comprise buffering agents.
[0104] Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
[0105] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well know n in the art. They may also contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are poly meric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
[0106] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like. [0107] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.
[0108] Compositions for rectal administration are preferable suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.
[0109] Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalants. The active compound or fit compounds are admixed under sterile condition with a physiologically acceptable carrier, and any preservatives, buffers, or propellants that may be required. Opthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
[0110] The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram body weight is typically sufficient. The specific dosage and dosage range that can be used depends on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound being administered. The determination of dosage ranges and optimal dosages for a particular patient is within the ordinary skill in the art.
[0111] The compounds of the present invention can be administered as pharmaceutically acceptable salts, esters, amides or prodmgs. The term "salts" refers to inorganic and organic salts of compounds of the present invention. The salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting a purified compound in its free base or acid form with a suitable organic or inorganic base or acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. The salts may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19 (1977).
[0112] Examples of pharmaceutically acceptable esters of the compounds of the present invention include Ci-Cs alkyl esters. Acceptable esters also include C5-C7 cycloalkyl esters, as well as arylalkyl esters such as benzyl. C1-C4 alkyl esters are commonly used. Esters of compounds of the present invention may be prepared according to methods that are well known in the art.
[0113] Examples of pharmaceutically acceptable amides of the compounds of the present invention include amides derived from ammonia, primary Ci-Cx alkyl amines, and secondary Ci-Cs dialkyl amines. In the case of secondary amines, the amine may also be in the form of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, C1-C3 primary alkyl amines and C1-C2 dialkyl secondary amines are commonly used. Amides of the compounds of the present invention may be prepared according to methods well known to those skilled in the art.
[0114] The term "prodrug" means compounds that are transformed in vivo to yield a compound of the present invention. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
[0115] To illustrate, if the compound of the invention contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as (Ci-Ce alkyl, (C2-Ci2)alkanoyloxymethyl, 1- (alkanoyloxy)ethyl having from 4 to 9 carbon atoms, l-methyl-l-(alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, l-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci- C2)alkylamino(C2-C3)alkyl (such as b-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N- di(Ci-C2)alkylcarbamoyl-(Ci-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2- C3)alkyl.
[0116] Similarly, if a compound of the present invention comprises an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C6)alkanoyloxy methyl, l-(( Ci-C6)alkanoyloxy)ethyl, 1- methyl-l-(( Ci-C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxy methyl, N-( Ci- C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C6)alkanoyl, a-amino(Ci-C4)alkanoyl, arylacyl and a-aminoacyl, or a-ammoacyl-a-aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, -P(0)(0H)2, - P(0)(0(Ci-C6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
[0117] The compounds of the present invention may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if the compound contains a double bond, both the cis and trans forms (designated as S and E, respectively), as well as mixtures, are contemplated.
[0118] Mixture of stereoisomers, such as diastereomeric mixtures, can be separated into their individual stereochemical components on the basis of their physical chemical differences by known methods such as chromatography and/or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e g., an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some compounds may be atropisomers (e.g., substituted biaryls). [0119] The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like. The present invention contemplates and encompasses both the solvated and unsolvated forms.
[0120] It is also possible that compounds of the present invention may exist in different tautomeric forms. All tautomers of compounds of the present invention are contemplated. For example, all of the tautomeric forms of the tetrazole moiety are included in this invention Also, for example, all keto-enol or imine-enamine forms of the compounds are included in this invention.
[0121] Those skilled m the art will recognize that the compound names and structures contained herein may be based on a particular tautomer of a compound. While the name or structure for only a particular tautomer may be used, it is intended that all tautomers are encompassed by the present invention, unless stated otherw ise.
[0122] It is also intended that the present invention encompass compounds that are synthesized in vitro using laboratory techniques, such as those well known to synthetic chemists; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds of the present invention may be synthesized using a combination of in vitro and in vivo techniques.
[0123] The present invention also includes isotopically-labelled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nrtrogen, oxygen, phosphorous, fluonne and chlonne, such as 2H, Ή, 13C, 14C, 15N, 160, 170, 180, 31P, 32P, 35S, 18F, and 36C1. In one aspect, the present invention relates to compounds wherein one or more hydrogen atom is replaced with deuterium (2H) atoms.
[0124] Compounds of the present invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically- labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detection. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of this invention can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
[0125] The compounds of the present invention may exist in vanous solid states including crystalline states and as an amorphous state. The different crystalline states, also called polymorphs, and the amorphous states of the present compounds are contemplated as part of this invention.
[0126] All patents, published patent applications and other publications recited herein are hereby incorporated by reference.
Compounds
[0127] In one aspect, the present invention relates to a compound having the general formula (A)k-Li, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, wherein:
[0128] A is a moiety that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
Figure imgf000037_0001
Figure imgf000038_0001
Li is a linker; each A is covalently linked to the Li as allowed by valence;
R1 is aryl, -N(R5)-X-R6, -SO2R5, or -0(CH2)mR5, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R2 is aryl, -NH-(C3-CIO) heteroaryl, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R3 is cyano, aryl, -NH-(C3-CIO) heteroaryl, (C3-Cio)heterocyclo, or -N(R5)-(CH2)m-X- (CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R4 is halo, cyano, aryl, OR5, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n- aiyl. -(CH2)n-heteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryd, or R5 and R6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic nng, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R7 is H, (Ci-C3)alkyl, or R7 and R26 taken together with the carbons they are attached to forming a carbon carbon double bond;
R8, R9, R10, R11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R12, R13, R14, R15 each is independently H, NH2, (Ci-C3)alkyl, -N(R5)-(CH2)m-N(R5)- X-R6, with proviso that no more than three substituents out of R12, R13, R14, and R15 are H, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R16 is NH2 or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R17 is cyano, heteroaryl, -(CH2)m-C(0)0-R6, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R18, R19, R20, R21 each independently is H, halo, (Ci-C3)alkyl, (Ci-C3)alkoxy, or - N(R5)-X-R6, with the proviso that no more than two substituents of R18, R19, R20, R21 are H; or R18, R19 taken together with the carbons they are attached to forming a (C3- Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R19, R20 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R20, R21 taken together with the carbons they are attached to forming a (C .-Ciolcycloalkvl or a (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Rw at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, - ( C H 2 ) 11 - h ete r 0 a ry L aryl, and heteroaryl;
X is a bond, -SO2-, -(CH2)nC(0)(CH2)m-, -C(0)NH-, -C(0)N(Rw)-, -NHC(0)NH-, or -(CH2)n-;
Yi is -NHR25, -NHC(0)R25, or-CHR25R26; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
[0129] In an embodiment, Li is -Lb-(La)t-H; wherein La at each occurrence is independently selected from the group consisting of a bond, CR5R6, C(R5R6)0, C(R5R6)C(R5R6)0, SO2, SO2NR5, SONR5, CONR5, NR5CONR6, NR5S02NR6, CO, CR5=CR6, R5, P(0)OR5, NR5C(=NCN)NR6, NR5C(=NCN), and
Figure imgf000040_0001
, any of which may be optionally substituted with 1 or more R" groups as allowed by valence;
H is hydrogen.
Lb is selected from the group consisting of:
Figure imgf000041_0001
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[0130] In an embodiment, moiety A is selected from the compounds listed in Table 6 in Example 6.
[0131] In one aspect, the present invention relates to a compound of the general formula (A)k-L-Q, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, wherein:
[0132] A is a compound that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
Figure imgf000042_0001
Figure imgf000043_0001
Q is a moiety that binds to a target protein which is sequestered to the E3 ubiquitin ligase and/or degraded upon interaction with the E3 ubiquitin ligase;
L is a linker; each A is covalently linked to the L as allowed by valence;
R1 is aryl, -N(R5)-X-R6, -SO2R5, or -0(CH2)mR5, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R2 is aryl, -NH-(C3-CIO) heteroaryl or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R3 is cyano, aryl, -NH-(C3-CIO) heteroaryl, (O-Cio)heterocyclo. or -N(R5)-(CH2)m-X- (CEh)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R4 rs halo, cyano, aryl, OR5, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R5 at each occurrence is independently H, (Cr-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cro) cycloalkyl, -(CH2)n-(C3-Cro)heterocyclo, -(CEhy aryl, -(CEbVheteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R7 is H, (Ci-C3)alkyl, or R7 and R26 taken together with the carbons they are attached to forming a carbon carbon double bond;
R8, R9, R10, R11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R12, R13, R14, R15 each is independently H, NH2, (Ci-C3)alkyl, -N(R5)-(CH2)m-N(R5)- X-R6, with proviso that no more than three substituents out of R12, R13, R14, and R15 are H, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R16 is NH2 or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R17 is cyano, heteroaryl, -(CH2)m-C(0)0-R6, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R18, R19, R20, R21 each independently is H, halo, (Ci-C: alkyl, (Ci-C3)alkoxy, or - N(R5)-X-R6, with the proviso that no more than two substituents of R18, R19, R20, R21 are H; or
R18, R19 taken together with the carbons they are attached to forming a (C3- Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R19, R20 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R20, R21 taken together with the carbons they are attached to forming a (G-Cio)cycloalkyl or a (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Rw at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl. cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, -(CLDn-heteroaryl. aryl, and heteroaryl;
X is a bond, -SO2-, -(CH2)nC(0)(CH2)m-, -C(0)NH-, -C(0)N(Rw)-, -NHC(0)NH-, or -(CH2)n-;
Yi is -NHR25, -NHC(0)R25, or-CHR25R26; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
[0133] In an embodiment, L is -Lb-(La)t-; wherein La at each occurrence is independently selected from the group consisting of a bond, CR5R6, C(R5R6)0, C(R5R6)C(R5R6)0, SO2, NR5, C(R5R6)NR5, SO2NR5, SONR5, C0NR5, NR5C0NR6, NR5S02NR6, CO, CR5=CR6, CºC, SIR5R6, P(0)R5, P(0)OR5, NR5C(=NCN)NR6, NR5C(=NCN), and NR5C(=CN02)NR6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Lb is selected from the group consisting of:
Figure imgf000045_0001
Figure imgf000046_0001
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. [0134] In an embodiment, L is -(CH2CH2)t-, -(CH20)t- or -(CH2CH20)t-.
[0135] In an embodiment, A is a moiety of Formula XI
Figure imgf000046_0002
or a pharmaceutically acceptable salt thereof, wherein:
R22 is H, halo, OH, -NR5R5, (Ci-C3)alkyl, (Ci-C3)alkoxy, (hydroxy)(Ci-C3)alkyl, cyano, -N(R5)-X-R6, -N(R5)-(CH2)m-N(R5)-X-R6, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R23 is H, halo, OH, -NR5R5, -(CH2)n-NR5R5, (Ci-C3)alkyl, (Ci-C3)alkoxy, - C(0)NR5R6, (hydroxy)(Ci-C3)alkyl, cyano, -N(R5)-X-R6, -N(R5)-(CHR5)m-X-R6, - N(R5)-(CH2)m-N(R5)-X-R6, aryl, heteroaryl, or R22 and R23 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl ring or a (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R24 is H, halo, OH, -NR5R5, -(CH2)n-NR5R5, (Ci-C3)alkyl, (Ci-C3)alkoxy, (halo)(Ci- C3)alkyl, (hydroxy)(Ci-C3)alkyl, cyano, -NO2, -N(R5)-X-R6, -N(R5)-(CH2)m-N(R5)- X-R6, aryl, heteroaryl, or R23 and R24 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl ring or a (C3-Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n- aryl, -(CH2)n-heteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryd, or R5 and R6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic nng, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Rw at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alky ny l. cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, and heteroaryl;
X is a bond, -SO2-, -(CH2)nC(0)(CH2)m-, -C(0)NH-, -C(0)N(R">, -NHC(0)NH-, or -(CH2)n-; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4.
[0136] In an embodiment, R22 is H; R23 is H; R24 is halo.
[0137] In an embodiment, A is a moiety of Formula XII, XIII, XIV, XV, XVI, XVII, or XVIII,
Figure imgf000048_0001
or a pharmaceutically acceptable salt thereof, wherein: R28, R29, R30, R31 is independently H, halo, OH, -NR5R5, -(CH2)n-NR5R5, (Ci-C3)alkyl, (Ci-C3)alkoxy, (halo)(Ci-C3)alkyl, (hydroxy)(Ci-C3)alkyl, cyano, -NO2, -N(R5)-X-R6, -N(R5)-(CH2)m-N(R5)-X-R6, aryl, heteroaryl, or R28, R29 taken together with the carbons to which they are attached to form a (C3-Cio)cycloalkyl or a (C3- Cio)heterocyclo, or R30, R31 taken together with the carbons to which they are attached to form a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R29, R30 taken together to form a bond, or R29, R30 taken together with the carbons to which they are attached to form a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo or an aryl or a heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n- aryl, -(CH2)n-heteroaryl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Rw at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, ary lalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, and heteroaryl;
X is a bond, -SO2-, -(CH2)nC(0)(CH2)m-, -C(0)NH-, -C(0)N(Rw)-, -NHC(0)NH-, or - (CH2)n-; m is 0, 1, 2, 3, or 4; ms 0, 1, 2, 3, or 4. Linker Li and L
[0138] The linker Li and L each is independently covalently bound to the E3 ubiquitin ligase binding moiety A. The linker L is also independently covalently bound to the target protein binding moiety Q. The covalent bond of linking is preferably through an amide, ester, thioester, keto group, carbamate (urethane), carbon or ether, each of which groups may be inserted anywhere on A moiety or Q moiety as allowed by valence, including any substituent or functional group in A moiety or Q moiety. In certain preferred aspects, the linker may be optionally substituted with (Ci-C6)alkyl, (Ci-C6)alkylene, (C i-G,) alkyne, aryl, heteroaryl, (C3-C8)cycloalkyl, or (C3-Cs)heterocyclo. In an embodiment, the linker Li or L is linked to A moiety via R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19,
R2°, R21 R22 Rly R24 R25 R26 R27 R23 R29 R '(i or R31 defmed abm e
[0139] In an embodiment, Li is -Lb-(La)t-H, wherein H is hydrogen.
[0140] In an embodiment, L is -Lb-(La)t-.
[0141] In an embodiment, t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
[0142] In an embodiment, La is selected from the group consisting of
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Lb is selected from the group consisting of:
Figure imgf000054_0001
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
Embodiments of A-Li
In an embodiment, the compound having general formula A-Li is selected from the compounds listed in Table 1.
Table 1: Embodiments of general formula A-Li
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0002
Embodiments of (A)k-L-Q
[0143] In an embodiment, the compound having general formula (A)k-L-Q is selected from the compounds listed in Table 2, Table 3, or Table 4.
Figure imgf000089_0001
Figure imgf000089_0003
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Table 3: Embodiments of general formula (A)k-L-O, having 0 moiety.
Figure imgf000117_0002
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0002
Table 4: Embodiments of general formula A-Li-La-0
[0144] In some embodiments, the compounds of the present invention have the general formula A-Lb-L -Q, wherein the moiety A, Lb, and La-Q are independently selected from Table 4. Any combination of the A, Lb, and La-Q listed in Table 4 are contemplated as the compound of the present invention. Lb is connected to the moiety A via a covalent bond at any position of A as allowed by valence. For clarity, La1.0-6 includes seven Lal moieties, wherein T is 0, 1, 2, 3, 4, 5, or 6 respectively. Likewise, La2.0-5 includes six La2 moieties, wherein T is 0, 1, 2, 3, 4, or 5 respectively; Lb6.1-3 includes three Lb6 moieties, having 1, 2, or 3 methylene chain respectively; Lb7.0-5 includes six Lb7 moieties, having 0, 1, 2, 3, 4, or 5 methylene chain respectively; Lb8.1-4 includes four Lb8 moieties, having 1, 2, 3, or 4 methylene chain respectively. R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45,
Figure imgf000220_0001
and R105 are each independently selected from the group consisting of H, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl, wherein said alkyl, haloalk l, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalky l, cycloalky lalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CFh)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CTl2)n-heteroaryl, aryl, and heteroaryl. In an embodiment, Lb
Figure imgf000221_0001
[0145] In an embodiment, the compound has the structure of 4.001- Lbl- Lal.0-6, 4.001- Lbl- La2.0-5, 4.002- Lbl- Lal.0-6, 4.002- Lbl- La2.0-5, 4.003- Lbl- La1.0-6, 4.003- Lbl- La2.0-5, 4.004- Lbl- Lal.0-6, 4.004- Lbl- La2.0-5, 4.005- Lbl- Lal.0-6, 4.005- Lbl- La2.0-5, 4.006- Lbl- Lal.0-6, 4.006- Lbl- La2.0-5, 4.007- Lbl- Lal.0-6, 4.007- Lbl- La2.0-5, 4.008- l- Lal.0-6, 4.008- Lbl- La2.0-5, 4.009- Lbl- La1.0-6, 4.009- Lbl- La2.0-5, 4.010- Lbl- Lal.0-6, 4.010- Lbl- La2.0-5, 4.011- Lbl- Lal.0-6, 4.011- Lbl- La2.0-5, or 4.012- Lbl- La2.0-
5.
[0146] In an embodiment, the compound has the structure of 4.001- Lb2- Lal.0-6, 4.001- Lb2- La2.0-5, 4.002- Lb2- La1.0-6, 4.002- Lb2- La2.0-5, 4.003- Lb2- Lal.0-6, 4.003- Lb2- La2.0-5, 4.004- Lb2- Lal.0-6, 4.004- Lb2- La2.0-5, 4.005- Lb2- Lal.0-6, 4.005- Lb2- La2.0-5, 4.006- Lb2- Lal.0-6, 4.006- Lb2- La2.0-5, 4.007- Lb2- Lal.0-6, 4.007- Lb2- La2.0-5, 4.008- Lb2- Lal.0-6, 4.008- Lb2- La2.0-5, 4.009- Lb2- La1.0-6, 4.009- Lb2- La2.0-5, 4.010- Lb2- Lal.0-6, 4.010- Lb2- La2.0-5, 4.011- Lb2- La1.0-6, 4.011- Lb2- La2.0-5, or 4.012- Lb2- La2.0- 5.
[0147] In an embodiment, the compound has the structure of 4.001- Lb3 - Lal.0-6, 4.001- Lb3 - La2.0-5, 4.002- Lb3 - Lal.0-6, 4.002- Lb3 - La2.0-5, 4.003- Lb3 - Lal.0-6, 4.003- Lb3 - La2.0-5, 4.004- Lb3 - Lal.0-6, 4.004- Lb3 - La2.0-5, 4.005- Lb3 - Lal.0-6, 4.005- Lb3 - La2.0- 5, 4.006- L 3 - Lal.0-6, 4.006- Lb3 - La2.0-5, 4007- Lb3 - L.l.0-6, 4.007- Lb3 - La2.0-5, 4.008- Lb3 - Lal.0-6, 4.008- Lb3 - La2.0-5, 4.009- L 3 - La1.0-6, 4.009- Lb3 - La2.0-5, 4.010- Lb3 - Lal.0-6, 4.010- Lb3 - La2.0-5, 4.011- Lb3 - Lal.0-6, 4.011- Lb3 - La2.0-5, or 4.012- Lb3 - La2.0-5.
[0148] In an embodiment, the compound has the structure of 4.001- Lb4 - Lal.0-6, 4.001- Lb4 - La2.0-5, 4.002- Lb4 - La1.0-6, 4.002- Lb4 - La2.0-5, 4.003- Lb4 - La1.0-6, 4.003- Lb4 - La2.0-5, 4.004- L 4 - La1.0-6, 4.004- Lb4 - La2.0-5, 4.005- Lb4 - La1.0-6, 4.005- Lb4 - La2.0- 5, 4.006- Lb4 - Lal.0-6, 4.006- Lb4 - La2.0-5, 4007- Lb4 - Lal.0-6, 4.007- Lb4 - La2.0-5, 4.008- Lb4 - Lal.0-6, 4.008- Lb4 - La2.0-5, 4.009- Lb4 - LJ.0-6, 4.009- Lb4 - La2.0-5, 4.010- Lb4 - Lai.0-6, 4.010- Lb4 - La2.0-5, 4.011- Lb4 - LJ.0-6, 4.011- Lb4 - La2.0-5, or 4.012- Lb4 - La2.0-5.
[0149] In an embodiment, the compound has the structure of 4.001- Lb 5 - Lal.0-6, 4.001- Lb5 - La2.0-5, 4.002- Lb5 - Lal.0-6, 4.002- Lb5 - La2.0-5, 4.003- Lb5 - La1.0-6, 4.003- Lb5 - La2.0-5, 4.004- Lb5 - LJ.0-6, 4.004- Lb5 - La2.0-5, 4.005- Lb5 - Lal.0-6, 4.005- Lb5 - La2.0- 5, 4.006- Lb5 - Lal.0-6, 4.006- Lb5 - La2.0-5, 4007- Lb5 - Lal.0-6, 4.007- Lb5 - La2.0-5, 4.008- Lb5 - Lal.0-6, 4.008- Lb5 - La2.0-5, 4.009- Lb5 - Lal.0-6, 4.009- Lb5 - La2.0-5, 4.010- Lb5 - Lal.0-6, 4.010- Lb5 - La2.0-5, 4.011- Lb5 - Lal.0-6, 4.011- Lb5 - La2.0-5, or 4.012- Lb5 - La2.0-5.
[0150] In an embodiment, the compound has the structure of 4.001- Lb6 - Lal.0-6, 4.001- Lb6 - La2.0-5, 4.002- Lb6 - LJ.0-6, 4.002- Lb6 - La2.0-5, 4.003- Lb6 - La1.0-6, 4.003- Lb6 - La2.0-5, 4.004- Lb6 - Lal.0-6, 4.004- Lb6 - La2.0-5, 4.005- Lb6 - Lal.0-6, 4.005- Lb6 - La2.0- 5, 4.006- Lb6 - Lal.0-6, 4.006- Lb6 - La2.0-5, 4007- Lb6 - Lal.0-6, 4.007- Lb6 - La2.0-5, 4.008- Lb6 - Lal.0-6, 4.008- Lb6 - La2.0-5, 4.009- Lb6 - Lal.0-6, 4.009- Lb6 - La2.0-5, 4.010- Lb6 - Lal.0-6, 4.010- Lb6 - La2.0-5, 4.011- Lb6 - Lal.0-6, 4.011- Lb6 - La2.0-5, or 4.012- Lb6 - La2.0-5.
[0151] In an embodiment, the compound has the structure of 4.001- Lb7 - Lal.0-6, 4.001- Lb7 - La2.0-5, 4.002- Lb7 - LJ.0-6, 4.002- Lb7 - La2.0-5, 4.003- Lb7 - Lal.0-6, 4.003- Lb7 - La2.0-5, 4.004- Lb7 - Lal.0-6, 4.004- Lb7 - La2.0-5, 4.005- Lb7 - Lal.0-6, 4.005- Lb7 - La2.0- 5, 4.006- Lb7 - Lal.0-6, 4.006- Lb7 - La2.0-5, 4007- Lb7 - Lal.0-6, 4.007- Lb7 - La2.0-5, 4.008- Lb7 - Lal.0-6, 4.008- Lb7 - La2.0-5, 4.009- Lb7 - Lal.0-6, 4.009- Lb7 - La2.0-5, 4.010- Lb7 - Lal.0-6, 4.010- Lb7 - La2.0-5, 4.011- Lb7 - Lal.0-6, 4.011- Lb7 - La2.0-5, or 4.012- Lb7 - La2.0-5.
[0152] In an embodiment, the compound has the structure of 4.001- Lb8 - Lal.0-6, 4.001- Lb8 - La2.0-5, 4.002- Lb8 - LJ.0-6, 4.002- Lb8 - La2.0-5, 4.003- Lb8 - LJ.0-6, 4.003- Lb8 - La2.0-5, 4.004- Lb8 - Lal.0-6, 4.004- Lb8 - La2.0-5, 4.005- Lb8 - Lal.0-6, 4.005- Lb8 - La2.0- 5, 4.006- Lb8 - Lal.0-6, 4.006- Lb8 - La2.0-5, 4007- Lb8 - Lal.0-6, 4.007- Lb8 - La2.0-5, 4.008- Lb8 - LJ.0-6, 4.008- Lb8 - La2.0-5, 4.009- L 8 - Lal.0-6, 4.009- Lb8 - La2.0-5, 4.010- Lb8 - Lal.0-6, 4.010- Lb8 - La2.0-5, 4.011- Lb8 - Lal.0-6, 4.011- Lb8 - La2.0-5, or 4.012- Lb8 - La2.0-5. [0153] In an embodiment, the compound has the structure of 4.001- Lb9 - Lal.0-6, 4.001- Lb9 - La2.0-5, 4.002- Lb9 - LJ.0-6, 4.002- Lb9 - La2.0-5, 4.003- Lb9 - Lal.0-6, 4.003- Lb9 - La2.0-5, 4.004- Lb9 - La1.0-6, 4.004- Lb9 - La2.0-5, 4.005- Lb9 - Lal.0-6, 4.005- Lb9 - La2.0- 5, 4.006- Lb9 - Lal.0-6, 4.006- Lb9 - La2.0-5, 4007- Lb9 - Lal.0-6, 4.007- Lb9 - La2.0-5, 4.008- Lb9 - Lal.0-6, 4.008- Lb9 - La2.0-5, 4.009- Lb9 - La1.0-6, 4.009- Lb9 - La2.0-5, 4.010- Lb9 - Lal.0-6, 4.010- Lb9 - La2.0-5, 4.011- Lb9 - LJ 0-6, 4.011- Lb9 - La2.0-5, or 4.012- Lb9 - La2.0-5.
[0154] In an embodiment, the compound has the structure of 4.001- LblO - Lal.0-6, 4.001- LblO - La2.0-5, 4.002- LblO - Lal.0-6, 4.002- Lb10 - La2.0-5, 4.003- LblO - La1.0-6, 4.003- LblO - La2.0-5, 4.004- LblO - Lal.0-6, 4.004- Lb10 - La2.0-5, 4.005- Lb10 - La1.0-6, 4.005- LblO - La2.0-5, 4.006- LblO - Lal.0-6, 4.006- Lb10 - La2.0-5, 4.007- Lb10 - La1.0-6, 4.007- LblO - La2.0-5, 4.008- LblO - Lal.0-6, 4.008- LblO - La2.0-5, 4.009- LblO - Lal.0-6, 4.009- LblO - La2.0-5, 4.010- LblO - Lal.0-6, 4.010- LblO - La2.0-5, 4.011- LblO - Lal.0-6, 4.011- LblO - La2.0-5, or 4.012- LblO - La2.0-5.
[0155] In an embodiment, the compound has the structure of 4.001- Lbll - LJ.0-6, 4.001- Lbl l - La2.0-5, 4.002- Lbll - Lal.0-6, 4.002- Lbll - La2.0-5, 4.003- Lbll - Lai.0-6, 4.003- Lbl l - La2.0-5, 4.004- Lbll - Lal.0-6, 4.004- Lbll - La2.0-5, 4.005- Lbll - LJ.0-6, 4.005-
Lbl l - La2.0-5, 4.006- Lbll - Lal.0-6, 4.006- Lbll - La2.0-5, 4.007- Lbll - Lal.0-6, 4.007-
Lbl l - La2.0-5, 4.008- Lbll - Lal.0-6, 4.008- Lbll - La2.0-5, 4.009- Lbll - Lal.0-6, 4.009-
Lbl l - La2.0-5, 4.010- Lbll - Lal.0-6, 4.010- Lbll - La2.0-5, 4.011- Lbll - LJ.O-6, 4.011-
Lbl 1 - La2.0-5, or 4.012- Lbl 1 - La2.0-5.
[0156] In an embodiment, the compound has the structure of 4.001- Lb 12 - LJ.0-6, 4.001- Lb12 - La2.0-5, 4.002- Lb12 - Lal.0-6, 4.002- Lb12 - La2.0-5, 4.003- Lb12 - LJ.O-6, 4.003- Lb12 - La2.0-5, 4.004- Lb12 - Lal.0-6, 4.004- Lb12 - La2.0-5, 4.005- Lb12 - La1.0-6, 4.005- Lb12 - La2.0-5, 4.006- Lb12 - Lal.0-6, 4.006- Lb12 - La2.0-5, 4.007- Lb12 - La1.0-6, 4.007- Lb12 - La2.0-5, 4.008- Lb12 - Lal.0-6, 4.008- Lb12 - La2.0-5, 4.009- Lb12 - La1.0-6, 4.009- Lb12 - La2.0-5, 4.010- Lb12 - Lal.0-6, 4.010- Lb12 - La2.0-5, 4.011- Lb12 - LJ.O-6, 4.011- Lb12 - La2.0-5, or 4.012- Lb12 - La2.0-5.
[0157] In an embodiment, the compound has the structure of 4.001- Lb 13 - LJ.O-6, 4.001- Lb13 - La2.0-5, 4.002- Lb13 - Lal.0-6, 4.002- Lb13 - La2.0-5, 4.003- Lb13 - La1.0-6, 4.003- Lbl3 - La2.0-5, 4.004- Lb13 - Lal.0-6, 4.004- Lb13 - La2.0-5, 4.005- Lb13 - LJ.O-6, 4.005- Lb13 - La2.0-5, 4.006- 13 - Lal.0-6, 4.006- U13 - La2.0-5, 4.007- U13 - Lal.0-6, 4.007- 13 - La2.0-5, 4.008- 13 - Lal.0-6, 4.008- Lb13 - La2.0-5, 4.009- Lbl3 - Lal.0-6, 4.009-
Lbl3 - La2.0-5, 4.010- Lb13 - Lal.0-6, 4.010- Lb13 - La2.0-5, 4.011- Lb13 - Lal.0-6, 4.011- Lbl3 - La2.0-5, or 4.012- Lbl 3 - La2.0-5.
[0158] In an embodiment, the compound has the structure of 4.001- Lbl4 - Lal.0-6, 4.001- Lb14 - La2.0-5, 4.002- Lb14 - Lal.0-6, 4.002- Lb14 - La2.0-5, 4.003- Lb14 - Lal.0-6, 4.003-
Lbl4 - La2.0-5, 4.004- Lb14 - Lal.0-6, 4.004- Lb14 - La2.0-5, 4.005- Lb14 - Lal.0-6, 4.005-
Lbl4 - La2.0-5, 4.006- Lb14 - Lal.0-6, 4.006- Lb14 - La2.0-5, 4.007- Lb14 - Lal.0-6, 4.007-
Lbl4 - La2.0-5, 4.008- Lb14 - Lal.0-6, 4.008- Lb14 - La2.0-5, 4.009- Lb14 - Lal.0-6, 4.009-
Lb14 - La2.0-5, 4.010- Lb14 - Lal.0-6, 4.010- Lb14 - La2.0-5, 4.011- Lb14 - Lal.0-6, 4.011-
Lbl4 - La2.0-5, or 4.012- Lb14 - La2.0-5.
^t
H
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Table 5: Specific Embodiments of general formula (A)k-L-Q.
Figure imgf000231_0002
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
< i/
Figure imgf000243_0001
Figure imgf000243_0002
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
[0159] In an embodiment, moiety A is selected from the compounds listed in Table 6 in Example 6.
[0160] In one aspect, moiety A is selected from the group consisting of:
3-[l-oxo-5-(quinazolin-4-ylamino)isoindolm-2-yl]piperidine-2,6-dione;
3-[5-[(4-aminothieno[2,3-d]pyrimidin-2-yl)amino]-l-oxo-isoindolin-2-yl]piperidine-
2,6-dione;
N-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5-yl]acetamide;
3- [5- [(2-aminopy rimidin-4-y l)amino] - 1 -oxo-isoindolin-2-yl]piperidine-2,6-dione; 6-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolm-5-yl]amino]pyridazine-3-carbonitrile; 3-[[2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5- yl] amino] acetyl] amino]benzamide;
2-[[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolm-5-yl]amino]acetic acid; N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]quinoline-2-carboxamide;
3-[6-[[2-(2-methyl-l-piperidyl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2-yl]piperidine-
2,6-dione;
3- [6- [(2-isoindolin-2-y l-2-oxo-ethyl)amino] - l-oxo-isoindolin-2-vl |piperidine-2.6- dione;
N-(cyclopropylmethyl)-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-
N-methyl-acetamide; acetic acid;3-[l-oxo-6-(quinazolin-4-ylamino)isoindolin-2-yl]piperidine-2,6-dione;
3- [6- [ [2-(3 -methyl- 1 -piperidyl)-2-oxo-ethyl] amino] - 1 -oxo-isoindolin-2-yl] piperidine-
2,6-dione;
3-[6-[(4-methyl-3-oxo-pyrazin-2-yl)amino]-l-oxo-isoindolin-2-yl]piperidine-2,6- dione;
3-[l-oxo-6-(quinoxalin-2-ylamino)isomdolin-2-yl]piperidine-2,6-dione; 3-[6-[(l-methylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-l-oxo-isoindolin-2- yl] pipendine-2,6-dione;
3-[6-(5,7-dihydrofuro[3,4-d]pyrimidin-2-ylamino)-l-oxo-isoindolin-2-yl]piperidine-
2,6-dione;
3-[6-[(6-methylpyrimidin-4-yl)amino]-l-oxo-isoindolin-2-yl]piperidine-2,6-dione;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-phenyl-acetamide;
3-[6-[[2-(2,4-dimethylpiperazin-l-yl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl] piperidine-2, 6-dione; 3-[6-(dimethylamino)-l-oxo-isoindolin-2-yl]pipendine-2,6-dione;
3-(l-oxo-6-phenyl-isoindolin-2-yl)piperidine-2,6-dione;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-5-yl]amino]-N,N-dimethyl-acetamide;
3-[6-[[2-(2-methylmorpholin-4-yl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl] piperidine-2, 6-dione;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-methyl-N-[(l- methylpyrazol-4-yl)methyl]acetamide;
N-benzyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide;
6- [ [2-(2,6-di oxo-3 -piped dyl)-3-oxo-isoindolm-5 -y 1] amino]py ridazine-3 -carbonitrile;
3- [6- [(6-methylpyrrolo[3,2-d]py rimidin-4-yl)amino] - 1 -oxo-isoindolin-2- yl] pipendine-2, 6-dione;
2-(dimethylamino)-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide;
N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]-5H-pyrrolo[2,3-b]pyridine-4- carboxamide;
N-cyclopropyl-2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]acetamide;
3-[l-oxo-6-(2-oxoimidazolidin-l-yl)isoindolin-2-yl]piperidine-2, 6-dione;
2-(2,6-dioxo-3-pipendyl)-3-oxo-isoindoline-5-carbonitrile;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]propanoic acid;
2-acetamido-N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]acetamide;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-5-yl]amino]acetamide;
3-[6-[[2-(3-methyl-5-oxo-piperazin-l-yl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl] piperidine-2, 6-dione;
N-[2-(2,6-dioxo-3-pipendyl)-3-oxo-isoindolm-5-yl]acetamide;
3-[6-[[2-(4-methyl-3-oxo-piperazin-l-yl)-2-oxo-ethyl]amino]-l-oxo-isoindolin-2- yl] pipendine-2, 6-dione;
N-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-5-yl]-3H-imidazo[4,5-b]pyridine-6- carboxamide;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-5-yl]amino]-N-tetrahydropyran-4-yl- acetamide;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-5-yl]amino]acetic acid;
3-[l-oxo-6-[[2-oxo-2-(l-piperidyl)ethyl]amino]isoindolin-2-yl]piperidine-2, 6-dione;
3-(l-oxo-7-phenyl-isoindolin-2-yl)piperidine-2,6-dione;
2-(2,6-dioxo-3-pipendyl)-3-oxo-isoindoline-4-carbonitrile;
2-[[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolm-4-yl]amino]acetic acid; 3-(7-fluoro-l-oxo-isoindolin-2-yl)piperidme-2,6-dione; 3-(5-amino-l-oxo-3,4-dihydroisoquinolin-2-yl)piperidine-2,6-dione; t-butyl 2-[2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindolin-l-yl]acetate; 3-[l-(2H-indol-3-yl)-3-oxo-isoindolin-2-yl]piperidine-2,6-dione;
2-(2,6-dioxo-3-piperidyl)-3-oxo-isoindoline-l-carbonitrile;
3-[l-(dimethylamino)-3-oxo-isoindolin-2-yl]piperidine-2,6-dione; 3-(2-oxopyrrolidin-l-yl)piperidine-2,6-dione; 3-(quinazolin-2-ylamino)piperidine-2,6-dione; (3Z)-3-benzylidenepiperidine-2,6-dione; 3-(quinoxalin-2-ylamino)piperidine-2,6-dione; 3-(pyrimidin-2-ylamino)piperidine-2,6-dione; N-(2,6-dioxo-3-piperidyl)-2-oxo-3H-pyridine-6-carboxamide;
3-(4-methyl- 1 , 1 ,3-trioxo- 1 ,2-benzothiazol-2-y l)piperidine-2,6-dione;
3-(8-amino-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione;
3-(5-amino-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione;
3-(4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione;
3-(5-methyl-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione;
3-(6-methyl-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione; and
3-(8-methyl-4-oxo-l,2,3-benzotriazin-3-yl)piperidine-2,6-dione.
Target Protein Binding Moiety Q
[0161] The target proteins to be bound by moiety Q 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. The term “protein” includes oligopeptides and polypeptide sequences of sufficient length that they can bind to a Q moiety according to the present invention. Any protein in a eukary otic system or a microbial system, including a virus, bacteria or fungus, as otherwise described herein, are targets for ubiquitmation mediated by the compounds according to the present invention. Preferably, the target protein is a eukaryotic protein.
[0162] The Q moiety according to the present invention include, for example, includes 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-containmg 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. Some of the members of these types of small molecule target protein binding moieties are exemplified below. Such small molecule target protein binding moieties also include pharmaceutically acceptable salts, enantiomers, solvates and polymorphs thereof These binding moieties are linked to the ubiquitin ligase binding moiety 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. In an embodiment, the ubiquitin ligase is cereblon.
[0163] Any protein, which can bind to moiety Q and acted on or degraded by an ubiquitin ligase is a target protein according to the present invention. In general, 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 catrabolism), 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 transporter activity, nuclear transport, ion transporter activity', channel transporter activity, carrier activity, permease activity, secretion activity, electron transporter activity, pathogenesis, chaperone regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular organization and biogenesis activity, translation regulator activity. Proteins of interest can include proteins from eurkaryotes and prokaiyotes 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.
[0164] In an embodiment, the target protein is selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, Bel, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, Squalene-hopene cyclase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphoi lase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokme receptors, JAW/STAT, retinoid X receptor, HIV 1 protease, HIV 1 integrase, influenza, neuramimidase, hepatitis B reverse transcriptase, sodium channel, protein P- glycoprotein (and MRP), tyrosine kinases, CD23, CD124, tyrosine kinase p56 lck, CD4,
CD5, IL-2 receptor, IL-1 receptor, TNF-alpha, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, Ras/Raf/ME/ERK pathway, interleukin- 1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus-1 (HSV-I) protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, c-Kit, TORb activated kinase 1, mammalian target of rapamycin, SHP2, androgen receptor, oxytocin receptor, microsomal transfer protein inhibitor, 5 alpha reductase, angiotensin II, glycine receptor, noradrenaline reuptake receptor, estrogen receptor, estrogen related receptors, focal adhesion kinase, Src, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kinase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), famesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-1, vitronectin receptor, integrin receptor, Her-2/neu, telomerase, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium channel protein, and chloride channel protein, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphynnogen oxidase, and enolpyruvylshikimate-phosphate synthase.
[0165] In an embodiment, Q is a moiety that is an Hsp90 inhibitor, a kinase inhibitor, a phosphatase inhibitor, an HDM2/MDM2 inhibitor, a human BET Bromodomain inhibitor, an HD AC inhibitor, a human lysine methyltransferase inhibitor, a RAF receptor inhibitor, a FKBP inhibitor, an angiogenesis inhibitor, an aryl hydrocarbon receptor inhibitor, an androgen receptor inhibitor, an estrogen receptor inhibitor, a thyroid hormone receptor inhibitor, an HIV protease inhibitor, an HIV integrase inhibitor, an acyl protein thioesterase 1 inhibitor, or an acyl protein thioesterase 2 inhibitor.
[0166] In an embodiment, Q is a moiety that is a TANK-binding kinase 1 (TBK1) inhibitor, an estrogen receptor a (ERa) inhibitor, a bromodomain-containing protein 4 (BRD4) inhibitor, an androgen receptor (AR) inhibitor, a platelet-derived growth factor receptor inhibitor, a p38 MAPK inhibitor, aBcr-Abl tyrosine-kinase inhibitor, an Her2 inhibitor, an EGFR inhibitor, an MDM2 inhibitor, a bromodomain-containing protein 2 (BRD2) inhibitor, an HD AC inhibitor, a DHFR inhibitor, or a c-Myc inhibitor.
[0167] In an embodiment, Q is a moiety selected from the group consisting of trimethoprim, vorinostat, tamoxifen, JQ1, Nutlin 3, afatinib, chloroalkane, dasatinib, BIRB796, FK-506, simvastatin, rapamycin, and sorafenib.
[0168] In an embodiment, Q is a moiety binding to a target protein. Such target protein can be degraded or sequestrated by an E3 ubiquitin ligase, wherein the E3 ubiquitin ligase is selected from cereblon (CRBN), damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), regulator of cullins 1 (ROC1), and Yon Hippel Lindau (VHL).
[0169] In an embodiment, the E3 ubiquitin ligase is CRBN.
[0170] In an embodiment, the compound having the general formula (A)k-Li or (A)k-L-Q described herein is capable of simultaneously binding to the target protein and the E3 ubiquitin ligase. In an embodiment, the binding causes ubiquitination of the target protein by the E3 ubiquitin ligase. In an embodiment, the binding causes degradation of the target protein by the proteasome.
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0002
[0171] The linker L can be covalently connected to Q moiety at any position allowed by valence. In an embodiment, the linker L is covalently connected to Q moiety via the specific position indicated as :
Figure imgf000273_0001
shown in the table below.
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
[0172]
[0173] In one aspect, the present invention relates to a pharmaceutical composition comprising the compound of Formula (A)k-L-Q or (A)k-Li and a pharmaceutically acceptable carrier, additive, and/or excipient.
[0174] In one aspect, the present invention relates to a method for treating a disease in a subject, said method comprising administering an effective amount of a compound having Formula (A)k-L-Q or (A)k-Li
[0175] In one aspect, the present invention relates to a method for treating a disease in a subject wherein dysregulated protein activity is responsible for said disease, said method comprising administering an effective amount of a compound having Formula (A)k-L-Q or (A)k-Li.
[0176] In an embodiment, the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, renal cell carcinomas, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovanan cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemias, lymphomas, Burkit s lymphoma, Non-Hodgkin's lymphoma, melanomas, myeloproliferative diseases, multiple myeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, Schwannomas, testicular cancer, thyroid cancer, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratocarcmomas. [0177] In another aspect, the present invention relates to a method of treating or preventing one or more autoimmune diseases or disorders comprising administering a composition comprising a pharmaceutically effective amount of the compound described herein and a pharmaceutically acceptable carrier to a subject in need thereof. In an embodiment, the autoimmune disease or disorder is selected from, such as multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, Fibromyalgia, Menier's syndrome; transplantation rejection (e.g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Grave's disease, and other autoimmune diseases or disorders
[0178] In an embodiment, the subject is a human.
[0179] In another aspect, the present invention relates to a method of modulating cereblon comprising administering the composition comprising the compounds having the general formula (A)k-Li or (A)k-L-Q described herein, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, to a subject in need thereof.
[0180] In another aspect, the present invention relates to a method of modulating proteasomal degradation of a protein comprising administering the composition comprising the compounds having the general formula (A)k-Li or (A)k-L-Q described herein, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, to a subject in need thereof.
[0181] In another aspect, the present invention relates to a method of modulating sequestration of a protein to the proteasome comprising administering the composition comprising the compounds having the general formula (A)k-Li or (A)k-L-Q described herein, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, to a subject in need thereof.
EXAMPLES
General Synthetic Schemes
[0182] Compounds of the present invention generally can be prepared beginning with commercially available starting materials and using synthetic techniques known to those of skill in the art. Outlined below are some reaction schemes suitable for preparing compounds of the present invention. Further exemplification is found in the specific examples provided.
Example 1: Competition Assay
[0183] CRBN binding is assessed with a MAPPIT-like assay by determining the ability of test compounds to compete with a trimethoprim-lenalidomide hybrid ligand for binding to CRBN in cells. The traditional MAPPIT assay, as described for example in Lemmens, et al “MAPPIT, a mammalian two-hybrid method for in-cell detection of protein-protein interactions,” Methods Mol Biol. 2015;1278:447-55, has been used to monitor protein-protein interactions. A bait protein (protein A) is expressed as a fusion protein in which it is genetically fused to an engineered intracellular receptor domain of the leptin receptor, which is itself fused to the extracellular domain of the erythropoietin (Epo) receptor. Binding of Epo ligand to the EpoR component results in activation of receptor-associated intracellular JAK2. However, activated JAK2 cannot activate the leptin receptor to trigger STAT3 binding and its phosphorylation because its tyrosine residues, normally phosphorylated by activated JAK2, have been mutated. Reconstitution of a JAK2 phosphorylatable STAT3 docking site is instead created through interaction of a protein B with protein A, whereby protein B is fused to a cytoplasmic domain of the gpl30 receptor (which now harbors appropriate tyrosine resides recognized by the activated JAK2 kinase). Thus, physical interaction of protein A with protein B reconstitutes and Epo triggers JAK2-STAT3 signaling pathway activation. Activation of STAT3 can be monitored by introduction of a STAT3-responsive reporter gene, including a luciferase-encoding gene or a gene encoding a fluorescent marker such as GFP or some other type of fluorescent protein (EGF etc ). In this manner, the MAPPIT assay provides a versatile assay to assess such recombinant protein-protein interactions, or compound- or hybrid ligand-induced protein-protem interactions, in intact cells.
[0184] Here, we use a similar MAPPIT-like assay to determine the ability of test compounds to compete with the trimpethoprim-lenalidomide-induced binding between DHFR and CRBN. Therefore, HEK293 cells transfected with the appropriate cDNAs encoding transgenes (encoding DHFR and CRBN fusion proteins), are used to generate a positive assay signal as a result of ternary protein/compound complex formation, including a DHFR-fusion protein, a tnmethopnm(TMP)-lenalidomide hybrid ligand (TMP is a ligand for DHFR), and a CRBN-gpl30 fusion protein (CRBN binds the ligand lenalidomide) - thus, a DHFR-TMP-LEN-CRBN complex formation. Formation of the complex results in activation of a STAT-responsive luciferase reporter gene. That signal is set to 100% luciferase activity. In a separate sample set up, cells are prepared in the same manner but, in addition, coincubated with a test compound whose interaction with CRBN is investigated. Binding to the CRBN fusion protein competes with binding of the hybrid ligand to the same CRBN protein, hence inhibiting the assay signal due to prevention of ternary' complex formation, which is required to generate an assay signal. Increasing concentrations of test compound are assessed to determine CRBN binding efficiency as determined in this type of ligand competition experiment in living cells. Specificity of signal inhibition is assessed by a parallel experimental set up in which test compound effect is assessed for inhibition of signal generated by a control gpl30 fusion protein (CTRL) that directly binds to the DHFR-fusion protein in the absence of hybrid ligand (i.e. a direct interaction of the proteins).
[0185] In more detail, HEK293T cells are cultured in Dulbecco’s modified Eagle’s medium supplemented with 10% fetal calf serum, incubated at 37 °C, 8% CO2. Cells are transfected with a plasmid encoding E. coli Dihydrofolate Reductase (DHFR) fused to the tails of the cytoplasmic domain of a mutated leptin receptor (pCLG-eDHFR), a plasmid encoding a CRBN prey fused to gpl30 cytoplasmic domain (pMGl-CRBN ) or a plasmid encoding a REM2 control prey that can directly interact with the leptin receptor of the DHFR fusion protein (pMGl-REM2), and the STAT3 responsive pXP2d2-rPAPI-luciferase reporter plasmid - using a standard transfection method, as described (Li evens, etal. "Array MAPPIT: high-throughput interactome analysis in mammalian cells." Journal of Proteome Research 8.2 (2009): 877-886). Cells are treated with leptin to activate the leptin receptor fusion protein and supplemented with 300 nM trimethoprim-lenalidomide fusion compound (hybrid ligand, where trimethoprim interacts with DHFR and lenalidomide with CRBN) without or w ith the indicated dose of test compound at 24 hours after transfection. Luciferase activity, induced by formation of the ternary complex including DHFR-trimethoprim-lenalidomide-CRBN, and consequential activation of STAT3 signaling, is measured 24 hours after compound treatment using the Luciferase Assay System kit (PROMEGA, Madison, WI) with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA). Data points represent the average luciferase activity of triplicate samples derived from cells treated with leptin + test compound for the REM2 control (CTRL) or cells treated with leptin + hybrid ligand + test compound (CRBN) relative to leptin (CTRL) or leptin + hybrid ligand (CRBN) only treated samples (the signals obtained in absence of added test compound for both cases is set at 100% of luciferase activity on y-axis). Error bars represent standard deviations. Curves are fit using 4-parameter nonlinear regression in GRAPHPAD PRISM software
Example 2: Recruitment Assays:
[0186] In this Example 2, a similar MAPPIT-like assay is applied as described in Example 1 to determine test compound-induced binding of a particular substrate protein of interest to CRBN. In this experimental set-up, cells are transfected with a construct encoding a CRBN- fusion protein and another one encoding a substrate-fusion protein. Test compound activity is assessed with increasing concentrations of test compounds (dose-response studies) to monitor the ability to promote CRBN-ligand-induced protein interaction.
[0187] Specifically. HEK293T cells are transfected with a plasmid encoding the MAPPIT receptor fusion wherein the protein of interest (CRBN or substrate protein) is genetically linked to a cytoplasmic domain of the leptin receptor, which itself is fused to the extracellular domain of the erythropoietin (Epo) receptor (pSEL-X, where X represents either CRBN or any of the tested substrate proteins of interest) or to the extracellular domain of the leptin receptor (pCLG-X, where X represents either CRBN or any of the tested substrate proteins of mterst), a plasmid encoding the MAPPIT gpl30 fusion (pMGl-Y, Y being either any of the tested substrate proteins or CRBN) and a STAT3-responsive luciferase-encoding reporter plasmid (pXP2d2-rPAPI-luciferase reporter plasmid), as described (Lievens, et al "Array MAPPIT: high-throughput mteractome analysis in mammalian cells." Journal of Proteome Research 8.2 (2009): 877-886). Full size proteins are fused for each of the target proteins tested, except in the case of IKZF1 where isoform 7 is used, and BRIM, where isoform 3 is applied. For the study, the following construct combinations are used: IKZF1 recruitment: pSEL-CRBN + pMGl-IKZFl (isoform 7); ASS1 recruitment: pSEL-CRBN + pMGl-ASSl; SALL4 recruitment: pSEL-SALL4 + pMGl-CRBN; DHFR recruitment: pCLG-DHFR + pMGl-CRBN; ESR1 recruitment: pSEL-CRBN + pMGl-ESRl; BRD4 recruitment: pSEL- CRBN + pMGl-BRD4(isoform 3). Cells are treated with erythropoietin (Epo; where pSEL- type receptor fusions constructs are used) or leptin (in the case pCLG-type receptor fusion constructs are applied) without or with the indicated dose of test compound at 24 hours after transfection Luciferase activity is measured 24 hours after test compound treatment using the Luciferase Assay System kit (PROMEGA, Madison, WI) with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA). Data points depict fold induction of the average luciferase activity of triplicate samples from Epo or leptin + test compound treated cells versus Epo or leptin only treated cells. Error bars represent standard deviations. Curves are fit using 4-parameter nonlinear regression in GRAPHPAD PRISM software.
Example 3: Protein Degradation Bioassays
[0188] The following bioassays were performed to evaluate the level of protein degradation observed in various cell types using representative compounds disclosed herein.
[0189] In each bioassay, cells were treated with varying amounts of compounds encompassed by the present disclosure. The degradation of the following proteins were evaluated in this study: TANK-binding kinase 1 (TBK1), estrogen receptor a (ERa), bromodomain-containing protein 4 (BRD4), androgen receptor (AR), and c-Myc.
1. TBK1 Western Protocol
[0190] Panc02.13 cells were purchased from ATCC and cultured in RPMI-1640 (Gibco), supplemented with 15% FBS (ATCC) and 10 Units/mL human recombinant insulin (Gibco). DMSO control and compound treatments (0.1 mM, 0.3 mM, and 1 mM) were carried out in 12- well plates for 16 h. TLR3 agonist Poly I:C (Invivogen; tlrl-pic) was added for the final 3 h. Cells were harvested, and lysed in RIPA buffer (50 mM Tris pHB, 150 mM NaCl, 1% Tx- 100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 16,000 g for 10 minutes, and supernatants were separated by SDS-PAGE. Immunoblotting was performed using standard protocols. The antibodies used were TBK1 (Cell Signaling #3504), pIRF3 (abeam #ab76493), and GAPDH (Cell Signaling #5174). Bands were quantified using a Biorad ChemiDoc MP imaging system.
2 ERRa Western Protocol
[0191] NAMALWA cells (ATCC) were cultured in RPMI-1640 (Life Technologies) supplemented with 15% FBS (Life Technologies). DMSO controls and compound incubations (0.1 mM, 0.3 mM, and 1 mM) were carried out in 24-well plates for 16 h. Cells were harvested and lysed with cell lysis buffer (Cell Signaling Technologies) containing protease inhibitors (Thermo Scientific). Lysates were clarified at 16,000 g for 10 minutes, and supernatants were separated by SDS-PAGE. Immunoblotting was performed using standard protocols. The antibodies used were ERRa (Cell Signaling #8644) and GAPDH (Cell Signaling #5174). Bands were quantified using a Bio-Rad ChemiDoc MP imaging system. 3. BRD4 Western Protocol
[0192] VCaP cells were purchased from ATCC and cultured in Dulbecco's Modified Eagle's Medium (ATCC), supplemented with 10% FBS (ATCC) and Penicillin/Streptomycin (Life Technologies). DMSO control and compound treatments (0.003 mM, 0.01 mM, 0.03 mM and 0.1 mM) were performed in 12-well plates for 16 h. Cells were harvested, and lysed in RIPA buffer (50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. Lysates were clarified at 16,000 g for 10 minutes, and protein concentration was determined. Equal amount of protein (20 mg) was subjected to SDS-PAGE analysis and followed by immunoblotting according to standard protocols. The antibodies used were BRD4 (Cell Signaling #13440), and Actin (Sigma #5441). Detection reagents were Clarity Western ECL substrate (Bio-rad #170-5060).
4. AR ELISA Protocol
[0193] VCaP cells were purchased from ATCC and cultured in Dulbecco's Modified Eagle's Medium (ATCC), supplemented with 10% FBS (ATCC) and Penicillin/Streptomycin (Life Technologies). DMSO control and compound treatments (0.0001 mM-1 mM) were performed in 96-well plates for 16 h. Cells were harvested, and lysed with Cell Lysis Buffer (Catalog#9803) (20 mM Tns-HCL (pH 7.5), 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Tnton, 2.5 mM sodium pyrophosphate, 1 mM B-glycerophosphate, 1 mM NaiVCL, 1 ug/ml leupeptin. Lysates were clarified at 16,000 g for 10 minutes, and loaded into the PathScan AR ELISA (Cell Signaling Catalog# 12850). The PathScan® Total Androgen Receptor Sandwich ELISA Kit is a solid phase sandwich enzyme-linked immunosorbent assay (ELISA) that detects endogenous levels of total androgen receptor protein. An Androgen Receptor Rabbit mAb has been coated onto the microwells. After incubation with cell lysates, androgen receptor protein is captured by the coated antibody. Following extensive washing, an Androgen Receptor Mouse Detection mAb is added to detect the captured androgen receptor protein. Anti-mouse IgG, HRP-lmked Antibody is then used to recognize the bound detection antibody. HRP substrate, TMB, is added to develop color. The magnitude of absorbance for the developed color is proportional to the quantity of total androgen receptor protein.
5. c-Myc ELISA Assay Protocol [0194] 22RV-1 cells were purchased from ATCC and cultured in RPMI+10% FBS media.
Cells were harvested using trypsin (Gibco #25200-114), counted and seeded at 30,000 cells/well at a volume of 75 pL/well in RPMI+10% FBS media in 96-well plates. The cells were dosed with compounds diluted in 0.1% DMSO, incubated for 18 h then washed and lysed in 50 uL RIPA buffer (50 mM Tris pH8, 150 mM NaCl, 1% Tx-100, 0.1% SDS, 0.5% sodium deoxycholate) supplemented with protease and phosphatase inhibitors. The lysates were clarified at 4000 rpm at 4° C. for 10 minutes then aliquots were added into a 96-well ELISA plate of Novex Human c-Myc ELISA kit from Life Technologies Catalog #KH02041. 50 ul of c-Myc Detection antibody was added into every well, the plates incubated at room temperature for 3 hrs, then washed with ELISA wash buffer. 100 uL of the anti-rabbit IgG- HRP secondary antibody was added to each well and incubated at room temperature for 30 minutes. The plates were washed with ELISA wash buffer, 100 pL TMB added to each well, and then monitored every 5 minutes for a color change. 100 pL of stop solution is added and the plates read at 450 nm.
Example 4: Preparation of the Compounds
[0195] The compounds of the present invention can be prepared by methods well known in the art of organic chemistry. See, for example, J. March, ‘Advanced Organic Chemistry’ 4th Edition, John Wiley and Sons. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those descnbed in T.W.
Greene and P.G.M. Wutts ‘Protective Groups in Organic Synthesis’ 3rd Edition, John Wiley and Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art. The products of the reactions are optionally isolated and purified, if desired, using conventional techniques, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials are optionally characterized using conventional means, including physical constants and spectral data.
[0196] In synthesizing compounds of the present invention, it may be desirable to use certain leaving groups. The term “leaving groups” (“LG”) generally refer to groups that are displaceable by a nucleophile. Such leaving groups are known in the art Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e g., mesylate, tosylate), sulfides (e.g., SCH3), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like. Examples of nucleophiles include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e g , alkoxides, amides, carbanions) and the like.
HPLC purification
[0197] Purification was performed using HPLC (H2O - MeOH; Agilent 1260 Infinity systems equipped with DAD and mass-detectors. Waters Sunfire C18 OBD Prep Column,
100 A, 5 pm, 19 mm X 100 mm with SunFire C18 Prep Guard Cartridge, 100 A, 10 pm, 19 mm X 10 mm) The material was dissolved in 0.7 mL DMSO. Flow : 30mL/min. Purity of the obtained fractions was checked via the analytical LCMS. Spectra were recorded for each fraction as it was obtained straight after chromatography in the solution form. The solvent was evaporated in the flow of N2 at 80°C. On the basis of post-chromatography LCMS analysis fractions were united. Solid fractions were dissolved in 0.5 mL MeOH and transferred into a pre-weighted marked vials. Obtained solutions were again evaporated in the flow of N2 at 80°C. After drying, products were finally characterized by LCMS and 'H NMR.
Analytical Methods
NMR
Instrument specifications:
Bruker AVANCE DRX 00 Vanan UNITY plus 400
LC/MS
Instrument specifications:
Agilent 1100 Series LC/MSD system with DAD\ELSD and Agilent LC/MSD VL (G1956A), SL (G1956B) mass-spectrometer.
Agilent 1200 Series LC/MSD system with DAD\ELSD and Agilent LC/MSD SL (G6130A), SL (G6140A) mass-spectrometer.
All the LC/MS data were obtained using positive/negative mode switching.
Column Zorbax SB-C18 1.8 pm 4.6x15mm Rapid Resolution cartridge (PN 821975- 932)
Mobile phase A - acetomtnle, 0.1% formic acid B - water (0.1% formic acid)
Flow rate 3ml/min Gradient 0 min - 100% B 0.01 min - 100% B 1.5 min - 0% B 1.8 mm - 0% B 1.81 min - 100% B Injection volume lpl
Ionization mode atmospheric pressure chemical ionization (APCI) Scan range m/z 80-1000
Example 5: Activity of Illsutrative Bifunctional Compound a. Synthesis of TMP-LEN
TMP-LEN was made according to the reaction scheme below.
Figure imgf000286_0001
[0198] To a solution of 4-pentynoic acid (51) (3.4g, 34.5 mmol) in 100 mL benzene, 2 drops of DMF were added, following by addition of oxalyl chloride (17.5g, 138 mmol). The mixture was stirred at 80°C for 2h and evaporated to dryness giving chloroanhydride (52)
(3. lg, 76%) that was used for the next step without additional purification.
[0199] To a solution of (50) (345mg, 1.33 mmol) in 30 mL THF, chloroanhydride (52) (315mg, 2.70 mmol) in 5 mL TF1F was added and the mixture was stirred at 75°C for 7h. The reaction mixture was quenched with 0.5 mL MeOH, stirred for lh and evaporated to dryness. The solid residue was washed with Et20 and dried giving compound (53) (541mg, 100%). [0200] To a solution of Compound (53) (33mg, 0.112 mmol), and TMP-azide (63mg, 0.109 mmol) in DMF-ThO, 2:1 (10 mL) , sodium ascorbate (24mg, 0.120 mmol) was added, following by addition of CuSO-r5FLO (27mg, 0.109 mmol) and the mixture was stirred for 15h at ambient temperature. The mixture was diluted with H2O, extracted with CHCI3, and the organic layer was discarded. Aqueous layer was evaporated to dryness, and the target product was purified on a Cl 8 reverse-phase HPLC column, eluting with a gradient MeCN- H2O-0.1% TFA. The fractions containing the target product were evaporated to dryness giving compound TMP-LEN (23mg, 23%) as a solid. b. Evaluation of lemlidomide hybrid lisand-induced binding between CRBN and DHFR
[0201] A similar MAPPIT-like assay as described in Example 1 was applied to evaluate binding between CRBN and DHFR (dihydrofolate reductase) induced by a hybrid molecule consisting of the DHFR ligand trimethoprim (TMP) fused to the CRBN ligand lenahdomide (LEN) through a PEG linker. As in the protocol described in Example 1, HEK293T cells were co-transfected with a plasmid encoding a fusion construct of the (E. coli) DHFR anchor protein fused to the chimeric MAPPIT receptor containing the leptin receptor extracellular domain linked to an engineered intracellular domain of the leptin receptor (pCLG-DHFR) and a gpl30-CRBN bait fusion construct, together with the STAT3 -responsive luciferase- encodmg reporter plasmid (pXP2d2-rPAPI-luciferase reporter plasmid), as described (Lievens, et al. "Array MAPPIT: high-throughput interactome analysis in mammalian cells." Journal of Proteome Research 8.2 (2009): 877-886). At 24h after transfection the cells were treated with leptin without and with the indicated concentration of TMP-LEN hybrid ligand, and another 24h later luciferase activity' was determined using the Luciferase Assay System kit (PROMEGA, Madison, WI) with an Ensight plate reader (PERKIN ELMER LIFE SCIENCES, Waltham, MA). The dose-response curve shown in Figure 3 represents the fold induction of the average luciferase activity of triplicate samples from leptin + test compound treated cells versus leptin only treated cells. Error bars represent standard deviations and curves were fit using 4-parameter nonlinear regression in GRAPHPAD PRISM software.
This example shows that the MAPPIT assay presented here can be applied to assess binding between two proteins induced by a hybrid ligand.
Example 6: Test Results
[0202] The following compounds were tested in the Competition Assay and/or Recruitment Assay described herein, and the results are listed below. Table 6: IC50 Competition values were determined using the protocol and reagents described in Example 1. EC50 values for recruitment of IKZF1, AS SI and SALL4 were determined using the protocols and reagents described in Example 2. Recruitment assessment was made for each compound, where TRUE = observation of recruitment of any tested substrate at any tested compound concentration from among IKZF1, ASS1 and SALL4, and FALSE = no observ ed recruitment of any tested substrate at any tested compound concentration from among IKF1, ASS1 and SALL4. NA represents instances where no substrate recruitment was observed at any tested concentration , » represents instances were an EC50 curve could not be calculated as values did not reach a plateau over the measured concentration range, and « represents instances where an EC50 could not be calculated because a value was read above 50% of control at the first concentration tested for the compound (13.7 nM).
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
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Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
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Figure imgf000307_0001
Figure imgf000308_0001
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Figure imgf000310_0001
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Figure imgf000312_0001
Figure imgf000313_0001
_
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Figure imgf000322_0001
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Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0001
Figure imgf000329_0001
Figure imgf000330_0001
Figure imgf000331_0001
Figure imgf000332_0001
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Figure imgf000337_0001
Figure imgf000338_0001
_
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
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Figure imgf000344_0001
Figure imgf000345_0001
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Figure imgf000347_0001
Figure imgf000348_0001
Figure imgf000349_0001
Figure imgf000350_0001
Figure imgf000351_0001
Figure imgf000352_0001
Figure imgf000353_0001
Figure imgf000354_0001
Figure imgf000355_0001
Figure imgf000356_0001
Figure imgf000357_0001
Figure imgf000358_0001
Figure imgf000359_0001
Figure imgf000360_0001
Figure imgf000361_0001
Figure imgf000362_0001
Figure imgf000363_0001
Figure imgf000364_0001
Figure imgf000365_0001
Figure imgf000366_0001
Figure imgf000367_0001
Figure imgf000368_0001
Figure imgf000369_0001
Figure imgf000370_0001
Figure imgf000371_0001
Figure imgf000372_0001
Table 7: IC50 Competition values were determined using the protocol and reagents described in Example 1. EC50 values for recruitment of the indicated target proteins were determined using the protocols and reagents described in Example 2. NA represents instances where no substrate recruitment was observed at any tested concentration , » represents instances were an EC50 curve could not be calculated as values did not reach a plateau over the measured concentration range, and « represents instances where an EC50 could not be calculated because a value was read above 50% of control at the first concentration tested for the compound (13.7 nM).
Figure imgf000373_0001
Example 7: Evaluation of CRBN binding and/or substrate recruitment of bifunctional compounds
[0203] For selected bifunctional compounds, the Competition Assay and/or Recruitment Assay described in Example 1 and Example 2, respectively, are applied to evaluate CRBN binding and/or substrate recruitment. The resulting dose-response curves are shown in Figure 3.
Example 8: Synthesis intermediates and final compounds
Intermediates synthesis Synthesis of Intermediate 1:
Figure imgf000374_0001
[0204] To a solution of SMI (5.0 g, 13.5 mmol) in DCM (50 mL) at 0°C under N2 atmosphere was added SM2 (3.8 g, 27.0 mmol) and mixture was then heated at 60 °C overnight.
[0205] The reaction was cooled to RT, concentrated and the residue dissolved in MeOH (50 mL). The mixture was heated at reflux for 3 hours then concentrated to afford target 1.1 (4.5 g. yield 94%) as a white solid. TLC: Ri= 0.15 (DMC/MeOH = 10: 1, v/v, 254 nm).
LCMS: (Method PO-POS): m/z 358.2 [M+H]+, 2.109 min.
[0206] To a solution of compound 1.1 (4.5 g, 12.6 mmol) in DCM (50 mL) was added SM3 (2.9 g, 15.1 mmol) and DIPEA (4.9 g, 37.8 mmol) and the resulting mixture was stirred at RT overnight.
[0207] The mixture was diluted with water (100 mL), extracted with DCM (50 mL x 3) and the combined organic extracts washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by column (eluent Petroleum DCM : MeOH =40: 1 , v:v) to give the product 1.2 (4.9 g, yield 83%) as a white solid.
[0208] To a solution of compound 1.2 (4.9 g, 10.4 mmol) m 1-4 dioxane (20 mL) was added 4N HCl/Dioxane (30 mL) and the mixture was stirred at RT for 4 h.
[0209] The mixture was concentrated and the residue was triturated with ether to afford Intermediate 1 (4 g, 93%) as a white solid. TLC: Rr 0.1 (DCM/MeOH = 10: 1, v/v, 254 nm) LCMS: ( P0(-i)-POS ): m z 416.2 [M+H]+, 3.457 min.
Figure imgf000374_0002
-ife) (FID No:CJP-0147-084-HNMR) d 7.40-7.37 (m, 2H), 7.31 - 7.27 (m, 1H), 7.22 - 7.19 (m, 4H), 7.14-7.11 (m, 3H), 6.79-6.77 (m, 2H), 6.66-6.64 (m, 2H), 4.25 (t, /=4.4 Hz, 2H), 4 13 (s,
2H), 3.54 - 3.53 (m, 2H), 2.89 (s, 3H), 2.40- 2.34 (m, 2H), 0.85 (t, J=1.2 Hz, 3H).
Synthesis of Intermediate 2
Figure imgf000374_0003
[0210] To the solution of the acid (21 g, 111.57 mmol) and the amine (20.53g, 111.57 mmol) in pyridine (300 mL) was added POCb (13.07 g, 133.89 mmol) at 0°C and the mixture stirred at room temperature for 30 min.
[0211] The mixture was diluted with water (600 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over NaaSOi and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ethenEtOAc, 1:1, v/v) to afford 2.1 (10 g, 31%) as ayellow solid. TLC: Rf= 0.49 (Petroleum Ether: EtOAc = 1:1, v/v, 254 nm). LCMS: (LCMS Method P2-POS). m/z 288.20 [M+H]+, 3.598 min.
[0212] To a solution of NH20H HC1 (11.49 g, 348 mmol) in MeOH (100 mL) at 0 °C was added KOH (29.29 g, 522 mmol) and the mixture was stirred for lh. The resulting precipitate was filtered off and the solution of free NH2OH was placed in a round bottom flask and cooled in an ice bath. Compound 2.1 (10 g, 34.8mmol) was added to the solution and the mixture was stirred at RT overnight.
[0213] The mixture was diluted with water (200 mL) and acidified with AcOEI to pH ~ 5, then kept in a refrigerator +4 °C for 3 h. The precipitate was collected by filtration, washed with water and crystallized from acetone/ THF ( 1: 1, v/v ) to afford Intermediate 2 (7g, 70%) as a white solid. TLC: Rf= 0 (EtOAc/Petroleum Ether = 1/1, v/v). LCMS: ( ethod P2-POS). m/z 289.20 [M+H]+, 2.820 min. Ή NMR: Ή NMR (400 MHz, DMSO -dP) (FID No:YJ- 0489-075 -HNMR) 10.32(s, 1H), 10.03(s, 1H), 8.65(s, 1H), 7.61 - 7.59 (m, 2H), 7.40 - 7.38 (m, 2H), 4.06 (s, 1H), 2.32 - 2.28 (m, 2H), 1.95 - 1.91 (m, 2H), 1.58 - 1.47 (m, 4H), 1.28 - 1.27 (m, 4H).
Synthesis of Intermediate 3
Figure imgf000375_0001
[0214] To a solution of SM (2.4 g, 5.25 mmol) in DCM (15 mL) was added TFA (10 mL) and the mixture was stirred at RT overnight. TLC showed SM was consumed. The solvent was removed under vacuum. The residue was triturated with water (25 mL * 2) to afford Intermediate 3 (2.00 g, 95%) as a light yellow solid. LCMS: (Method P2-POS ): m/z 401.10 [M+H]+, 3.209 min. ¾ NMR: (400 MHz, DMSO-de, FID No: WFL-0259-100-1- 20190227 -HNMR) 5 12.43 (s, 1H), 7.50 (d, J= 8.8 Hz, 2H), 7.47 - 7.41 (m, 2H), 4.45 (t, J= 7.2 Hz, 1H), 3.43 (dd, J= 16.8, 6.8 Hz, 1H), 3.32 (dd, J= 16.8, 7.4 Hz, 1H), 2.60 (s, 3H), 2.41 (s, 3H), 1.63 (s, 3H).
Synthesis of Intermediate 9
Figure imgf000376_0001
[0215] To a solution of SMI (46 g, 0.3 mol) in MeOH (300 mL) at 0°C was added SOCh (59 g, 0.5 mol) and the mixture was heated at 70 °C for 2 h. The mixture was then concentrated to afford product 9.1 (42 g, 84%) as a brown solid. TLC: Rf= 0.65 (DCM: MeOH = 20:1, v/v, 254 nm). 'H NMR: 'H NMR (400 MHz, DMSO-r/r,) (FID No CJP- 0147-055-HNMR) 59.69 (m, 1H), 7.18 - 7.16 (m, 1H), 7.07 (t, J= 8Hz, 1H), 7.00-6.98 (m, 1H), 3.79 (s, 3H), 2.27 (s, 3H).
[0216] To a solution of 9.1 (65 g, 0.39 mol) in DCM (500 mL) was added imidazole (91.4g, 1.17 mol) and TBSCI (70.5 g, 0.47 mol) and the mixture was stirred at RT for 2 h
[0217] The mixture was diluted with water (800 mL) and extracted with DCM (300 mL x 3). The combined organic layers was washed with brine (400 mL), dried overNa2SC>4, filtered and concentrated to afford product 9.2 (100 g, 91%) as a brown oil. TLC: Ri= 0.8 (DCM: MeOH = 20: 1 , v/v, 254 nm). Ή NMR: Ή NMR (400 MHz, D SO-c/.,) (FID No:FGX41-013-HNMR) 57.35-7.33 (m, 1H), 7.18 (t, J=8.4 Hz, 1H), 7.04 - 7.01 (m, 1H), 3.80 (s, 3H), 2.31 (s, 3H), 0.98 (s, 9H), 0.21 (s, 6H).
[0218] To a solution of compound 9.2 (100 g, 0.36 mol) in CCL (500 mL) was added NBS (71.2 g, 0.40 mol) and AIBN (5.9 g, 0.036 mol) and the mixture was heated at reflux for 3 h. [0219] The mixture was concentrated and the residue diluted with water (500 mL) and extracted with DCM (200 mL X 3). The combined organic layers were washed with brine (300 mL), dried over Na2S04, filtered and concentrated to afford product 9.3 (120 g, 94%) as a brown oil. TLC: Ri= 0.3 (DCM:MeOH = 40:1, v/v, 254 nm) ¾ NMR: ¾ NMR (400 MHz, DMSO-c e) (FID No:FGX41-025-HNMR) 57.47 - 7.45 (m, 1H), 7.37 (t, J= 8 Hz, 1H), 7.16 - 7.14 (m, 1H), 4.95 (s, 2H), 3.86 (s, 3H) , 1 03 (s, 9H), 0.29 (s, 6H).
[0220] To a solution of compound 9.3 (90 g, 0.25 mol) m ACN (600 mL) was added SM2 (45.1 g, 0.28 mol) and DIPEA (96.9 g, 0.75 mol) and the mixture was heated at 400 C overnight.
[0221] The mixture was concentrated and the residue was triturated with EtOAc (150 mL x 2) to afford compound 9.4 (60 g, 63%) as a white solid. TLC: Rf= 0.28 (DCM:MeOH = 10:1, v/v, 254 nm). LCMS: (LCMS Method Pl-POS ): m/z 375.1 [M+H] +, 2.117 min.
[0222] To a solution of compound 9.4 (50 g, 0.13 mol) in THF (400 mL) was added TBAF (1 M solution in THF, 160 mL, 0.16 mol) and the mixture was stirred at RT for 3 h.
[0223] The mixture was concentrated under reduce pressure and the residue was triturated with EtOAc (150 mL x 2) to afford product 9.5 (28 g, 80%) as a white solid. TLC: Rf= 0.5 (DCM:MeOH = 10:1, v/v, 254 nm). LCMS: (LCMS Method P2-POS): m/z 261.0 [M+H] +, 1.611 min
[0224] To a solution of compound 9.5 (16.0 g, 61.5 mmol) in DMF (100 mL) was added SM3 (8.4 g, 43.1 mmol), NarCCb (13.0 g, 123 mmol) and KI (2.0 g, 12.3 mmol) and the mixture was heated at 60 °C for 6 hours.
[0225] The mixture diluted with water (800 mL), extracted with EtOAc (200 mL x 3) and the combined organic layers washed with brine (300 mL), dried over Na2SOu filtered and concentrated. The residue was purified by silica gel column (DCM/MeOH = 200: 1 to 40: 1 , v/v) to afford product 9.6 (6.0 g, 26%) as a white solid. TLC: Rf= 0.6 (DCM:MeOH = 10:1, v/v, 254 nm). LCMS: (LCMS Method SI 2): m/z 373.1 [M-H] , 3.779 min.
[0226] To a solution of compound 9.6 (14 g, 37.4 mmol) in DCM (100 mL) at 0°C was added TFA (40 mL) and the mixture was stirred at RT for 6 h.
[0227] The mixture was concentrated and the residue nnsed with ether (100 mL) to afford Intermediate 9 (llg, 92%) as a white solid. TLC: Rf= 0.2 (DCM:MeOH = 10:1, v/v, 254 nm). LCMS: (LCMS Method Pl-POS): m/z 319.1 [M+H] +, 1.774 min. 'H NMR: 1HNMR (400 MHz, DMSO-r/e) (FID No:CJP-0147-102) 51097 (s, 1H), 7.46 (t, 7=8 Hz, 1H), 7.34 - 7.32 (m, 1H), 7.17 - 7.15 (m, 1H), 5.13 - 5.08 (m, 1H), 4.84 (s, 2H), 4.42 - 4.24 (m, 2H), 2.91 - 2.86 (m, 1H) , 2.61 - 2.56 (m, 1H), 2.49 - 2.40 (m, 1H), 2.02 - 1.98 (m, 2H).
Synthesis of Intermediates 10- 13
Figure imgf000378_0001
[0228] To a solution of Intermediate 9 in DMF (0.25 M) was added HATU (2.0 eq.) and DIPEA (3.0 eq.) and the mixture was stirred at RT for 30 min. The amino-azide (1.2 eq.) was then added and stirring was continued at RT for 16 h. The mixture was diluted with water, extracted by DCM/MeOH (15/1) and the combined organic layers were washed with brine, dried over NaiSOr, filtrated, concentrated. The residue was purified by Biotage C18 column or p-TLC to afford Intermediate 10 - 13.
[0229] Intermediate 10 was purified by Biotage Cl 8 Column (40% ACN in water) to afford Intermediate 10 (yield: 43%) as a colorless oil. LCMS: (Method SI 2): mlz 563.3 [M+H] +, 1.233 min. ¾ NMR: (400 MHz, DMSO-de, FID No: CJP-0147-104-HNMR) d 11.00 (s, 1H), 8.11 (t, 7= 5.6 Hz, 1H), 747 (t, .7=8.0 Hz, 1H), 7.34 (d, 7=6.4 Hz 1H), 7.13 (d, 7=8.0 Hz 1H), 5.16-5.11 (m, 1H), 4.64 (s, 2H), 4.48-4.32 (m, 2H), 3.60-3.58 (m, 2H), 3.50- 3.48 (m, 4H), 3.43-3.38 (m, 8H), 3.39-3.28 (m, 6H), 2.97-2.90 (m, 1H), 2.63-2.61 (m, 1H), 2.44-2.37(m, 1H), 2.04-2.00 (m, 1H)
[0230] Intermediate 11 was purified by Biotage Cl 8 Column (40% ACN in water) to afford Int 11 (yield: 25%) as a semi-solid. LCMS: (LCMS Method SI 2): mlz 519.3 [M+H] +, 2.333 min. ¾ NMR: (400 MHz, DMSO-de, FID No: CJP-0147-099-HNMR) d 11.00 (s, 1H), 8.11 (t, 7=5.6 Hz, 1H), 7.47 (t, 7=8.0 Hz, 1H), 7.34 (d, 7=6.4 Hz 1H), 7.13 (d, 7=8.0 Hz 1H), 5.16-5.11 (m, 1H), 4.64 (s, 2H), 4.48-4.32 (m, 2H), 3.59-3.57 (m, 2H), 3.50-3.44 (m, 8H), 3.38-3.31 (m, 6H), 2.96-2.90 (m, 1H), 2.62-2.59 (m, 1H), 2.43-2.36(m, 1H), 2.03-1.99 (m, 1H).
[0231] Intermediate 12 was purified by prep-TLC (DCM: MeOH = 10:1, v/v) to afford Intermediate 12 (yield: 63%) as a yellow oil. TLC: Rf= 0.18 (DCM: MeOH = 20:1, v/v, 254 nm). LCMS: (LCMS Method P2): m/z =475.30 [M+H] . 2.516 min. ¾NMR: 'H NIY1R (400 MHz, Chloroform-ri) (FID NO:ZJ-0523-016-HNMR) d 8.14 (s, 1H), 7.57 (d, J= 7.6 Hz, 1H), 7.47 (t, J= 7.8 Hz, 1H), 7.02 (d, J= 8.2 Hz, 1H), 6.85 (s, 1H), 5.23 (dd , J= 13.4, 5.2 Hz, 1H), 4.61 (s, 2H), 4.52 (d, = 16.4 Hz, 1H), 4.38 (d,J= 16.6 Hz, 1H), 3.64 - 3.61 (m , 2H), 3.60 - 3.55 (m, 6H), 3.33 (dd, J= 5.6, 4.4 Hz, 2H), 3.03 - 2.89 (m, 1H), 2.84 (ddd , J = 17.8, 13.0, 5.2 Hz, 1H), 2.40 (qd, J= 13.0, 5.0 Hz, 1H), 2.24 (ddd, J= 10.2, 5.2, 2.8 Hz, 1H), 1.58 - 1.36 (m, 2H).
[0232] Intermediate 13 was purified by Biotage Cl 8 Column (40% ACN in water) to afford Int-13 (yield: 27%) as a white solid. LCMS: (LCMS Method PO-POS): m/z 387.1 [M+H] +, 2.165 mm. ¾ NMR:¾ NMR (400 MHz, DMSO-de, FID No: LL-0450-112- HNMR) 5 11.00 (s, 1H), 8.30 (t, J= 5.4 Hz, 1H), 7.47 (t, J= 7.8 Hz, 1H), 7.35 (d, = 7.2 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 5.14 (dd, J= 13.4, 5.1 Hz, 1H), 4.66 (d, J= 2.2 Hz, 2H), 4.46 (d, J= 17.4 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 3.43 - 3.37 (m, 2H), 3.37 - 3.33 (m, 2H),
2.99 - 2.86 (m, 1H), 2.61 (d, J= 16.8 Hz, 1H), 2.41 (m, 1H), 2.02 (m, 1H).
Synthesis of Compounds 5.49-5.52 Listed in Table 5 General Procedures
[0233] To a solution of azide (1.0 eq.) in tert-butanol/H20 (1/1, v/v) (0.03 M) was added Intermediate 2 (1.0 eq.), followed by CuS04-5H20 (0.2 eq.) and sodium ascorbate (1.0 eq.) and the mixture was heated at 80 °C, for 5 h under a N2 atmosphere. The mixture was diluted with water, extracted with DCM/MeOH (15/1) and the combined organic layers were washed with brine, dried over NarSCri, filtrated, concentrated and purified by prep-TLC or prep- HPLC to afford compounds 5.49-5.52.
[0234] Compound 5.49 was purified by prep-HPLC (5-60% ACN in water containing 0.1% TFA) to afford the compound 5.49 (yield 5%) as a white solid. LCMS: (LCMS Method ,572- 5MIN): m/z 851.5 [M+H] +, 1.047min. 'H NMR: (400 MHz, DMSO-rie) (FID No:CJP-0147- 115-HNMR) 511.00 (s, 1H), 10.32 (s, 1H), 9.94 (s, 1H), 8.42 (s, 1H), 8.11 (t, .7= 6.0 Hz, 1H), 7.76-7.50 (m, 4H),7.46 (t, .7=8.0 Hz, 1H), 7.35-7.33(m,lH),7.14-1.12 (m, 1H), 5.16-5.11 (m,lH), 4.64 (s, 2H), 4.54 (t, J= 5.2 Hz, 2H), 4.47-4.31 (m, 2H), 3.84 (t , J= 5.2 Hz, 2H), 3.53-3.47 (m, 3H), 3.46-3.44(m, 3H), 3.44-3.41 (m, 8H), 3.40-3.26 (m,3H), 2.95-2.89 (m,
1H), 2.63-2.58 (m,lH), 2.443-2.40 (m, 1H), 2.33-2.28 (m, 2H), 2.02-1.94 (m, 3H), 1.59-1.51 (m, 4H), 1.49-1.21(m,4H) [0235] Compound 5.50 was purified by prep-HPLC (5-60% ACN in water containing 0.1% TFA) to afford the compound 5.50 (yield 8%) as a colorless oil. LCMS: (LCMS Method S12- 5MIN): m/z 807.4 [M+H] +, 2.165mm. 'H NMR: (400 MHz, DMSO-rie) (FID No:CJP-0147- 116-HNMR) 511.00 (s, 1H), 10.33 (s, 1H), 9.95 (s, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.10 (t , 7 = 5.6 Hz, 1H), 7.75-765 (m, 4H), 7.46 (t, 7=4.8 Hz,IH), 7.35-7.33(m,lH), 7.14-1.11 (m,
1H), 5.15-5.10 (m,lH), 4.63 (s, 2H), 4.54 (t, 7= 5.2 Hz, 2H), 4.46-4.30 (m, 2H), 3.84 (t, 7 = 5.2 Hz, 2H), 3.84-3.44 (m, 2H), 3.42-3.40 (m, 2H), 3.40 (s, 4H), 3.33-3.28 (m, 2H), 3.25-3.16 (m,2H), 2.95-2.92 (m, 1H), 2.86-2.58 (m,lH), 2.50-2.42 (m, 1H), 2.39-2.30 (m, 2H), 2.00-
1.94 (m, 3H), 1.59-1.49 (m, 5H),1.39-1.21(m,2H)
[0236] Compound 5.51 was purified by prep-TLC (DCM/MeOH=10/l, v/v) to afford compound 5.51 (yield: 12%) as a yellow solid. TLC: Rf= 0.29 (Petroleum Ether: EtOAc =
5:1, v/v, 254 nm). LCMS: (LCMS MethodP2): m/z 763 45 [M+H] +, 2.421 min. 'H NMR: 'H NMR (400 MHz, DMSO-76) (FID NO:ZJ-0523-018-HNMR) d 11.00 (s, 1H), 10.33 (s, 1H),
9.95 (s, 1H), 8.65 (s, 1H), 8.42 (s, 1H), 8.09 (s, 1H), 7.73 (s, 2H), 7.66 (s, 2H), 7.44 (d, 7 =
7.9 Hz, 1H), 7.34 (d, 7= 7.6 Hz, 1H), 7.12 (d, 7= 8.2 Hz, 1H), 4.58 (d, 7= 37.0 Hz, 4H),
4.41 (s, 1H), 4.34 (s, 1H), 3.84 (d, 7= 6.6 Hz, 2H), 3.55 - 3.45 (m, 4H), 3.40 (d, 7= 6.0 Hz, 2H), 3.25 (d, 7= 5.6 Hz, 2H), 3.17 (d, 7= 5.0 Hz, 2H), 2.60 (d, 7= 17.2 Hz, 1H), 2.40 (d, 7 = 12.6 Hz, 1H), 2.30 (t,7= 7.6 Hz, 2H), 1.94 (t, 7= 7.4 Hz, 3H), 1.53 (d, 7= 35.6 Hz, 4H),
1.28 (s, 4H), 1.09 (t, 7= 7.0 Hz, 1H).
[0237] Compound 5.52 was purified by prep-HPLC (5-60% ACN in water containing 0.1% TFA) to afford compound 5.52 (yield: 34%) as a brown solid. LCMS: (LCMS Method S12 ): m/z 675.3 [M+H] +, 2 170 min. ¾ NMR: (400 MHz, DMSO-de, FID No: LL-0450-115- HNMR) 510.99 (s, 1H), 10.32 (s, 1H), 9.94 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 7.72 (s, 2H), 7.67 (s, 2H), 7.43 (t, 7= 7.8 Hz, 1H), 7 33 (s, 1H), 7.10 (d, 7= 7.8 Hz, 1H), 5.11 (dd, 7 =
13.2, 5.2 Hz, 1H), 4.64 (d, 7= 2.2 Hz, 2H), 4.51 (s, 2H), 4.39 (s, 1H), 4.34 (s, 1H), 3.66 - 3.58 (m, 2H), 2.91 (ddd, 7= 17.4, 13.6, 5.2 Hz, 1H), 258 (d, 7= 17.2 Hz, 1H), 2.40 (td, 7 = 13.0, 4.4 Hz, 1H), 2.31 (s, 2H), 2.07 (s, 4H), 1.94 (s, 3H), 1.58 (d, 7= 7.2 Hz, 2H), 1.54 - 1.45 (m, 2H), 1.35 - 1.23 (m, 4H).
Synthesis of compounds 5.53 and 5.56 Listed in Table 5
[0238] To a solution of the azide (1.0 eq.) in THF (008 M) was added PPh3 (2.0 eq.) and 2 M HC1 (4.0 eq.) and the mixture was stirred at RT overnight. More PPh; (1.0 eq.) was added and stirring was continued for a further 8 h. The solvent was removed under vacuum and the residue was triturated with diethyl ether to afford the title amine intermediates, which were used directly in the next step without any further purification.
[0239] To a solution of Intermediate 1 in DMF (0.045 M) was added the amine intermediate (1.2 eq.) followed by TBTU (1.5 eq.) and DIPEA (3.0 eq.) and the mixture was stirred at RT for 16 h under aN2 atmosphere. The mixture was diluted with water, extracted with DCM/MeOH (15/1) and the combined organic layers were washed with brine, dried over Na2SC>4, filtrated, concentrated. The residue was purified by prep-TLC or prep-ElPLC to afford compounds 5.53 and 5.56.
[0240] Compound 5.53 was purified by prep-HPLC (5-80% ACN in water containing 0.1% TFA) to afford the compound 5.53 (yield 6%) as a white solid. LCMS: (LCMS Method «572- 5MIN): /z 934.4 [M+H] +, 2.356min. 'H NMR: (400 MHz, DMSO-rie) (FID No:CJP-0147- 132-HNMR) 58(t, J= 5.2 Hz,lH) 12, 7.73-7.62 (m, 2H), 7.46 (t, .7=8.0 Hz,IH), 7.39-7.33 (m, 3H), 7.29-7.26 (m, 1H), 7.21-7.11 (m, 8H), 6.74-6.59 (m, 4H), 5.15-5.12 (m, 1H), 4.64 (s, 2H), 4.48-4.34 (m, 4H), 4.22 (t, J= 5.6 Hz,IH), 3,91 (t, J= 5.2 Hz,IH), 3.43-3.32 (m, 14H), 3.19-3.18 (m, 2H), 2.97-2.90 (m, 3H), 2.68-2.58 (m, 3H), 2.39-2.37 (m, 3H), 2.25 (s, 3H), 2.02-1.99 (m, 1H), 1.66-1.62 (m, 1H), 1.40-1.32 (m, 1H), 0.91 (t, 7=7.6 Hz, 1H), 0.86-080 (m, 3H).
[0241] Compound 5.56 was purified by prep-HPLC (5-80% ACN in water containing 0.1% TFA) to afford compound 5.56 (yield: 10%) as a white solid. LCMS: (LCMS Method S12) m/z 758.3 [M+H] +, 3 088 min. ¾ NMR: (400 MHz, DMSO-de, FID No: LL-0450-120- HNMR) d 9.80 (s, 1H), 8.59 (s, 1H), 8.15 (d, .7= 5.8 Hz, 1H), 7.63 (s, 1H), 7.44 (t, J= 7.8 Hz, 1H), 7.38 (dd, J= 8.0, 6.8 Hz, 2H), 7.34 - 7.26 (m, 2H), 7.22 - 7.17 (m, 4H), 7.15 - 7.09 (m, 4H), 6.77 (d, J= 8.8 Hz, 2H), 6.64 (d, J= 8.8 Hz, 2H), 4.77 (dd, J= 10.2, 4.7 Hz, 1H), 4.62 (d, J= 17.6 Hz, 3H), 4.43 (d, J= 18.0 Hz, 2H), 4.18 (s, 2H), 3.92 (d, J= 33.0 Hz, 3H), 3.21 (d, J= 19.4 Hz, 4H), 2.85 (s, 3H), 2.37 (d, J= 7.4 Hz, 2H), 2.26 (s, 2H), 2.23 - 2.18 (m, 1H), 2.10 - 2.00 (m, 1H), 0.84 (t, J= 7.4 Hz, 3H).
Synthesis of Compounds 5.54 and 5.55 Listed in Table 5
[0242] To a solution of the bis-amme (1.0 eq.) in DCM (0.47 M) was added (Bo O (1.0 eq.) and TEA (2.5 eq.) and the mixture was stirred at RT for 2 h. The solvent was removed under vacuum and the residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SC»4, filtered and concentrated to afford the mono-boc-amine, which was used directly in the next step without any further purification. [0243] To a solution of acid intermediate 1, 4 or 9 (1.0 eq.) in DMF (0.15 M) was added the mono-boc-amme (1.2 eq.) followed by TBTU (1.5 eq.) and DIPEA (3.0 eq.) and the mixture was stirred at RT for 16 h under a N2 atmosphere. The mixture was diluted with water and extracted by DCM/MeOH (30/1). The combined organic layers were washed with brine, dried over NaiSCfi, filtered, concentrated and the residue was purified by column chromatography on silica gel to afford the boc-protected intermediates.
[0244] To a solution of boc-protected intermediates in dioxane was added 4 M HC1 in dioxane (8 eq.) and the mixture was stirred at RT for 2 - 4 h. The solvent was removed under vacuum to afford title HC1 salt, which were used directly in the next step.
[0245] To a solution of Intermediate 1 (1.0 eq.) in DMF (0.045 M) was added the amine HC1 salt (1.2 eq.) followed by TBTU (1.5 eq.) and DIPEA (3.0 eq.) and the mixture was stirred at RT for 16 h under aN2 atmosphere. The mixture was diluted with water and extracted by DCM/MeOH (15/1). The combined organic layers were washed with brine, dried over NaiSOi, filtrated, concentrated and the residue purified by prep-TLC or prep- HPLC to afford the final compounds.
[0246] Compound 5.54 was purified by prep-TLC (DCM/MeOH=10/l, v/v) to afford compound 5.54 (yield: 13%) as an off-white solid. TLC: Rr= 0.15 (DCM: MeOH = 10:1, v/v, 254 nm). LCMS: (LCMS Method P2) mlz 846.50 [M+H] +, 0.490 min. ¾ NMR (400 MHz, DMSO-ώ) (FID NO:ZJ-0523-039-HNMR) d 11.00 (s, 1H), 8.11 (t, J= 5.8 Hz, 1H), 7.69 (s, 1H), 7.46 (t, J= 7.8 Hz, 1H), 7.35 (t, J= 8.0 Hz, 3H), 7.30 - 7.25 (m, 1H), 7.22 - 7.17 (m, 4H), 7.14 - 7.10 (m, 4H), 5.13 (dd, J= 13.2, 5.2 Hz, 1H), 4.63 (d, J= 1.6 Hz, 2H), 4.44 (d, J = 17.6 Hz, 1H), 4.33 (d, J= 17.6 Hz, 1H), 3.93 (t, J = 5.6 Hz, 2H), 3.43 (s, 3H), 3.41 - 3.34 (m, 4H), 3.27 (q, J= 6.2 Hz, 3H), 3.18 (d, J= 5.8 Hz, 2H), 3.02 (s, 2H), 2.72 (s, 2H), 2.44 - 2.32 (m, 4H), 2.29 (s, 1H), 2.03 - 1.97 (m, 1H), 1.24 (d, J = 2.8 Hz, 3H), 0.86 - 0.84 (m, 3H).
[0247] Compound 5.55 was purified by prep-TLC (DCM/MeOH=10/l, v/v) to afford compound 5.55 (yield: 11%) as an off-white solid. LCMS: (LCMS Method .P2): m/z 890.4 [M+H] +, 3.172 min. ¾ NMR (400 MHz, DMSO -ds) (FID NO:CJP-0147-137-HNMR) d 11.00 (s, 1H), 8.12 (t, J = 5.6 Hz, 1H), 7.68 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.39-7.28 (m, 4H), 7.21-7.11 (m, 8H), 6.74-6.59 (m, 4H), 5.16-5.11 (m, 1H), 4.64 (s, 2H), 4.72-4.31 (m, 2H), 3.92 (t, J= 5.6 Hz, 2H), 3.46-3.41 (m, 10H), 3.36 - 3.32 (m, 2H), 3.29-3.26 (m, 2H), 3.19-3.16 (m, 2H), 2.99-2.88 (m, 3H), 2.70-2.58 (m, 3H), 2.39 - 2.34 (m, 2H), 2.27 (s, 3H), 2.02 - 1.98(m, 1H), 1.26-1.24 (m, 1H), 0.84 (t, .7= 7.2 Hz, 3H). Synthesis of Compounds 5.57-5.60 Listed in Table 5
[0248] To a solution of Intermediate 3 (1.0 eq.) in DMF (0.05 M) was added the amine HC1 salt (1.2 eq.) followed by TBTU (1.5 eq.) and DIPEA (3.0 eq.) and The mixture was stirred at RT for 16 h under a N2 atmosphere. The mixture was diluted with water and extracted by DCM/MeOH (15/1). The combined organic layers were washed with bnne, dried over Na2S04, filtrated, concentrated and the residue purified by prep-TLC or prep HPLC to afford compounds 5.57-5.60.
[0249] Compound 5.57 was purified by prep-TLC (DCM/MeOH=8/l, v/v) to afford compound 5.57(yield 4%) as a yellow solid. LCMS: (LCMS Method S12-5MIN ): m/z 919.5 [M+H] +, 3.033min. Ή NMR: (400 MHz, DMSO -de) (FID No:CJP-0147-135-HNMR)
511.00 (s, 1H), 8.27 (t, 7=5.6 Hz, 1H), 8.12 (t, 7=5.6 Hz,IH), 7.49-7.47 (m, 3H), 7.43-7.35 (m, 2H), 7.35-7.33 (m, 1H), 7.13 (d, 7= 8 Hz, 1H), 5.14-5.11 (m, 1H), 4.64 (s, 2H), 4.52-4.48 (m, 1H), 4.43-4.30 (m, 2H), 3.52-3.43 (m, 13H), 3.33-3.25 (m, 4H), 3.22-3.21 (m, 5H), 2.92- 2.82 (m, 1H), 2.62-2.59 (m,4H), 2.50-2.40 (m, 4H), 2.03-1.99 (m,lH), 1.62 (s, 3H).
[0250] Compound 5.58 was purified by prep-TLC (DCM/MeOfM 0/1. v/v) to afford compound 5.58 (yield 4%) as a white solid. LCMS: (LCMS Method S12-5M1N). m z 875.2 [M+H] +, 2.898min. ¾ NMR: (400 MHz, DMSO-rie) (FID No:CJP-0147-138-HNMR)
511.00 (s, 1H), 8.27 (t, 7=5.6 Hz, 1H), 8.13 (t, 7=5.6 Hz,IH), 7.49-7.43 (m, 5H), 7.40 (d,
7=7.6 Hz, 1H), 7.13 (d, 7=8.0 Hz, 1H), 5.14-5.11 (m, 1H), 4.64 (s, 2H), 4.52-4.47 (m, 2H), 4.43-4.31 (m, 1H), 3.51 (d, 7=9.2 Hz, 8H), 3.46-3.43 (m, 4H), 3.32-3.21 (m, 6H), 2.96-2.88 (m, 1H), 2.62-2.59 (m,4H), 2.50-2.40 (m, 4H), 2.02-1.99 (m,lH), 1.62 (s, 3H)
[0251] Compound 5.59 was purified by Pre-HPLC (5-50% ACN in water containing 0.1% TFA) to afford compound 5.59 (yield: 7%) as an off-white soild. LCMS : (LCMS Method P2): m z 831.30 [M+H] +, 1.678 min. 'l l NMR (400 MHz, DMSO-rie) (FID NO:ZJ-0523-038-HNMR) d 11.00 (s, 1H), 8.27 (t, 7= 5.8 Hz, 1H), 8.13 (t, 7= 5.8 Hz, 1H), 7.49 - 7.42 (m, 5H), 7.34 (d, 7= 7.6 Hz, 1H), 7.12 (d, 7= 8.2 Hz, 1H), 5.13 (d, 7= 8.4 Hz, 1H), 4.64 (s, 2H), 4.52 - 4.42 (m, 3H), 4.33 (d, 7= 17.6 Hz, 2H), 3.52 (s, 3H), 3.45 (q, 7= 3.2 Hz, 4H), 3.27 (d, 7= 10.8 Hz, 4H), 2.97 - 2.85 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 1.99 (d, 7= 7.0 Hz, 1H), 1.61 (s, 2H), 1.47 (s, 1H), 1.28 - 1.23 (m, 3H).
[0252] Compound 5.60 was purified Purified by prep-HPLC (5-50% ACN in water containing 0.1% TFA) to afford compound 5.60 (yield: 30%) as a white solid. LCMS:
(LCMS Method S12): m z 743.2 [M+H] +, 2.842 mm. H NMR: (400 MHz, DMSO-de, FID No: LL-0450-145-HNMR) d 10.96 (d, J= 2.8 Hz, 1H), 8.34 (d, J= 5.6 Hz, 1H), 7.66 - 7.54 (m, 1H), 7.52 - 7.43 (m, 3H), 7.41 (s, 2H), 7.34 (dd, = 7.6, 3.2 Hz, 1H), 7.15 (s, 1H), 5.10 (s, 1H), 4.61 (d, J= 3 0 Hz, 2H), 4.49 (tt,J= 9.6, 4.8 Hz, 1H), 4.45 - 4.38 (m, 1H), 4.32 (dd, ./ = 17.6, 14.8 Hz, 1H), 3.44 (d, = 6.8 Hz, 1H), 3.23 (q, = 5.6 Hz, 5H), 2.95 - 2.81 (m, 1H), 2.59 (d, J= 11.8 Hz, 2H), 2.44 - 2.35 (m, 3H), 2.34 - 2.26 (m, 1H), 1.95 - 1.87 (m, 1H), 1.85 - 1.77 (m, 1H), 1.57 (d, J= 15.2 Hz, 3H), 1.06 (t, J= 6.8 Hz, 1H).
Example 9: Competition and Recruitment Activity
[0253] The competition and recruitment activities of the compounds described herein were measured according to the assays illustrated in Example 1 and Example 2. The strength of IC50 or EC50 is reported from strongest to weakest (i.e. +++ to +), while “NA” being Not Applicable.
Figure imgf000384_0001
Figure imgf000385_0001
Figure imgf000385_0002

Claims

Claims
1. A compound having the general formula (A)k-Li, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, wherein:
A is a moiety that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X;
Figure imgf000386_0001
V VI
Figure imgf000387_0001
IX X
Li is a linker; each A is covalently linked to the Li as allowed by valence;
R1 is aryl, -N(R5)-X-R6, -SO2R5, or -0(CH2)mR5, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R2 is aryl, -NH-(C3-CIO) heteroaryl, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R3 is cyano, aryl, -NH-(C3-CIO) heteroaryl, (C3-Cio)heterocyclo, or -N(R5)-(CH2)m-X- (CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R4 is halo, cyano, aryl, OR5, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n- aryl, -(CH2)n-heteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; R6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryl, or R5 and R6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R7 is H, (Ci-C3)alkyl, or R7 and R26 taken together with the carbons they are attached to forming a carbon carbon double bond;
R8, R9, R10, R11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R12, R13, R14, R15 each is independently H, NH2, (Ci-C3)alkyl, -N(R5)-(CH2)m-N(R5)- X-R\ with proviso that no more than three substituents out of R12, R13, R14, and R15 are H, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R16 is NH2 or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R17 is cyano, heteroaryl, -(CH2)m-C(0)0-R6, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R18, R19, R20, R21 each independently is H, halo, (Ci-C )alkyl, (Ci-C3)alkoxy, or - N(R5)-X-R6, with the proviso that no more than two substituents of R18, R19, R20, R21 are H; or
R18, R19 taken together with the carbons they are attached to forming a (C3- Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R19, R20 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R20, R21 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence; Rw at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (CvCio)cycloalkyL -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n-aryl, -(Cfhln-heteroaryl. aryl, and heteroaryl;
X is a bond, -SO2-, -(CH2)nC(0)(CH2)m-, -C(0)NH-, -C(0)N(Rw)-, -NHC(0)NH-, or -(CH2)n-;
Yi is NHR25, -NHC(0)R25, or CHR25R26; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
2. The compound of claim 1, wherein Li is -Lb-(La)t-H; wherein La at each occurrence is independently selected from the group consisting of a bond, CR¾6, C(R5R6)0,
Figure imgf000389_0001
NR5C(=NCN), andNR5C(=CN02)NR6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
H is hydrogen.
Lb is selected from the group consisting of:
Figure imgf000389_0002
Figure imgf000390_0001
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
3. A compound of the general formula (A)k-L-Q, or a salt, enantiomer, stereoisomer, polymorph, or N-oxide thereof, wherein:
A is a compound that binds to an E3 ubiquitin ligase and has the structure selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, and Formula X,
II
I
III IV
Figure imgf000391_0001
IX X
Q is a moiety that binds to a target protein which is sequestered to the E3 ubiquitin ligase and/or degraded upon interaction with the E3 ubiquitin ligase;
L is a linker; each A is covalently linked to the L as allowed by valence;
R1 is aryl, -N(R5)-X-R6, -SO2R5, or -0(CEE)mR5, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R2 is aryl, -NH-(C3-CIO) heteroaryl, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more R" groups as allowed by valence; R3 is cyano, aryl, -NH-(C3-CIO) heteroaryl, (C3-Cio)heterocyclo, or -N(R5)-(CH2)m-X- (CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R4 is halo, cyano, aryl, OR5, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R5 at each occurrence is independently H, (Ci-C3)alkyl, (C3-Cio)heterocyclo, (C3- Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CH2)n- aiyl. -(CH2)n-heteroaryl, ary l, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R6 at each occurrence is independently OH, (Ci-C3)alkyl, -(Ci-C3)alkoxy, (C3- Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3- Cio)heterocyclo, -(CH2)n-aryl, -(CH2)n-heteroaryl, aryl, heteroaryd, or R5 and R6 taken together with the atoms they are attached to forming a nitrogen containing (C3- Cio)heterocyclic ring, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R7 is H, (Ci-C3)alkyl, or R7 and R26 taken together with the carbons they are attached to forming a carbon carbon double bond;
R8, R9, R10, R11 each independently is H, halo, OH, cyano, (Ci-C3)alkyl, (Ci- C3)alkoxy, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R12, R13, R14, R15 each is independently H, NH2, (Ci-C3)alkyl, -N(R5)-(CH2)m-N(R5)- X-R6, with proviso that no more than three substituents out of R12, R13, R14, and R15 are H, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R16 is NH2 or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R17 is cyano, heteroaryl, -(CH2)m-C(0)0-R6, or -N(R5)-(CH2)m-X-(CH2)n-R6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R18, R19, R20, R21 each independently is H, halo, (Ci-C3)alkyl, (Ci-C3)alkoxy, or - N(R5)-X-R6, with the proviso that no more than two substituents of R18, R19, R20, R21 are H; or R18, R19 taken together with the carbons they are attached to forming a (C3- Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R19, R20 taken together with the carbons they are attached to forming a (C3-Cio)cycloalkyl or a (C3-Cio)heterocyclo, or R20, R21 taken together with the carbons they are attached to forming a (C .-Ciolcycloalkvl or a (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
R25 is aryl, heteroaryl, or (C3-Cio)heterocyclo, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Rw at each occurrence is independently H, halo, cyano, nitro, oxo, alkyl haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C3-Cio)heterocyclo, (C3-Cio)cycloalkyl, -(CH2)n-(C3-Cio) cycloalkyl, -(CH2)n-(C3-Cio)heterocyclo, -(CLLVaryl, -(CH2)n-heteroaryl, aryl, and heteroaryl;
X is a bond, -SO2-, -(CH2)nC(0)(CH2)m-, -C(0)NH-, -C(0)N(Rw)-, -NHC(0)NH-, or -(CH2)n-;
Yi is -NHR25, -NHC(0)R25, or-CHR25R26; m is 0, 1, 2, 3, or 4; k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; n is 0, 1, 2, 3, or 4.
4. The compound of claim 3, wherein L is -Lb-(La)t-; wherein La at each occurrence is independently selected from the group consisting of a bond, CR5R6, C(R5R6)0, C(R5R6)C(R5R6)0, S02, NR5, C(R5R6) NR5, SO2NR5, SONR5, CONR5, NR5CONR6, NR5S02NR6, CO, CR5=CR6, CºC, SIR5R6, P(0)R5, P(0)0R5, NR5C(=NCN)NR6, NR5C(=NCN), and NR5C(=CN02)NR6, any of which may be optionally substituted with 1 or more Rw groups as allowed by valence;
Lb is selected from the group consisting of:
Figure imgf000394_0001
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.
5. The compound of claim 3, wherein L is -(CThClfcy, -(CH20)t- or -(CTkCThC t-.
6. The compound of any of claims 3-5, wherein Q is a moiety that binds to a target protein, wherein said target protein is selected from the group consisting of B7.1 and B7, TINFRlm, TNFR2, NADPH oxidase, Bel, C5a receptor, HMG-CoA reductase, PDE V phosphodiesterase type, PDE IV phosphodiesterase type 4, PDE I, PDEII, PDEIII, Squalene-hopene cyclase, CXCR1, CXCR2, nitric oxide (NO) synthase, cyclo-oxygenase 1, cyclo-oxygenase 2, 5HT receptors, dopamine receptors, G Proteins, Gq, histamine receptors, 5-lipoxygenase, tryptase serine protease, thymidylate synthase, purine nucleoside phosphorylase, GAPDH trypanosomal, glycogen phosphorylase, carbonic anhydrase, chemokine receptors, JAW/STAT, retinoid X receptor, HIV 1 protease, HIV 1 mtegrase, influenza, neuramirmdase, hepatitis B reverse transcriptase, sodium channel, protein P-gly coprotein (and MRP), tyrosine kinases, CD23, CD 124, tyrosine kinase p56 lck, CD4, CD5, IL-2 receptor, IL-1 receptor, TNF-alpha, ICAM1, Cat+ channels, VCAM, VLA-4 integrin, selectins, CD40/CD40L, newokinins and receptors, inosine monophosphate dehydrogenase, p38 MAP Kinase, Ras/Raf/ME/ERK pathway, interleukin- 1 converting enzyme, caspase, HCV, NS3 protease, HCV NS3 RNA helicase, glycinamide ribonucleotide formyl transferase, rhinovirus 3C protease, herpes simplex virus- 1 (HSY-I) protease, cytomegalovirus (CMV) protease, poly (ADP-ribose) polymerase, cyclin dependent kinases, vascular endothelial growth factor, c-Kit, TGFp activated kinase 1, mammalian target of rapamycin, SHP2, androgen receptor, oxytocin receptor, microsomal transfer protein inhibitor, 5 alpha reductase, angiotensin II, glycine receptor, noradrenaline reuptake receptor, estrogen receptor, estrogen related receptors, focal adhesion kinase, Src, endothelin receptors, neuropeptide Y and receptor, adenosine receptors, adenosine kmase and AMP deaminase, purinergic receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2X1-7), famesyltransferases, geranylgeranyl transferase, TrkA a receptor for NGF, beta-amyloid, tyrosine kinase Flk-1, vitronectin receptor, integrin receptor, Her-2/neu, telomerase, cytosolic phospholipaseA2 and EGF receptor tyrosine kinase, ecdysone 20-monooxygenase, ion channel of the GABA gated chloride channel, acetylcholinesterase, voltage-sensitive sodium channel protein, calcium channel protein, and chloride channel protein, acetyl-CoA carboxylase, adenylosuccinate synthetase, protoporphyrinogen oxidase, and enolpyruvylshikimate-phosphate synthase.
7. The compound of any of claims 3-5, wherein Q is a moiet that is an Hsp90 inhibitor, a kinase inhibitor, a phosphatase inhibitor, an HDM2/MDM2 inhibitor, a human BET Bromodomain inhibitor, an HD AC inhibitor, a human lysine methyltransferase inhibitor, a RAF receptor inhibitor, a FKBP inhibitor, an angiogenesis inhibitor, an aryl hydrocarbon receptor inhibitor, an androgen receptor inhibitor, an estrogen receptor inhibitor, a thyroid hormone receptor inhibitor, an HIV protease inhibitor, an HIV integrase inhibitor, an acyl protein thioesterase 1 inhibitor, or an acyl protein thioesterase 2 inhibitor.
8. The compound of any of claims 3-5, wherein Q is a moiety that is a TANK-binding kinase 1 (TBK1) inhibitor, an estrogen receptor a (ERa) inhibitor, a bromodomain- containing protein 4 (BRD4) inhibitor, an androgen receptor (AR) inhibitor, a platelet-derived growth factor receptor inhibitor, a p38 MAPK inhibitor, aBcr-Abl tyrosine-kinase inhibitor, an Her2 inhibitor, an EGFR inhibitor, an MDM2 inhibitor, a bromodomain-containing protein 2 (BRD2) inhibitor, an HD AC inhibitor, a DHFR inhibitor, or a c-Myc inhibitor.
9. The compound of any of claims 3-5, wherein Q is a moiety selected from the group consisting of trimethoprim, vorinostat, tamoxifen, JQ1, Nutlin 3, afatinib, chloroalkane, dasatinib, BIRB796, FK-506, simvastatin, rapamycin, and sorafenib.
10. The compound of any one of claims 1-9, wherein the E3 ubiquitin ligase is selected from cereblon (CRBN), damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), regulator of cullins 1 (ROC1), and Von Hippel Lindau (VHL).
11. The compound of claim 10, wherein the E3 ubiquitin ligase is CRBN.
12. The compound of any one of claims 3-11, wherein the compound is capable of simultaneously binding to the target protein and the E3 ubiquitin ligase.
13. The compound of claim 12, wherein the binding causes ubiquitination of the target protein by the E3 ubiquitin ligase.
14. The compound of claim 12, wherein the binding causes degradation of the target protein by the proteasome.
15. A pharmaceutical composition comprising the compound of claim 1 or 3 and a pharmaceutically acceptable carrier, additive, and/or excipient.
16. A method for treating a disease in a subject wherein dysregulated protein activity is responsible for said disease, said method comprising administering an effective amount of a compound according to claim 3.
17. The method of claim 16, wherein the disease is a cancer.
18. The method of claim 17, wherein the cancer is selected from the group consisting of squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, renal cell carcinomas, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, uterine cancer, leukemias, lymphomas, Burkitt's lymphoma, Non- Hodgkin's lymphoma, melanomas, myeloproliferative diseases, multiple myeloma, sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, Schwannomas, testicular cancer, thyroid cancer, astrocytoma, Hodgkin's disease, Wilms' tumor, and teratocarcinomas.
19. The method of claim 17, wherein the cancer is multiple myeloma.
20. The method of claim 16, wherein the disease is an autoimmune disease or disorder.
21. The method of claim 20, wherein the the autoimmune disease or disorder is selected from, such as multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, Fibromyalgia, Menier's syndrome; transplantation rejection (e.g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Grave's disease, and other autoimmune diseases or disorders.
22. A method of modulating cereblon comprising administering the composition of claim 15 to a subject in need thereof.
23. A method of modulating proteasomal degradation of a protein comprising administering the composition of claim 15 to a subject in need thereof.
24. A method of modulating sequestration of a protein to the proteasome comprising administering the composition of claim 15 to a subject in need thereof.
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