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WO2017197056A1 - Dégronimères ciblant un bromodomaine pour la dégradation de protéines cibles - Google Patents

Dégronimères ciblant un bromodomaine pour la dégradation de protéines cibles Download PDF

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Publication number
WO2017197056A1
WO2017197056A1 PCT/US2017/032053 US2017032053W WO2017197056A1 WO 2017197056 A1 WO2017197056 A1 WO 2017197056A1 US 2017032053 W US2017032053 W US 2017032053W WO 2017197056 A1 WO2017197056 A1 WO 2017197056A1
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Prior art keywords
formula
alkyl
aliphatic
aryl
membered
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PCT/US2017/032053
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English (en)
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Andrew J. Phillips
Chris G. NASVESCHUK
James A. Henderson
Yanke LIANG
Mark E. FITZGERALD
Ryan E. MICHAEL
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C4 Therapeutics, Inc.
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Publication of WO2017197056A1 publication Critical patent/WO2017197056A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • This invention provides a Degronimer that has an E3 Ubiquitin Ligase targeting moiety (Degron) that can be linked to a Targeting Ligand for a bromodomain protein selected for in vivo degradation to achieve a therapeutic effect, and methods of use and compositions thereof as well as methods for their preparation.
  • Degron E3 Ubiquitin Ligase targeting moiety
  • 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
  • the UPP in fact is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, biogenesis of organelles, cell cycling, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscular degeneration, morphogenesis of neural networks, modulation of cell surface receptors, ion channels and the secretory pathway, the response to stress and extracellular modulators, ribosome biogenesis and viral infection.
  • 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.
  • Defective proteasomal degradation has been linked to a variety of clinical disorders including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, muscular dystrophies, cardiovascular disease, and cancer among others.
  • E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled“Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled“New insights into ubiquitin E3 ligase mechanism”; Deshaies et al.
  • Proteinex, Inc. filed a patent application in February 1999 that issued as U.S. Patent 6,306,663 claiming a method of generating a compound for activating the ubiquitination of a Target Protein which comprises covalently linking a Target Protein binding element able to bind specifically to the Target Protein via a ubiquitination recognition element.
  • Proteinex described that the invention can be used to control protein levels in eukaryotes. While the‘663 patent may have been based on the first patent application to describe the high level concept of how to manipulate the UPP system to degrade selected proteins in vivo, the patent did not provide sufficient detail to allow persons of skill to easily construct the range of proposed compounds.
  • ubiquitination recognition elements For example, for the ubiquitination recognition elements, the skilled person was told among other things to use standard methods for drug discovery and screen for appropriate small molecules that would bind to the ligase. Proteinex also emphasized the use of peptides as ubiquitination recognition elements, which can pose significant difficulties for oral drug administration.
  • Patent 7,041,298 filed in September 2000 by Deshaies et al. and granted in May 2006 titled“Proteolysis Targeting Chimeric Pharmaceutical”, which described a“PROTAC” consisting of a small molecule binder of MAP- AP-2 linked to a peptide capable of binding the F-box protein ⁇ -TRCP.
  • Information in the‘298 patent is also presented in the corresponding publication by Sakamoto et al. (Proc. Natl. Acad. Sci. USA 2001, 98, 8554-8559) titled “Protacs: Chimeric Molecules That Target Proteins to the Skp1– Cullin–F Box Complex for Ubiquitination and Degradation".
  • Sakamoto et al. The publication by Sakamoto et al.
  • PROTAC2 Protacs to Target Cancer- Promoting Proteins for Ubiquitination and Degradation
  • the first E3 ligase successfully targeted with a small molecule was MDM2, which ubiquitinates the tumor suppressor p53.
  • the targeting ligand was an HDM2/MDM2 inhibitor identified in Vassilev et al. (Science 2004, 303, 844-848) titled "In Vivo Activation of the P53 Pathway by Small-Molecule Antagonists of MDM2".
  • cereblon is a thalidomide binding protein. Cereblon forms part of an E3 ubiquitin ligase protein complex which interacts with damaged DNA binding protein 1, forming an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1) where it functions as a substrate receptor to select proteins for ubiquitination.
  • ROC1 also known as RBX1
  • thalidomide binds to the cereblon E3 ubiquitin ligase led to research to investigate incorporating thalidomide and certain derivatives into compounds for the targeted destruction of proteins.
  • Two seminal papers were published in Science in 2014: G. Lu et al., The Myeloma Drug Lenalidomide Promotes the Cereblon-Dependent Destruction of Ikaros Proteins, Science, 343, 305-309 (2014); and J. Kronke et al., Lenalidomide Causes Selective Degradation of IKZF1 and IKZF3 in Multiple Myeloma Cells, Science, 343, 301-305 (2014).
  • WO 2015/160845 assigned to Arvinas Inc. titled“Imide Based Modulators of Proteolysis and Associated Methods of Use” describes protein degradation compounds that incorporate thalidomide and certain derivatives which bind to a cereblon E3 ligase. Additional patent applications filed by Arvinas Inc. directed towards the degradation of a Target Protein using known E3 ligase ligands to direct the Target Protein to the proteasome for degradation include U.S. 2016/0058872 titled“Imide Based Modulators of Proteolysis and Associated Methods of Use”; U.S. 2016/0045607 titled”Estrogen-related Receptor Alpha Based PROTAC Compounds and Associated Methods of Use”; U.S.
  • the compounds of the present invention are referred to below as“Degronimers” because they accomplish degradation of a bromodomain containing protein by the proteasome.
  • the Degronimers include a“Targeting Ligand” that binds to a bromodomain containing protein, a“Degron” which binds (typically non- covalently) to an E3 Ligase (typically the cereblon component) and optionally a linker that covalently links the Targeting Ligand to the Degron.
  • a method to treat a host with a disorder mediated by a bromodomain containing protein includes administering an effective amount of the Degronimer or its pharmaceutically acceptable salt to the host, typically a human.
  • the Degronimer causes the degradation of the bromodomain containing protein in vivo.
  • Degronimers have been discovered that have the ability to ubiquitinate Targeted Proteins by binding both E3 Ubiquitin Ligase (typically through cereblon) and a selected Targeted Protein.
  • a Degronimer of Formula I, II, III, IV, V, VI, VII, VIII, IX, or X is provided:
  • composition or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, optionally in a pharmaceutically acceptable carrier to form a composition;
  • A is independently selected from C(R 11 ), and N wherein in certain embodiments the number of nitrogen atoms is 0, 1, 2, 3, or 4 per ring (as allowed by context) and is selected to produce a stable ring and a pharmaceutically acceptable Degronimer.
  • the ring can be, in non-limiting embodiments as allowed by context, a pyridine, diazine, triazine, pyrimidine, pyridazine, pyrazine, triazine or tetrazine.
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • X is independently selected from C(R 11 ), N, N(R 9 ), N(O), O, and S as permitted by valency and by ring stability under ambient conditions (as appropriate in context); and wherein there is typically not more than 1, 2, or 3 heteroatoms.
  • non-limiting examples are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, furazan, oxadiazole, thiadiazole, diazole and tetrazole.
  • X is independently selected from C(H), C(R 11 ), N, N(R 9 ), N(O), O, and S as permitted by valency and by ring stability under ambient conditions; and wherein there is typically not more than 1, 2, or 3 heteroatoms in the X-bearing ring except that the ring may have 4 nitrogens to form a tetrazole;
  • X’ is selected from O, S, and -N(R 9 );
  • Q is either C or N;
  • T is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, or
  • T and R 1 together with the carbon to which they are attached form a 3, 4, 5, or 6 membered spirocarbocycle or a 3, 4, 5, or 6 membered spiroheterocycle;
  • T and R 1 form a 3, 4, 5, or 6 membered spirocarbocycle or a 3, 4, 5, or 6 membered spiroheterocycle that is substituted with R 11 , SO2heterocycle, or SO2alkyl;
  • W is selected from C(R 11 ) and N;
  • R 2 and R 3 are independently selected from hydrogen, deuterium, alkyl, hydroxyl, alkoxy, aliphaticoxy, amine, -NH(aliphatic including alkyl), -N(aliphatic including alkyl)2, fluorine, chlorine, bromine, iodine, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroaliphatic, aliphatic, and carbocyclic;
  • R 1 , R 2’ , R 4 , R 4 ’, R 5 , R 5’ , R 6 , R 6’ , R 7 , R 7’ , R 13 , and R 13’ are independently selected from hydrogen, deuterium, alkyl, aliphatic, hydroxyl, alkoxy, aliphaticoxy, amine, cyano, -NH(aliphatic including alkyl), -N(aliphatic, including alkyl) 2 , fluorine, chlorine, bromine, iodine, haloalkyl (including–CFH 2 , CHF 2 , and -CF 3 ), alkenyl, alkynyl, aryl, heteroaryl, heterocyclo and carbocyclic;
  • R 4 substituents can form a 1, 2 , 3 or 4 carbon bridged ring
  • R 4’ and R 7’ can form a 3, 4, 5, or 6 membered fused ring
  • R 5’ and R 6’ can form a 3, 4, 5, or 6 membered fused ring
  • R 4 ’ and R 5’ can form a 1, 2, 3, or 4 carbon bridged ring
  • R 4 ’ and R 6’ can form a 1, 2, 3, or 4 carbon bridged ring
  • R 8 is N(R 9 ), CH 2 , CHR 9 , C(R 9 ) 2 , O, or S;
  • R 9 is selected at each instance from hydrogen, deuterium, alkyl, -C(O)H, -C(O)OH, - C(O)(aliphatic, including alkyl), -C(O)O(aliphatic, including alkyl), alkenyl, and alkynyl; aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic;
  • R 10 is Linker-Degron
  • R 11 and R 11A are independently selected at each instance from hydrogen, alkyl, alkenyl, alkynyl, fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, cyano, azide, amino, -NH(aliphatic or alkyl), -N(aliphatic or alkyl) 2 , -NHSO 2( aliphatic or alkyl, -N(aliphatic or alkyl)SO 2 (aliphatic or alkyl), -NHSO2(aryl or heteroaryl), -N(aliphatic including alkyl)SO2aryl, -NHSO2alkenyl, - N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, cyano, nitro, nitroso, -SH, -Salkyl, - S(O)alkyl, -S(O) 2 alkyl,
  • Linker is a chemical group that attaches the Degron to a Targeting Ligand
  • Degron is a chemical group that interacts with an E3 ligase to cause ubiquitination of nearby protein(s), and in particular, the Target Protein.
  • alkyl when used in the formula above in some embodiments it may independently refer to a C 1 -C 6 , C 1 -C 5, C 1 -C 4 , C 1 -C 3 or C 1 -C 2 moiety.
  • both R 1 and T are hydrogen or deuterium.
  • composition or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, optionally in a pharmaceutically acceptable carrier to form a composition;
  • Q is either C or N;
  • T is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, or
  • T and R 1 together with the carbon to which they are attached form a 3, 4, 5, or 6 membered spirocarbocycle or a 3, 4, 5, or 6 membered spiroheterocycle;
  • T and R 1 form a 3, 4, 5, or 6 membered spirocarbocycle or a 3, 4, 5, or 6 membered spiroheterocycle that is substituted with R 11 , SO2heterocycle, or SO2alkyl;
  • W is selected from C(R 11 ) and N;
  • W2 is selected from C(R 11 ) 2 and N(R 9 );
  • R 2’ is independently selected from hydrogen, deuterium, alkyl, hydroxyl, alkoxy, amine, - NH(aliphatic or alkyl), -N(aliphatic or alkyl)2, fluorine, chlorine, bromine, iodine, haloalkyl (including–CFH 2 , CHF 2 , and -CF 3 ), alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, aliphatic, heteroaliphatic,
  • a Degronimer of Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX is provided:
  • composition or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, prodrug, optionally in a pharmaceutically acceptable carrier to form a composition;
  • X 11 is bond, CH2 or CH(aliphatic including alkyl), and the other variables are as defined above.
  • the Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX is bifunctional with E3 Ubiquitin Ligase targeting moieties (Degrons) linked to Targeting Ligands, which function to recruit Targeted Proteins to E3 Ubiquitin Ligase for degradation.
  • a disorder treatable by such Degronimers is abnormal cellular proliferation, such as a tumor or cancer, wherein the Targeted Protein is an oncogenic protein or a signaling mediator of an abnormal cellular proliferative pathway and its degradation decreases abnormal cell growth.
  • Degronimers and methods are presented for the treatment of a patient with a disorder mediated by a protein that is targeted for selective degradation that includes administering an effective amount of one or a combination of the Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XX, Formula XI, Formula XII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX, described herein to a patient (typically a human) in need thereof, optionally in a pharmaceutically acceptable carrier.
  • the disorder is selected from a benign growth, neoplasm, tumor, cancer, immune disorder, autoimmune disorder, inflammatory disorder, graft-versus-host rejection, viral infection, bacterial infection, an amyloid- based proteinopathy, a proteinopathy, or fibrotic disorder.
  • the patient is a human.
  • the present invention provides the administration of an effective amount of a Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX, to treat a patient, for example, a human, having an infectious disease, wherein the therapy targets a Target Protein of the infectious agent or the host optionally in combination with another bioactive agent.
  • the disease state or condition may be caused by a microbial agent or other exogenous agent such as a virus (as non- limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus, EBV, viral pneumonia, drug-resistant viruses, Bird flu, RNA virus, DNA virus, adenovirus, poxvirus, Picornavirus, Togavirus, Orthomyxovirus, Retrovirus or Hepadnovirus), bacteria (including but not limited to Gram-negative, Gram-positive, Atypical, Staphylococcus, Streptococcus, E.
  • a virus as non- limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus, EBV, viral pneumonia, drug-resistant viruses, Bird flu, RNA virus, DNA virus, adenovirus, poxvirus, Picorn
  • Coli Salmonella, Helicobacter pylori, meningitis, gonorrhea, Chlamydiaceae, Mycoplasmataceae, etc), fungus, protozoa, helminth, worms, prion, parasite, or other microbe.
  • the structure of the Degronimer is typically selected such that it is sufficiently stable to sustain a shelf life of at least two, three, four, or five months under ambient conditions.
  • each of the R groups described herein must be sufficiently stable to sustain the corresponding desired shelf life of at least two, three, four or five months under ambient conditions.
  • One of ordinary skill in the art is well aware of the stability of chemical moieties and can avoid those that are not stable or are too reactive under the appropriate conditions.
  • the Degronimer (Degron, Linker and Targeting Ligand), including any of the“R” groups defined herein, and variables where appropriate, may be optionally substituted as described below in Section I. Definitions, if desired to achieve the target effect, results in a stable R moiety and final Degronimer that makes chemical sense to the routineer, and if the final Degronimer for therapy is pharmaceutically acceptable. Also, all R groups, with or without optional substituents, should be interpreted in a manner that does not include redundancy (i.e., as known in the art, alkyl substituted with alkyl is redundant; however for examples, alkoxy substituted with alkoxy is not redundant).
  • the present invention provides Degron moieties which are covalently linked to a Targeting Ligand through a Linker which can be of varying length and functionality, as described in more detail below.
  • the Degron moiety is linked directly to the Targeting Ligand (i.e., the Linker is a bond).
  • the Linker can be any chemically stable group that attaches the Degron to the Targeting Ligand.
  • the Linker has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms of which one or more carbons can be replaced by a heteroatom such as O, N, S, P, as long as the resulting molecule has a stable shelf life for at least 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable.
  • the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 contiguous atoms in the chain.
  • the chain may include 1 or more ethylene glycol units, and in some embodiments, may have at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more contiguous, partially contiguous or non-contiguous ethylene glycol units in the Linker.
  • the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 branches which can be independently alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl substituents, which in one embodiment, each branch has 10, 8, 6, 4, 3, 2 carbons or one carbon.
  • the Target Protein is a protein that is not druggable in the classic sense in that it does not have a binding pocket or an active site that can be inhibited or otherwise bound, and cannot be easily allosterically controlled.
  • the Targeted Protein is a protein that is druggable in the classic sense. Examples of Targeted Proteins are provided below. Degronimers of the present invention offer important clinical benefits to patients, in particular for the treatment of the disease states and conditions modulated by the selected Target Proteins that are bound to the Targeting Ligand.
  • the present invention thus includes at least the following features:
  • a method for manufacturing a medicament intended for the therapeutic use of treating a tumor including any of the tumors described herein, characterized in that a Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XXI, Formula XXI, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX, as described herein is used in the manufacture;
  • a method for manufacturing a medicament intended for the therapeutic use of treating an immune, autoimmune or inflammatory disorder characterized in that a Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX, as described herein is used in the manufacture; (o) A Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, as described herein
  • a method for manufacturing a medicament intended for the therapeutic use of treating a viral infection including but not limited to HIV, HBV, HCV and RSV, characterized in that a Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XX, Formula XI, Formula XII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX, as described herein is used in the manufacture;
  • a pharmaceutical formulation comprising an effective host-treating amount of the Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX, or a pharmaceutically acceptable salt or prodrug thereof together with a pharmaceutically acceptable carrier or diluent; (s) A Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula IX, Formula X,
  • FIG.1B-1D present examples of BRD2 Bromodomain 1 Targeting Ligands wherein R is the point at which the Linker is attached.
  • crystal structure PDB 2ydw the crystal structure PDB 2yek; the crystal structure PDB 4a9h; the crystal structure PDB 4a9f; the crystal structure PDB 4a9i; the crystal structure PDB 4a9m; the crystal structure PDB 4akn; the crystal structure PDB 4alg, and the crystal structure PDB 4uyf.
  • FIG.1E-1G present examples of BRD2 Bromodomain 2 Targeting Ligands wherein R is the point at which the Linker is attached.
  • R is the point at which the Linker is attached.
  • FIG.1E-1G present examples of BRD2 Bromodomain 2 Targeting Ligands wherein R is the point at which the Linker is attached.
  • the crystal structure PDB 3oni Filippakopoulos P. et al. “Selective Inhibition of BET Bromodomains.” Nature 468: 1067-1073 (2010); the crystal structure PDB 4j1p; McLure K.G. et al.“RVX-208: an Inducer of ApoA-I in Humans is a BET Bromodomain Antagonist.”
  • Plos One 8 e83190-e83190 (2013); Baud M.G. et al.“Chemical biology.
  • FIG.1H presents examples of BRD4 Bromodomain 1 Targeting Ligands wherein R is the point at which the Linker is attached.
  • R is the point at which the Linker is attached.
  • FIG.1H presents examples of BRD4 Bromodomain 1 Targeting Ligands wherein R is the point at which the Linker is attached.
  • FIG. 1I-1J present examples of BRD4 Bromodomain 2 Targeting Ligands wherein R is the point at which the Linker is attached.
  • R is the point at which the Linker is attached.
  • FIG.1K presents examples of BRDT Targeting Ligands wherein R is the point at which the Linker is attached.
  • FIG. 1K presents examples of BRDT Targeting Ligands wherein R is the point at which the Linker is attached.
  • the crystal structure PDB 4flp and the crystal structure PDB 4kcx see, the crystal structure PDB 4flp and the crystal structure PDB 4kcx.
  • FIG.1L-1O present examples of BRD9 Targeting Ligands wherein R is the point at which the Linker is attached.
  • R is the point at which the Linker is attached.
  • the crystal structure PDB 4nqn the crystal structure PDB 4uit; the crystal structure PDB 4uiu; the crystal structure PDB 4uiv; the crystal structure PDB 4z6h; the crystal structure PDB 4z6i; the crystal structure PDB 5e9v; the crystal structure PDB 5eu1; the crystal structure PDB 5f1h; and, the crystal structure PDB 5fp2.
  • FIG. 1P-1V present examples of BET Bromodomain-Containing Protein Targeting Ligands wherein R is the point at which the Linker is attached.
  • FIG.1W-1X present examples of the BRD4 Bromodomains of PCAF and GCN5 receptors 1 Targeting Ligands wherein R is the point at which the Linker is attached.
  • R is the point at which the Linker is attached.
  • PDB crystal structure 5tpx Discovery of a PCAF Bromodomain Chemical Probe”
  • the PDB crystal structure 5mlj (“Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe”
  • Humphreys P. G. et al. J. Med. Chem.60: 695 (2017).
  • FIG.1Y-1RR present examples of BRD4 Bromodomain 1 Targeting Ligands wherein R or linker-TL is the point at which the Linker is attached.
  • R or linker-TL is the point at which the Linker is attached.
  • FIG.1Y-1RR present examples of BRD4 Bromodomain 1 Targeting Ligands wherein R or linker-TL is the point at which the Linker is attached.
  • FIG.1SS is a dendrogram of the human bromodomain family of proteins organized into eightsubfamilies, which are involved in epigenetic signaling and chromatin biology. Any of the proteins of the bromodomain family in FIG.1SS can be selected as a Target Protein according to the present invention.
  • the compounds in any of the Formulas described herein may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer; such as rotamer, as if each is specifically described unless specifically excluded by context.
  • the present invention includes Degronimers of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX, with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.
  • isotopes that can be incorporated into Degronimers of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 Cl, and 125 I respectively.
  • isotopically labelled compounds can be used in metabolic studies (with, for example 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In one non-limiting embodiment, deuterium is 90, 95 or 99% enriched at a desired location.
  • the substitution of a hydrogen atom for a deuterium atom can be provided in any Degronimer of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX,.
  • substitution of a hydrogen atom for a deuterium atom can independently occur in one or more groups selected from any of the R groups or variables described herein.
  • the alkyl residue may be deuterated (in non-limiting embodiments, CDH 2 , CD 2 H, CD 3, CH 2 CD 3 , CD 2 CD 3 , CHDCH 2 D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.).
  • the unsubstituted carbons may be deuterated when two substituents are combined to form a cycle.
  • the compound of the present invention may form a solvate with a solvent (including water). Therefore, in one non-limiting embodiment, the invention includes a solvated form of the compound.
  • solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a compound of the invention and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 -DMSO.
  • a solvate can be in a liquid or solid form.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group. In one non- limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6.
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • C 1 - C 6 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed.
  • C1-C4 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- dimethylbutane, and 2,3-dimethylbutane.
  • the alkyl group is optionally substituted.
  • the term“alkyl” also encompasses cycloalkyl or carbocyclic groups.
  • alkyl, alkoxy, haloalkyl, etc. can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context.
  • Alkenyl is a linear or branched aliphatic hydrocarbon groups having one or more carbon- carbon double bonds that may occur at a stable point along the chain.
  • the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkenyl radicals include, but are not limited to ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl.
  • the term“alkenyl” also embodies“cis” and“trans” alkenyl geometry, or alternatively,“E” and“Z” alkenyl geometry. In an alternative embodiment, the alkenyl group is optionally substituted.
  • Alkenyl also encompasses cycloalkyl or carbocyclic groups possessing at least one point of unsaturation.
  • Alkynyl is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain.
  • the specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • the alkynyl group is optionally substituted.
  • the term“Alkynyl” also encompasses cycloalkyl or carbocyclic groups possessing at least one triple bond.
  • Alkylene is a bivalent saturated hydrocarbon. Alkylenes, for example, can be a 1, 2, 3, 4, 5, 6, 7 to 8 carbon moiety, 1 to 6 carbon moiety, or an indicated number of carbon atoms, for example C 1 -C 2 alkylene, C 1 -C 3 alkylene, C 1 -C 4 alkylene, C 1 -C 5 alkylene, or C 1 -C 6 alkylene.
  • Alkenylene is a bivalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C 2 -C 4 alkenylene.
  • Alkynylene is a bivalent hydrocarbon having at least one carbon-carbon triple bond.
  • Alkynylenes for example, can be a 2 to 8 carbon moiety, 2 to 6 carbon moiety, or an indicated number of carbon atoms, for example C 2 -C 4 alkynylene.
  • Halo and “Halogen” refers to fluorine, chlorine, bromine or iodine.
  • Haloalkyl is a branched or straight-chain alkyl groupssubstituted with 1 or more halo atoms described above, up to the maximum allowable number of halogen atoms.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.“Perhaloalkyl” means an alkyl group having all hydrogen atoms replaced with halogen atoms.
  • Examples include but are not limited to, trifluoromethyl and pentafluoroethyl.
  • “Chain” indicates a linear chain to which all other chains, long or short or both, may be regarded as being pendant. Where two or more chains could equally be considered to be the main chain,“chain” refers to the one which leads to the simplest representation of the molecule.
  • Haloalkoxy indicates a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • Heterocycloalkyl is an alkyl group as defined herein substituted with a heterocyclo group as defined herein.
  • Arylalkyl is an alkyl group as defined herein substituted with an aryl group as defined herein.
  • Heteroarylalkyl is an alkyl group as defined herein substituted with a heteroaryl group as defined herein.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14 aryl”).
  • an aryl group has 6 ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1– naphthyl and 2–naphthyl).
  • an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl).“Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • the one or more fused carbocyclyl or heterocyclyl groups can be 4 to 7 or 5 to 7-membered saturated or partially unsaturated carbocyclyl or heterocyclyl groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4- methylenedioxyphenyl group.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described above.
  • the aryl group is an unsubstituted C6–14 aryl.
  • the aryl group is a substituted C 6–14 aryl.
  • An aryl group may be optionally substituted with one or more functional groups that include but are not limited to, halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo.
  • the term“heterocyclyl” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
  • Heterocyclic rings comprise monocyclic 3-8 membered rings, as well as 5-16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems).
  • Said“heterocyclyl” group may be optionally substituted, for example, with 1, 2, 3, 4 or more substituents that include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino.
  • substituents include but are not limited to, hydroxyl, Boc, halo, haloalkyl, cyano, alkyl, aralkyl, oxo, alkoxy, and amino.
  • saturated heterocyclo groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g.
  • pyrrolidinyl imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • partially saturated heterocyclyl radicals include but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.
  • Examples of partially saturated and saturated heterocyclo groups include but are not limited to, 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-
  • Heterocyclo groups also include radicals where heterocyclic radicals are fused/condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms.
  • unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms for example, indoline, isoindoline
  • unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms
  • heteroaryl denotes aryl ring systems that contain one or more heteroatoms selected from O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized.
  • Examples include but are not limited to, unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-l,2,4-triazolyl, IH-1 ,2,3-triazolyl, 2H-l,2,3-triazolyl]; unsaturated 5- to 6- membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3- furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atom
  • the term“optionally substituted” denotes the substitution of a group herein by a moiety including, but not limited to, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C12 cycloalkyl, C3- C 12 cycloalkenyl, C 1 –C 12 heterocycloalkyl, C 3 -C 12 heterocycloalkenyl, C 1 -C 10 alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, C 1 -C 10 alkylamino, C 1 –C 10 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfonamino, arylsulfonamino, C1-C10 alkylimino, arylimino, C1-C10 alkylsulfonimino, arylsulfonimino, hydroxyl, halo
  • any suitable group may be present on a“substituted” or “optionally substituted” position if indicated that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to, e.g., halogen (which can independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C2-C6 alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; thioalkyl including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl linkages; aminoalkyl groups including groups having more than one N atoms; aryl (e.g., phenyl, biphenyl, naphthyl, or the like, each
  • “optionally substituted” includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, -CHO, -COOH, -CONH 2 , alkyl including C 1 -C 6 alkyl, alkenyl including C 2 -C 6 alkenyl, alkynyl including C2-C6alkynyl, -C1-C6alkoxy, alkanoyl including C2-C6alkanoyl, C1-C6alkylester, (mono- and di-C1-C6alkylamino)C0-C2alkyl, haloalkyl including C1-C6haloalkyl, hydoxyC1-C6alkyl, ester, carbamate, urea, sulfonamide,-C 1 -C 6 alkyl(heterocyclo), C 1 -C 6 alkyl(hexa)-2-C2 alkyl, haloalkyl including C1-
  • “Aliphatic” refers to a saturated or unsaturated, straight, branched, or cyclic hydrocarbon. “Aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, and thus incorporates each of these definitions.
  • "aliphatic” is used to indicate those aliphatic groups having 1-20 carbon atoms. The aliphatic chain can be, for example, mono-unsaturated, di-unsaturated, tri-unsaturated, or polyunsaturated, or alkynyl.
  • Unsaturated aliphatic groups can be in a cis or trans configuration.
  • the aliphatic group contains from 1 to about 12 carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms.
  • the aliphatic group contains from 1 to about 8 carbon atoms.
  • the aliphatic group is C1- C2, C1-C3, C1-C4, C1-C5 or C1-C6.
  • the specified ranges as used herein indicate an aliphatic group having each member of the range described as an independent species.
  • C 1 - C6 aliphatic indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • C 1 -C 4 aliphatic as used herein indicates a straight or branched alkyl, alkenyl, or alkynyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • the aliphatic group is substituted with one or more functional groups that results in the formation of a stable moiety.
  • heteroaliphatic refers to an aliphatic moiety that contains at least one heteroatom in the chain, for example, an amine, carbonyl, carboxy, oxo, thio, phosphate, phosphonate, nitrogen, phosphorus, silicon, or boron atoms in place of a carbon atom.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • heteroaliphatic is used to indicate a heteroaliphatic group (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
  • the heteroaliphatic group is optionally substituted in a manner that results in the formation of a stable moiety.
  • Nonlimiting examples of heteroaliphatic moieties are polyethylene glycol, polyalkylene glycol, amide, polyamide, polylactide, polyglycolide, thioether, ether, alkyl-heterocycle-alkyl, -O-alkyl-O-alkyl, alkyl-O- haloalkyl, etc.
  • A“dosage form” means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like.
  • A“dosage form” can also include an implant, for example an optical implant.
  • an“effective amount” as used herein, means an amount which provides a therapeutic or prophylactic benefit.
  • endogenous refers to any material from or produced inside an organism, cell, tissue or system.
  • exogenous refers to any material introduced from or produced outside an organism, cell, tissue or system.
  • moduleating mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and/or compared with the level of a response in an otherwise identical but untreated subject.
  • the term encompasses perturbing and/or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, preferably, a human.
  • parenteral administration of an immunogenic composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.
  • s.c. subcutaneous
  • i.v. intravenous
  • i.m. intramuscular
  • intrasternal injection or infusion techniques.
  • the terms“peptide,”“polypeptide,” and“protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds.
  • a protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein's or peptide's sequence.
  • Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds.
  • Polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others.
  • the polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.
  • To“treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.
  • ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • “pharmaceutical compositions” are compositions comprising at least one active agent, and at least one other substance, such as a carrier.
  • “Pharmaceutical combinations” are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein.
  • “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, non-toxic, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion.
  • Lists of additional suitable salts may be found, e.g.,
  • carrier applied to pharmaceutical compositions/combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • A“pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition/combination that is generally safe, non-toxic and neither biologically nor otherwise inappropriate for administration to a host, typically a human. In one embodiment, an excipient is used that is acceptable for veterinary use.
  • A“patient” or“host” or“subject” is a human or non-human animal in need of treatment or prevention of any of the disorders as specifically described herein, for example that is modulated by a natural (wild-type) or modified (non-wild type) protein that can be degraded according to the present invention, resulting in a therapeutic effect.
  • the host is a human.
  • A“host” may alternatively refer to for example, a mammal, primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird and the like.
  • A“therapeutically effective amount” of a pharmaceutical composition/combination of this invention means an amount effective, when administered to a host, to provide a therapeutic benefit such as an amelioration of symptoms or reduction or diminution of the disease itself.
  • a Degronimer (compound) of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, or Formula X is provided:
  • T is hydrogen
  • T is hydrogen and R 1 is methyl.
  • alkyl is a small alkyl, in other nonlimiting embodiments alkyl contains a branch point (for example isopropyl).
  • Non-limiting examples of compounds described by Formula I include: ,
  • Non-limiting examples of Formula IV include:
  • the compound of Formula IV is selected from:
  • Non-limiting examples of Formula V include:
  • alkyl when used in the formula above in some embodiments it may independently refer to a C 1 -C 6 , C 1 -C 5, C 1 -C 4 , C 1 -C 3 or C 1 -C 2 moiety.
  • both R 1 and T are hydrogen or deuterium.
  • T is hydrogen
  • T is h dro en and R 1 is meth l.
  • a 1 is CR 18 R 18’ , C ⁇ O, C ⁇ S, C ⁇ CH 2 , SO 2 , S(O);
  • a 2 is CR 14 R 14’ , C ⁇ O, C ⁇ S, C ⁇ CH 2, SO 2 , S(O);
  • a 3 is CR 15 R 15’ , C ⁇ O, C ⁇ S, C ⁇ CH2, SO2, S(O);
  • X’’ is independently selected from NH, N(R 9 ), CH 2 , CH(R 11 ), C(R 11 ) 2 , C(R 16 )(R 16’ ), O, and S;
  • Z is independently selected from O, S, and CH2;
  • n 0, 1, or 2;
  • R 14 , R 14’ , R 15 , R 15’ , R 16 , R 16’ , R 18 , R 18’ , R 19 , R 19’ are independently selected from: hydrogen, deuterium, alkyl, hydroxyl, alkoxy, amine, -NHalkyl, -Nalkyl2;
  • R 18 and R 18’ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O; or R 14 and R 14’ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 15 and R 15’ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 16 and R 16’ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 19 and R 19’ form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 14’ and R 15’ form a 1 or 2 carbon bridged ring
  • R 14’ and R 19’ form a 1 or 2 carbon bridged ring
  • R 19’ and R 16’ form a 1 or 2 carbon bridged ring
  • X’ is independently selected from NH, N(R 9 ), CH 2 , CH(R 11 ), C(R 11 ) 2 , C(R 16 )(R 16’ ), O, and S;
  • Q 1 , Q 2 , Q 3 , and Q 4 are independently selected from CH, C(R 11 ), and N;
  • R 17 in each instance is independently selected from hydrogen, deuterium, alkyl, alkenyl, alkynl, fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, azide, amino, -NHalkyl, -N(alkyl) 2 , -NHSO2alkyl, -N(alkyl)SO2alkyl, -NHSO2aryl, -N(alkyl)SO2aryl, -NHSO2alkenyl, - N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, cyano, nitro, nitroso, -SH, -Salkyl, - S(O)alkyl, -S(O) 2 alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, hal
  • R 17 substituents together with the carbon atom(s) to which they are bound can form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 17 substituents together with the carbon atom(s) to which they are bound can form a 1 or 2 carbon bridged ring or a 3, 4, 5, or 6 membered fused ring.
  • the com ound of Formula VII is selected from (VIIaa),
  • R 30 is NH, S, or O.
  • R 41 and R 42 are independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 - C 4 alkynyl, C 3 -C 10 cycloalkyl, aryl, heteroaryl, aliphatic or heteroaliphatic;
  • R 43 is hydrogen, CF3, -C2H5, C1-C4alkyl, C1-C4alkenyl, C1-C4alkynyl, CH2R 45 ;
  • R 44 is C 1 -C 16 alkyl, C 1 -C 16 alkenyl, C 1 -C 16 alkynyl, C 3 -C 10 cycloalkyl, -(CH 2 ) 0 - 6 aryl, or - (CH 2 ) 0 - 6 heteroaryl;
  • R 45 is hydrogen, -OH, F, Cl, -CH3, -CF3, -CH2Cl, -CH2F, or CH2OH;
  • R 51 is hydrogen or C1-C10alkyl
  • R 52 is hydrogen or C 1 -C 10 alkyl
  • R 53 is hydrogen, C1-C10alkyl, or C1-C10cycloalkyl
  • R 54 is C1-C10alkyl, C1-C10cycloalkyl, heterocycloalkyl, cycloalkylalkyl,
  • heterocycloalkylalkyl aryl, arylalkyl, heteroaryl, or heteroarylalkyl
  • R 56 is methyl, ethyl, or cyclopropyl
  • a Degron of Formula NI, Formula NII, or Formula NV is used in the resent invention:
  • W 201 is CR 206 R 207 , C ⁇ O, C ⁇ S, C ⁇ CH 2, SO 2 , S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ;
  • W 202 is CR 208 R 209 , C ⁇ O, C ⁇ S, C ⁇ CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ;
  • X 200 is independently selected from NH, NR 203 , CH2, CHR 203 , C(R 203 )2, O, and S;
  • n 200 is 0, 1, 2, or 3;
  • n 0, 1, 2, or 3;
  • n 0, 1, or 2;
  • R 202 is alkyl or hydrogen
  • alkyl is C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , or methyl;
  • R 201 and R 202 are combined to form a 4, 5, 6, 7, 8, 9, or 10 membered heterocyclo or heteroaryl species, wherein the heterocyclo or heteroaryl species is substituted with R 212 at any desired position, wherein the heterocyclo or heteroaryl species is optionally further substituted with one or more substituents selected from R 205 ;
  • R 201 * is selected from:
  • R 203 is selected at each instance from: alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkene, and alkyne, and in addition to these can also be selected from aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl;
  • R 204 is selected at each instance from: alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, -NHalkyl, -N(alkyl) 2 , -NHSO 2 alkyl, -N(alkyl)SO 2 alkyl, -NHSO 2 aryl, - N(alkyl)SO 2 aryl, -NHSO 2 alkenyl, -N(alkyl)SO 2 alkenyl, -NHSO 2 alkynyl, -N(alkyl)SO 2 alkynyl, and haloalkyl; and in addition to these can also be selected from aliphatic, heteroaliphatic, aryl, heteroaryl and heteroalkyl;
  • R 204 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring;
  • R 205 and R 214 are selected at each instance from: hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, -NHalkyl, -N(alkyl) 2 , -NHSO 2 alkyl, -N(alkyl)SO 2 alkyl, -NHSO 2 aryl, -N(alkyl)SO 2 aryl, -NHSO 2 alkenyl, -N(alkyl)SO 2 alkenyl, -NHSO 2 alkynyl, -N(alkyl)SO2alkynyl, and haloalkyl; and in addition to these can also be selected from aliphatic, heteroaliphatic (including heteroalkyl), aryl, heteroaryl, heterocyclic;
  • R 205 is independently selected from C(O)R 204 , cyano, aryl, aryloxy, heterocyclo, heteroaryl, arylalkyl, alkoxy, hydroxyl, O-arylalkyl, or cycloalkyl;
  • R 205 can be optionally substituted, for example, with one or more substituents selected from alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, - NHalkyl, -N(alkyl)2, aryl, heterocyclo, heteroaryl, haloalkyl, and cycloalkyl;
  • R 206 , R 207 , R 208 , R 209 , R 210 , and R 211 are independently selected from hydrogen, alkyl, hydroxyl, alkoxy, amine, -NHalkyl, and -Nalkyl 2;
  • R 206 and R 207 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 208 and R 209 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 210 and R 211 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O; or R 206 and R 208 form a 1 or 2 carbon bridged ring;
  • R 206 and R 210 form a 1 or 2 carbon bridged ring
  • R 208 and R 210 form a 1 or 2 carbon bridged ring
  • R 214 and R 206 form a 3, 4, 5, or 6 carbon fused ring
  • R 214 and R 210 form a 3, 4, 5, or 6 carbon fused ring
  • R 214 and R 208 form a 1 or 2 carbon bridged ring
  • R 214 and R 204 form a 3, 4, 5, or 6 carbon fused ring wherein R 205 is on the carbon alpha to R 214 or a 1, 2, 3, or 4 carbon bridged ring wherein R 205 is not on the carbon alpha to R 214 ;
  • R 212 is the point at which the linker is attached
  • R 222 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO 2 , F, Cl, Br, I, CF 3 , NH 2 , NHalkyl, N(alkyl) 2 , NR 225 R 225 , NHR 225 , aliphatic, heteroaliphatic, and COR 204 ; and in addition to these can also be selected from aliphatic and heteroaliphatic;
  • R 225 is selected at each instance from: alkyl, -C(O)H, -C(O)OH.–C(O)alkyl, -C(O)Oalkyl, alkenyl, or alkynyl or alternatively can be aliphatic, heteroaliphatic, aryl, heteroaryl or heterocnch
  • W 401 is CR 401 R 402 , C ⁇ O, C ⁇ S, C ⁇ CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl) 2 , P(O)alkyl, P(O)OH, P(O)NH 2 ;
  • X 400 is independently selected from NH, NR 412 , CH 2 , CHR 412 , C(R 412 ) 2 , O, or S; n 200 is 0, 1, 2, or 3;
  • A is independently selected from C(R 11 ), and N wherein in certain embodiments the number of nitrogen atoms is 0, 1, 2, 3, or 4 per ring (as allowed by context) and is selected to produce a stable ring and a pharmaceutically acceptable Degronimer.
  • the ring can be, in non-limiting embodiments as allowed by context, a pyridine, diazine, triazine, pyrimidine, pyridazine, pyrazine, triazine or tetrazine.
  • Z 20 is NH, O, S, or NR 412 ;
  • R 410 when R 410 is bonded to a A that is carbon, then A is CR 410 , and when R 410 is bonded to a Z 20 or Z 402 that is nitrogen, then Z 20 or Z 402 is NR 410 , etc;
  • R 11 is independently selected at each instance from hydrogen, alkyl, alkenyl, alkynyl, fluorine, chlorine, bromine, iodine, hydroxyl, alkoxy, cyano, azide, amino, -NH(aliphatic or alkyl), -N(aliphatic or alkyl)2, -NHSO2(aliphatic or alkyl), -N(aliphatic or alkyl)SO2(aliphatic or alkyl), - NHSO 2( aryl or heteroaryl), -N(aliphatic including alkyl)SO 2 aryl, -NHSO 2 alkenyl, - N(alkyl)SO 2 alkenyl, -NHSO 2 alkynyl, -N(alkyl)SO 2 alkynyl, cyano, nitro, nitroso, -SH, -Salkyl, - S(O)alkyl, -S(O)2alkyl, -C(O)
  • R 401 , R 402 , R 403 , R 404 , R 407 , R 408 , and R 415 are independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, carbocyclic, aryl, heteroaryl, hydroxyl, halo, azide, CN-, alkoxy, amine, -NHalkyl, and -Nalkyl2, -NH(aliphatic), and -N(independently aliphatic)2, each of which may be optionally substituted as described in the Definition Section, if desired to achieve the target effect, results in a stable compound that makes chemical sense to the routineer, and the group is not redundant (i.e., as known in the art, alkyl substituted with alkyl is redundant; however for examples, alkoxy substituted with alkoxy is not redundant);
  • R 401 and R 402 together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered spiro-carbocycle, or a 4-, 5-, or 6-membered spiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 403 and R 404 together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered spiro-carbocycle, or a 4-, 5-, or 6-membered spiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O;
  • R 407 and R 408 together with the carbon to which they are attached form a 3-, 4-, 5-, or 6- membered spiro-carbocycle, or a 4-, 5-, or 6-membered spiro-heterocycle comprising 1 or 2 heteroatoms selected from N and O; or R 401 and R 403 form a 1 or 2 carbon bridged ring;
  • R 401 and R 407 form a 1 or 2 carbon bridged ring
  • R 403 and R 407 form a 1 or 2 carbon bridged ring
  • R 415 and R 401 form a 3, 4, 5, or 6 carbon fused ring
  • R 415 and R 407 form a 3, 4, 5, or 6 carbon fused ring
  • R 415 and R 403 form a 1 or 2 carbon bridged ring
  • R 141 and R 405 form a 3, 4, 5, or 6 carbon fused ring wherein R 405 is on the carbon alpha to R 415 or a 1, 2, 3, or 4 carbon bridged ring wherein R 405 is not on the carbon alpha to R 415 ;
  • R 405 is selected at each instance from: alkyl, alkene, alkyne, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, halogen, hydroxyl, alkoxy, azide, amino, -NH(alkyl or aliphatic), - N(independently alkyl or aliphatic)2, -NHSO2(aliphatic, including alkyl), -N(alkyl or aliphatic)SO 2( alkyl or aliphatic), -NHSO 2 aryl, -N(alkyl or aliphatic)SO 2 aryl, -NHSO 2 alkenyl, - N(alkyl or aliphatic)SO 2 alkenyl, -NHSO 2 alkynyl, -N(alkyl or aliphatic)SO 2 alkynyl, and halo(alkyl or aliphatic), each of which is provided to form a stable compound as known to those of skill in
  • R 405 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring;
  • R 410 is the point at which the linker is attached
  • R 411 is selected at each instance from: hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyl, heterocyclic, heteroalkyl, carbocyclic, heteroaliphatic, aliphatic, alkoxy, aryl, heteroaryl, alkylamino, alkylhydroxyl, -NHalkyl, -Nalkyl2, -NH(aliphatic), -N(independently aliphatic)2, amino, cyano, nitro, nitroso, sulfone, sulfoxide, thioalkyl, thiol and haloalkyl, each of which is optionally substituted as described in the Definition Section, if desired to achieve the target effect, results in a stable compound that makes chemical sense to the routineer;
  • R 412 is selected at each instance from: hydrogen, alkyl, aliphatic, heteroaliphatic, heterocyclic, heteroaryl, aryl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)(aliphatic, aryl, heteroaliphatic, aryl or heteroaryl), -C(O)O(aliphatic, aryl, heteroaliphatic, aryl or heteroaryl), alkene, and alkyne, each of which is optionally substituted as described in the Definition Section, if desired to achieve the target effect, results in a stable compound that makes chemical sense to the routineer;
  • R 413 and R 414 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy, amino, -NHalkyl, and -N(alkyl)2, each of which is optionally substituted as described in the Definition Section, if desired to achieve the target effect, results in a stable compound that makes chemical sense to the routineer; and
  • R 417 is selected from: ,
  • the R 410 can be placed on any available ring atom on either of the fused rings, except when excluded by context (such as where valency precludes), for example, as shown in the formulas:
  • the Degron covalently or non-covalently binds to an E3 ligase to afford degradation of the targeted protein.
  • the E3 ligase is cereblon.
  • the E3 ligase is VHL.
  • Non-limiting examples of Degrons for use in the present invention include the thalidomide analogues described in WO 2014180882, WO 2014147531, WO 2014068506, WO 2014018866, WO 2013130849, US 20130143922, WO 2012177678, US 20120283292, WO 2012135299, WO 2012079022, WO 2012079075, WO 2012068512, JP 2011012014, US 20100240651, WO 2010053732, WO 2009145899, JP 2009215195, JP 2009001528, WO 2008115516, WO 2008033567, WO 2008027542, WO 2007136640, and US 20070197791.
  • the Degron is selected from: thalidomide, lenalidomide, pomalidomide, CC-122, CC-223, CC-292 or analogues thereof. In one embodiment the Degron is thalidomide or an analogue thereof. In another embodiment the Degron is lenalidomide or an analogue thereof. In one embodiment the Degron is pomalidomide or an analogue thereof. In another embodiment the Degron is CC-122 or an analogue thereof. In one embodiment the Degron is CC-223 or an analogue thereof. In another embodiment the Degron is CC-292 or an analogue thereof. In one embodiment the Degron is thalidomide.
  • the Degron is lenalidomide. In one embodiment the Degron is pomalidomide. In another embodiment the Degron is CC-122. In one embodiment the Degron is CC-223. In another embodiment the Degron is CC- 292.
  • a Linker is included in the Degronimers of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, and Formula XXIX,.
  • Linker is a bond or a chemically stable group that attaches a Degron to a Targeting Ligand.
  • any of the Linkers described herein can be used in either direction, i.e., either the left end is linked to the Degron and the right end to the Target Linker, or the left end is linked to the Target Linker and the right end is linked to the Degron.
  • any desired linker can be used as long as the resulting compound has a stable shelf life for at least 2 months, 3 months, 6 months or 1 year as part of a pharmaceutically acceptable dosage form, and itself is pharmaceutically acceptable.
  • the Linker has a chain of 2 to 14, 15, 16, 17, 18 or 20 or more carbon atoms of which one or more carbons can be replaced by a heteroatom such as O, N, S, or P.
  • the chain has 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous atoms in the chain.
  • the chain may include 1 or more ethylene glycol units that can be contiguous, partially contiguous or non-contiguous (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units).
  • the chain has at least 1, 2, 3, 4, 5, 6, 7, or 8 contiguous chains which can have branches which can be independently alkyl, heteroalkyl, aryl, heteroaryl, alkenyl, or alkynyl, aliphatic, heteroaliphatic, cycloalkyl or heterocyclic substituents.
  • the linker can include or be comprised of one or more of ethylene glycol, propylene glycol, lactic acid and/or glycolic acid.
  • propylene glycol adds hydrophobicity, while propylene glycol adds hydrophilicity.
  • Lactic acid segments tend to have a longer half-life than glycolic acid segments.
  • Block and random lactic acid-co-glycolic acid moieties, as well as ethylene glycol and propylene glycol, are known in the art to be pharmaceutically acceptable and can be modified or arranged to obtain the desired half-life and hydrophilicity.
  • these units can be flanked or interspersed with other moieties, such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve the appropriate drug properties.
  • moieties such as aliphatic, including alkyl, heteroaliphatic, aryl, heteroaryl, heterocyclic, cycloalkyl, etc., as desired to achieve the appropriate drug properties.
  • the Linker is a moiety selected from Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, and Formula LVII:
  • X 1 and X 2 are independently selected from bond, NH, NR 25 , CH2, CHR 25 , C(R 25 )2, O, and S;
  • R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from bond, alkyl, -C(O)- -C(O)O-, - OC(O)-, -C(O)alkyl, -C(O)Oalkyl, -C(S)-, -SO2-, -S(O)-, -C(S)-, -C(O)NH-, -NHC(O)-, - N(alkyl)C(O)-, -C(O)N(alkyl)-, -O-, -S-, -NH-, -N(alkyl)-, -CH(-O-R 26 )-, -CH(-NHR 25 )-, -CH(- NH 2 )-, -CH(-NR 25
  • R 20 , R 21 , R 22 , R 23 , and R 24 can in addition to those above be independently selected from heteroarylalkyl, aryl, arylalkyl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, carbocycle, or -O-(CH2)1-12-O-, -NH-(CH2)1-12-NH-, -NH-(CH2)1- 12 -O-, or -O-(CH 2 ) 1-12 -NH-, -S-(CH 2 ) 1-12 -O-, -O-(CH 2 ) 1-12 -S-, -S-(CH 2 ) 1-12 -S-, -S-(CH 2 ) 1-12 -NH-, - NH-(CH2)1-12-S-, (and wherein the 1-12 can be independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, and wherein one or more of the CH2 or
  • Certain nonlimiting examples include -O-CH(CH 3 )-CH(CH 3 )CH-O-, -O-CH 2 -CH(CH 3 )CH-O-, -O- CH(CH 3 )-CH 2 CH-O-, etc.
  • R 20 , R 21 , R 22 , R 23 , and R 24 is optionally substituted with one or more substituents selected from R 101 or alternatively as described in Section 1. Definitions;
  • R 25 is selected at each instance from: alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkenyl, or alkynyl or alternatively can be aliphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic;
  • R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, and alkyne; or in addition to these can also be selected from aryl, heteroaryl, heterocyclic, aliphatic and heteroaliphatic;
  • R 4 is independently selected from hydrogen, deuterium, alkyl, aliphatic, hydroxyl, alkoxy, aliphaticoxy, amine, cyano, -NH(aliphatic including alkyl), -N(aliphatic, including alkyl) 2 , fluorine, chlorine, bromine, iodine, haloalkyl (including–CFH2, CHF2, and -CF3), alkenyl, alkynyl, aryl, heteroaryl, heterocyclo and carbocyclic; and
  • R 101 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl) 2 , aliphatic, and heteroaliphatic.
  • the Linker is a moiety selected from Formula LVIII, LIX, and LX: (LVIII),
  • each variable is as it is defined in Formula LI.
  • a carbocyclic ring is used in place of the heterocycle.
  • Formula LI, Formula LII, Formula LIII, Formula LIV, Formula LV, Formula LVI, or Formula LVII include:
  • X 1 is attached to the Targeting Ligand. In another embodiment X 2 is attached to the Targeting Ligand. ,
  • the Linker group is an optionally substituted (poly)ethylene glycol having at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, ethylene glycol units, or optionally substituted alkyl groups interspersed with optionally substituted, O, N, S, P or Si atoms.
  • the Linker is flanked, substituted, or interspersed with an aryl, phenyl, benzyl, alkyl, alkylene, or heterocycle group.
  • the Linker may be asymmetric or symmetrical.
  • the Linker is a substituted or unsubstituted polyethylene glycol group ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units.
  • the Linker group may be any suitable moiety as described herein.
  • the Linker is selected from:
  • n1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
  • R 61 is H, methyl, or ethyl.
  • the Linker is selected from:
  • n2, o1, p1, q1, and r1 are independently 1, 2, 3, 4, or 5;
  • R 61 is H, methyl, or ethyl.
  • the Linker is selected from: ,
  • n2, o1, p1, q2, and r1 are independently 1, 2, 3, 4, or 5.
  • the Linker is selected from:
  • R 71 is -O-, -NH, Nalkyl, heteroaliphatic, aliphatic or -NMe.
  • the Linker is selected from:
  • the Linker is selected from:
  • the Linker is selected from: , , , , and .
  • Linker can be a 4-24 carbon atom linear chains, wherein one or more the carbon atoms in the linear chain can be replaced or substituted with oxygen, nitrogen, amide, fluorinated carbon, etc., such as the following:
  • Linker can be a nonlinear chain, and can be, or include, aliphatic or aromatic or heteroaromatic cyclic moieties.
  • the Linker may include contiguous, partially contiguous or non- contiguous ethylene glycol unit groups ranging in size from about 1 to about 12 ethylene glycol units, between 1 and about 10 ethylene glycol units, about 2 about 6 ethylene glycol units, between about 2 and 5 ethylene glycol units, between about 2 and 4 ethylene glycol units, for example, 1, 2, 3, 4, 6, 6, 7, 8, 9, 10, 11 or 12 ethylene glycol units.
  • the Linker may have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 fluorine substituents.
  • the Linker is perfluorinated.
  • the Linker is a partially or fully fluorinated poly ether.
  • fluorinated Linkers include:
  • selectivity may be enhanced by varying Linker length where the ligand binds some of its targets in different binding pockets, e.g., deeper or shallower binding pockets than others. Therefore, the length can be adjusted as desired.
  • Targeted Proteins Degradation of cellular proteins is required for cell homeostasis and normal cell function, such as proliferation, differentiation and cell death.
  • a primary pathway for degradation of cellular proteins is through ubiquitin-dependent proteolysis. Protein ubiquitination is mediated by sequential reactions of ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3).
  • the bromodomain is currently the only protein domain known to bind specifically to acetylated lysine residues in histone tails.
  • Bromodomains which are approximately 110 amino acids long, are found in a large number of chromatin-associated proteins and have now been identified in approximately 70 human proteins, often adjacent to other protein motifs. Proteins that contain a bromodomain may contain additional bromodomains, as well as other functional motifs. For example, many HATs also contain a bromodomain. Interactions between bromodomains and modified histones are an important mechanism underlying chromatin structural changes and gene regulation. Bromodomain-containing proteins have been implicated in disease processes including cancer, inflammation and viral replication.
  • this invention targets for ubiquitination and degradation in vivo a bromodomain containing protein that mediates a disorder to be treated.
  • the selected bromodomain containing protein may modulate a disorder in a human via a mechanism of action such as modification of a biological pathway, pathogenic signaling, modulation of a signal cascade or cellular entry.
  • the bromodomain containing protein has histone acetyl transferase activity. In one embodiment, the bromodomain containing protein is BRD2, BRD3, BRD4, BRDT or ASH1L.
  • the bromodomain containing protein is a non-BET protein.
  • the non-BET protein is BRD7 or BRD9. III.
  • the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX can be used in an effective amount to treat a host with any of the disorders described herein, including a human, in need thereof, optionally in a pharmaceutically acceptable carrier.
  • the method comprises administering an effective amount of the active compound or its salt as described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant, i.e., a pharmaceutically acceptable composition, optionally in combination or alternation with another bioactive agent or combination of agents.
  • the reduction in the Target Protein level afforded by the Formula I, II, V or VII Degronimers of the present invention provides treatment of the implicated disease state or condition, which is modulated through the Target Protein by lowering the level of that protein in the cell, e.g., cell of a patient.
  • the term“disease state or condition” when used in connection with a Formula I, II, V or VII compound is meant to refer to any disease state or condition wherein protein dysregulation occurs that involves the selected Target Protein and where degradation of such protein in a patient may provide beneficial therapy or relief of symptoms to a patient in need thereof. In certain instances, the disease state or condition may be cured.
  • the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX are useful as therapeutic agents when administered in an effective amount to a host, including a human, to treat a tumor, cancer (solid, non-solid, diffuse, hematological, etc), abnormal cellular proliferation, immune disorder, inflammatory disorder, blood disorder, a myelo- or lymphoproliferative disorder such as B- or T- cell lymphomas, multiple myeloma, breast cancer, prostate cancer, AML, ALL, ACL
  • Nonlimiting examples of uses for cereblon binders are multiple myeloma, a hematological disorder such as myelodysplastic syndrome, cancer, tumor, abnormal cellular proliferation, breast cancer, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, HIV/AIDS, HBV, HCV, hepatitis, Crohn’s disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis, Behcet’s disease, tuberculosis, and myelofibrosis.
  • a hematological disorder such as myelodysplastic syndrome, cancer, tumor, abnormal cellular proliferation, breast cancer, prostate cancer, AML, ALL, ACL, lung cancer, pancreatic cancer, colon cancer, skin cancer, melanoma, HIV/AIDS, HBV, HCV, hepatitis, Crohn’s disease, sarcoidosis, graft-versus-host disease, r
  • myelo- or lymphoproliferative disorder such as B- or T-cell lymphomas, Waldenstrom’s macroglobulinemia, Wiskott-Aldrich syndrome, or a post-transplant lymphoproliferative disorder
  • an immune disorder including autoimmune disorders for example as Lupus, Addison disease, Celiac disease, dermatomyositis, Graves disease, thyroiditis, multiple sclerosis, pernicious anemia, arthritis, and in particular rheumatoid arthritis, or type I diabetes
  • a disease of cardiologic malfunction including hypercholesterolemia
  • infectious disease including viral and/or bacterial infection, as described generally herein
  • an inflammatory condition including asthma, chronic peptic ulcers, tuberculosis, rheumatoid arthritis, periodontitis and ulcerative colitis.
  • the present invention provides the administration of an effective amount of a compound to treat a patient, for example, a human, having an infectious disease, wherein the therapy targets a Target Protein of the infectious agent or host (Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XX, Formula XI, Formula XII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX),
  • the disease state or condition may be caused by a microbial agent or other exogenous agent such as a virus (as non-limiting examples, HIV, HBV, HCV, HSV, HPV, RSV, CMV, E
  • Coli Salmonella, Helicobacter pylori, meningitis, gonorrhea, Chlamydiaceae, Mycoplasmataceae, etc), fungus, protozoa, helminth, worms, prion, parasite, or other microbe.
  • the condition treated with a compound of the present invention is a disorder related to abnormal cellular proliferation.
  • Abnormal cellular proliferation notably hyperproliferation, can occur as a result of a wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction.
  • Psoriasis is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with significant hyperproliferation of the epidermis.
  • Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.
  • hyperproliferative cell disorders include blood vessel proliferation disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancers.
  • Blood vessel proliferative disorders include angiogenic and vasculogenic disorders. Proliferation of smooth muscle cells in the course of development of plaques in vascular tissue cause, for example, restenosis, retinopathies and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.
  • Fibrotic disorders are often due to the abnormal formation of an extracellular matrix.
  • fibrotic disorders include hepatic cirrhosis and mesangial proliferative cell disorders.
  • Hepatic cirrhosis is characterized by the increase in extracellular matrix constituents resulting in the formation of a hepatic scar.
  • Hepatic cirrhosis can cause diseases such as cirrhosis of the liver.
  • An increased extracellular matrix resulting in a hepatic scar can also be caused by viral infection such as hepatitis. Lipocytes appear to play a major role in hepatic cirrhosis.
  • Mesangial disorders are brought about by abnormal proliferation of mesangial cells.
  • Mesangial hyperproliferative cell disorders include various human renal diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic micro- angiopathy syndromes, transplant rejection, and glomerulopathies.
  • Rheumatoid arthritis is generally considered an autoimmune disease that is thought to be associated with activity of autoreactive T cells, and to be caused by autoantibodies produced against collagen and IgE.
  • Bechet CAD
  • ARDS acute respiratory distress syndrome
  • ischemic heart disease CAD
  • post- dialysis syndrome CAD
  • leukemia CAD
  • acquired immune deficiency syndrome CAD
  • vasculitis lipid histiocytosis
  • septic shock inflammation in general.
  • Cutaneous contact hypersensitivity and asthma are just two examples of immune responses that can be associated with significant morbidity.
  • Others include atopic dermatitis, eczema, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, ulceris, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.
  • immunologically mediated leukocyte infiltration In atopic dermatitis, and eczema in general, immunologically mediated leukocyte infiltration (particularly infiltration of mononuclear cells, lymphocytes, neutrophils, and eosinophils) into the skin importantly contributes to the pathogenesis of these diseases. Chronic eczema also is associated with significant hyperproliferation of the epidermis. Immunologically mediated leukocyte infiltration also occurs at sites other than the skin, such as in the airways in asthma and in the tear producing gland of the eye in keratoconjunctivitis sicca.
  • compounds of the present invention are used as topical agents in treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjogren's Syndrome, including keratoconjunctivitis sicca secondary to Sjogren's Syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcer, ulceris, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.
  • novel method may also be useful in reducing the infiltration of skin by malignant leukocytes in diseases such as mycosis fungoides.
  • These compounds can also be used to treat an aqueous-deficient dry eye state (such as immune mediated keratoconjunctivitis) in a patient suffering therefrom, by administering the compound topically to the eye.
  • Disease states which may be treated according to the present invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot-Marie-Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease 1 (PKD1) or 2 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay- Sachs disease, Turner syndrome.
  • autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility
  • Further disease states or conditions which may be treated by the disclosed compounds according to the present invention include Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig's disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's disease, Coronary heart disease, Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barré syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome, Vasculitis.
  • Alzheimer's disease Amyotrophic lateral
  • Still additional disease states or conditions which can be treated by the disclosed compounds according to the present invention include aceruloplasminemia, Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha 1- antitrypsin deficiency, alpha-1 proteinase inhibitor, emphysema, amyotrophic lateral sclerosis Alström syndrome, Alexander disease, Amelogenesis imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, Anemia Angiokeratoma Corporis
  • neoplasia or“cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
  • malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal and may cause the death of the patient unless adequately treated.
  • neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.
  • Exemplary cancers which may be treated by the present disclosed compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's s
  • Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast
  • the disclosed compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX can be used in an effective amount alone or in combination with another compound of the present invention or another bioactive agent to treat a host such as a human with a disorder as described herein.
  • the disclosed compounds described herein can be used in an effective amount alone or in combination with another compound of the present invention or another bioactive agent to treat a host such as a human with a disorder as described herein.
  • bioactive agent is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy.
  • the compound of the present invention and the bioactive agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or other pharmacokinetic parameter.
  • the compound of the present invention and the bioactive agent are administered to a host in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other.
  • the bioactive agent is an immune modulator, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor.
  • a checkpoint inhibitor including as non-limiting examples, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor.
  • VISTA V-domain Ig suppressor of T-cell activation
  • the immune modulator is an antibody, such as a monoclonal antibody.
  • PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb).
  • CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus).
  • LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics).
  • BMS-986016 Bristol-Myers Squibb
  • GSK2831781 GaxoSmithKline
  • IMP321 Primary BioMed
  • LAG525 Novartis
  • MGD013 Non-Genics
  • An example of a TIM-3 inhibitor is TSR- 022 (Tesaro).
  • one of the active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist.
  • Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
  • fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen- resistant tumors.
  • anti-estrogen compounds are provided in WO 2014/19176 assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO 2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US 2015/0005286, WO 2014/205136, and WO 2014/205138.
  • anti-estrogen compounds include: SERMS such as anordrin, ciprofene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestratnt; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate,
  • SERMS
  • an active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist.
  • an androgen such as testosterone
  • the prostate or testicular cancer is androgen-resistant.
  • anti-androgen compounds are provided in WO 2011/156518 and US Patent Nos. 8,455,534 and 8,299,112.
  • anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.
  • the bioactive agent is an ALK inhibitor.
  • ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113,.
  • the bioactive agent is an EGFR inhibitor.
  • EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib (ASP8273), soloartinib (EGF816), PF- 06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD- 019), transtinib, WZ-3146, WZ8040, CNX-2006, and
  • the bioactive agent is an HER-2 inhibitor.
  • HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.
  • the bioactive agent is a CD20 inhibitor.
  • CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab.
  • the bioactive agent is a JAK3 inhibitor.
  • JAK3 inhibitors include tasocitinib.
  • the bioactive agent is a BCL-2 inhibitor.
  • BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en- 1-yl]methyl]piperazin-l-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(lH- pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4- [[(2R)-4-(dimethylamino)-1- phenylsulfanylbutan-2-yl] amino]-3- nitrophenyl]sulfonylbenzamide) (navianeth
  • the bioactive agent is a kinase inhibitor.
  • the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
  • PI3K phosphoinositide 3-kinase
  • BTK Bruton’s tyrosine kinase
  • Syk spleen tyrosine kinase
  • PI3 kinase inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib , Palomid 529, ZSTK474, PWT33597, CUDC- 907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2-(2-Isopropyl- 5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2- methylpropanamide), MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or Methyl(oxo) ⁇ [(2R)-l-phenoxy-2-butanyl]oxy ⁇ phosphon
  • BTK inhibitors examples include ibrutinib (also known as PCI-32765)(ImbruvicaTM)(1- [(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en- 1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N-(3-((5- fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011/0117073, incorporated herein in its entirety), Dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2- methylpyrimi
  • Syk inhibitors include, for example, Cerdulatinib (4-(cyclopropylamino)-2-((4-(4- (ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H- indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-( ⁇ 5- Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl ⁇ amino)-2,2-dimethyl-3-oxo-2,3- dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trime
  • the bioactive agent is a MEK inhibitor.
  • MEK inhibitors are well known, and include, for example, trametinib/GSKl120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H- yl ⁇ phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)- 3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC 1935369 ((S)-N-(2,3- dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide),
  • the bioactive agent is a Raf inhibitor.
  • Raf inhibitors include, for example, Vemurafinib (N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3- yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3- (trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide;4- methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4- dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-methyl-3-(1-methyl-6- (pyri)-2-(
  • the bioactive agent is an AKT inhibitor, including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, a FLT-3 inhibitor, including but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW- 2449, or a combination thereof.
  • AKT inhibitor including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine
  • a FLT-3 inhibitor including but not limited to, P406, Dovitinib, Quizartinib (
  • the bioactive agent is an mTOR inhibitor.
  • mTOR inhibitors include but are not limited to rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus.
  • MEK inhibitors include but are not limited to tametinib/GSKl120212 (N-(3- ⁇ 3-Cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H- yl ⁇ phenyl)acetamide), selumetinob (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)- 3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC1935369 ((S)-N-(2,3- dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518/GDC-0973 (l- ( ⁇
  • AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)- 1,5-dimethyl-6-oxo-l,6-dihydropyridine-3-carboxamide).
  • the bioactive agent is a RAS inhibitor.
  • RAS inhibitors include but are not limited to Reolysin and siG12D LODER.
  • the bioactive agent is a HSP inhibitor.
  • HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol.
  • Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK- 0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a focal adhesion kinase inhibitor, a Map kinase kinase (mek) inhibitor, a
  • the bioactive agent is selected from, but are not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DM1, Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoi
  • the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent.
  • Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds.
  • General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosul
  • chemotherapeutic agents include but are not limited to 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU)
  • Additional therapeutic agents that can be administered in combination with a degronimer disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzom
  • the disclosed compound is administered in combination with an anti-infective agent, for example but not limited to an anti-HIV agent, anti-HCV agent, anti- HBV agent, or other anti-viral or anti-bacterial agent.
  • an anti-infective agent for example but not limited to an anti-HIV agent, anti-HCV agent, anti- HBV agent, or other anti-viral or anti-bacterial agent.
  • the anti-HIV agent can be, but is not limited to, for example, a nucleoside reverse transcriptase inhibitor (NRTI), other non-nucloeoside reverse transcriptase inhibitor, protease inhibitor, fusion inhibitor, among others.
  • NRTI nucleoside reverse transcriptase inhibitor
  • Nucleoside/Nucleotide Reverse Transcriptase Inhibitors include, but are not limited to, Abacavir or ABC (Ziagen), Didanosine or ddl (Videx), Emtricitabine or FTC (Emtriva), Lamivudine or 3TC (Epivir), ddC (zalcitabine), Stavudine or d4T (Zerit), Tenofovircor TDF (Viread), D-D4FC (Reverset), and Zidovudine or AZT or ZDV (Retrovir).
  • NRTIs Non-nucleoside Reverse Transcriptase Inhibitors
  • Deavirdine Resscriptor
  • Efavirenz Sustiva
  • Etravirine Intelence
  • Nevirapine Nevirapine
  • Rilpivirine Rilpivirine
  • Anti-HIV Protease Inhibitors include, but are not limited to, Atazanavir or ATV (Reyataz), Darunavir or DRV (Prezista), Fosamprenavir or FPV (Lexiva), Indinavir or IDV (Crixivan), Lopinavir + ritonavir, or LPV/r (Kaletra), Nelfinavir or NFV (Viracept), Ritonavir or RTV (Norvir), Saquinavir or SQV (Invirase), Tipranavir, or TPV (Aptivus), Cobicistat (Tybost), Atazanavir + cobicistat, or ATV/COBI (Evotaz), Darunavir + cobicistat, or DRV/COBI (Prezcobix).
  • Anti-HIV Fusion Inhibitors include, but are not limited to, Enfuvirtide or ENF or T- 20 (Fuzeon). Anti-HIV also include, but are not limited to, Maraviroc or MVC (Selzentry). Anti- HIV Integrase Inhibitors include, but are not limited to Dolutegravir (Tivicay), Elvitegravir (Vitekta), Raltegravir (Isentress).
  • Anti-HIV combinations agents include Abacavir + Dolutegravir + lamivudine,or ABC/DTG/3TC (Triumeq), Abacavir +lamivudine or ABC/3TC (Epzicom), Abacavir + lamivudine + zidovudine, or ABC/3TC/ZDV (Trizivir), Efavirenz + emtricitabine + tenofovir or EFV/FTC/TDF (Atripla, Tribuss), elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide or EVG/COBI/FTC/TAF or ECF/TAF (Genvoya; (Stribild), emtricitabine + rilpivirine + tenofovir or FTC/RPV/TAF (Odefsey); Emtricitabine + rilpivirine + tenofovir or FTC/RPV/TDF (Compler
  • anti-HIV compounds include, but are not limited to Racivir, L-FddC, L-FD4C, SQVM (Saquinavir mesylate), IDV (Indinavir), SQV (Saquinavir), APV (Amprenavir), LPV (Lopinavir), fusion inhibitors such as T20, among others, fuseon and mixtures thereof, including anti-HIV compounds presently in clinical trials or in development.
  • NNRTIs may be selected from the group consisting of nevirapine (BI-R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781 (N-[4- chloro-3-(3-methyl-2-butenyloxy)phenyl]-2methyl3-furancarbothiamide), etravirine (TMC125), Trovirdine (Ly300046.HCl), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl 3′,3′-dichloro-4′,4′′-dimethoxy-5′,5′′- bis(methoxycarbonyl)-6,6-diphenylhexenoate),
  • the disclosed compound when used to treat an HCV infection can be administered in combination with another anti-HCV agent.
  • Anti-HCV agents are known in the art. To date, a number of fixed dose drug combinations have been approved for the treatment of HCV. Harvoni® (Gilead Sciences, Inc.) contains the NS5A inhibitor ledipasvir and the NS5B inhibitor sofosbuvir. TechnivieTM (AbbVie, Inc.) is a fixed-dose combination containing ombitasvir, an NS5A inhibitor; paritaprevir, an NS3/4A protease inhibitor; and ritonavir, a CYP3A inhibitor.
  • DaklinzaTM (daclatasvir, Bristol-Myers Squibb) is a HCV NS5A inhibitor indicated for use with sofosbuvir for the treatment of chronic genotype 3 infection.
  • ZepatierTM (Merck & Co.) has recently been approved for the treatment of chronic HCV genotypes 1 and 4.
  • ZepatierTM is a fixed-dose combination product containing elbasvir, an HCV NS5A inhibitor, and grazoprevir, an HCV NS3/4A protease inhibitor.
  • ZepatierTM is indicated with or without ribavirin.
  • Epclusa® (Gilead Sciences, Inc.) is a fixed-dose combination tablet containing sofosbuvir and velpatasvir.
  • Additional anti-HCV agents and combinations thereof include those described in U.S. Patent Nos: 9,382,218; 9,321,753; 9,249,176; 9,233,974; 9,221,833; 9,211,315; 9,194,873; 9,186,369; 9,180,193; 9,156,823; 9,138,442; 9,133,170; 9,108,999; 9,090,559; 9,079,887; 9,073,943; 9,073,942; 9,056,090; 9,051,340; 9,034,863; 9,029,413; 9,011,938; 8,987,302; 8,945,584; 8,940,718; 8,927,484; 8,921,341; 8,884,030; 8,841,278; 8,822,430; 8,772,022; 8,765,722; 8,742,101; 8,741,946; 8,674,085; 8,673,288; 8,669,234; 8,663,648; 8,61
  • the additional therapy is a monoclonal antibody (MAb).
  • MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs may“coat” the cancer cell surface, triggering its destruction by the immune system.
  • bevacizumab targets vascular endothelial growth factor(VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels.
  • VEGF vascular endothelial growth factor
  • cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2).
  • MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.
  • the bioactive agent is an immunosuppressive agent.
  • the immunosuppressive agent can be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
  • Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g.
  • Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15- deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody
  • compositions comprising an effective amount of the disclosed compound or pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier for any of the uses described herein.
  • the pharmaceutical composition may contain the disclosed compound or salt as the only active agent, or, in an alternative embodiment, the disclosed compound and at least one additional active agent.
  • Compounds disclosed herein may be administered by any suitable route desired by the healthcare provider, including orally, topically, systemically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular injection, intraveneous, intra- arterial, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • compositions of the disclosure will be administered in a therapeutically effective amount by the desired mode of administration.
  • Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease.
  • the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10, 25, 50 or 100 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 50 to 500, 75 to 500, or 200 mg to about 600 mg of the active compounds and optionally for example from about 0.1 mg to about 2000 mg, from about 10, 25, 50 or 100 mg to about 1000 mg, from about 50 to 500, 75 to 500,from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • Examples are dosage forms with at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, 750 or 800 mg of active compound, or its salt.
  • a dosage from about 0.1 to about 200 mg/kg, from about 0.01 mg/kg to about 250 mg/kg body weight, more preferably about 0.1 mg/kg to up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20 or 30 mg/kg, in at least one dose.
  • the dosage may be the amount of compound needed to provide a serum concentration of the active compound of up to about 10 nM, 50 nM, 100 nM, 200 nM, 300 nM, 400 nM, 500 nM, 600 nM, 700 nM, 800 nM, 900 nM, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M, 30 ⁇ M, or 40 ⁇ M.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution.
  • Some dosage forms, such as tablets and capsules are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • “Pharmaceutically acceptable carriers” for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).
  • sterile saline and phosphate-buffered saline at physiological pH can be used.
  • Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition.
  • sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid can be added as preservatives.
  • antioxidants and suspending agents can be used.
  • Carriers include excipients must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the disclosed compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound, as decribed in more detail herein.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils.
  • Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the disclosed compounds of the present invention.
  • a biological buffer can be any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range.
  • buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like.
  • the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.
  • compositions of the disclosure can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • oral including buccal and sub-lingual
  • rectal including nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • parenteral including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous administration or in a form suitable for administration by inhalation or insufflation.
  • the preferred manner of administration is intravenous or oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • permeation enhancer excipients including polymers such as: polycations (chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
  • polycations chitosan and its quaternary ammonium derivatives, poly-L- arginine, aminated gelatin
  • polyanions N-carboxymethyl chitosan, poly-acrylic acid
  • thiolated polymers carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan- thiobutylamidine, chitosan-thi
  • the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the active agent can be combined with any oral, non- toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well.
  • suitable inert carrier such as ethanol, glycerol, water, and the like
  • flavoring, coloring and/or sweetening agents can be added as well.
  • Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
  • Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as an continuous infusion system.
  • a formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
  • Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active disclosed compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.
  • microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue.
  • Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single/-multiple dose dry powder inhalers (DPI).
  • DPI dry powder inhalers
  • the devices most commonly used for respiratory delivery include nebulizers, metered-dose inhalers, and dry powder inhalers.
  • nebulizers include jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung.
  • Additional non-limiting examples of drug delivery devices and methods include, for example, US20090203709 titled“Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor” (Abbott Laboratories); US20050009910 titled“Delivery of an active drug to the posterior part of the eye via subconjunctival or periocular delivery of a prodrug”, US 20130071349 titled“Biodegradable polymers for lowering intraocular pressure”, US 8,481,069 titled“Tyrosine kinase microspheres”, US 8,465,778 titled“Method of making tyrosine kinase microspheres”, US 8,409,607 titled“Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods”, US 8,512,738 and US 2014/0031408 titled“Biodegradable intravitreal tyrosine kinase implants”, US 2014/0294986
  • the compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula X, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, or Formula XXIX can be used in an effective amount alone or in combination to treat a host such as a human with any of the disorders as described herein.
  • the second active compound is an immune modulator, including but not limited to a checkpoint inhibitor such as an anti-PD1, anti-CTLA, anti-LAG-3, anti-Tim, etc antibody, small molecule, peptide, nucleotide or other inhibitor (including but not limited to ipilimumab (Yervoy), Pembrolizumab (Keytruda) and nivolumab (Opdivo).
  • a checkpoint inhibitor such as an anti-PD1, anti-CTLA, anti-LAG-3, anti-Tim, etc antibody
  • small molecule peptide
  • nucleotide or other inhibitor including but not limited to ipilimumab (Yervoy), Pembrolizumab (Keytruda) and nivolumab (Opdivo).
  • one of the active compounds described herein is administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist.
  • SERM selective estrogen receptor modulator
  • SERD selective estrogen receptor degrader
  • Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen-like action during breast cancer progression which actually stimulates tumor growth.
  • fulvestrant a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors.
  • anti-estrogen compounds are provided in WO 2014/19176 assigned to Astra Zeneca, WO2013/090921, WO 2014/203129, WO 2014/203132, and US2013/0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US 2015/0005286, WO 2014/205136, and WO 2014/205138.
  • anti-estrogen compounds include: SERMS such as anordrin, ciprofene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestratnt; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate,
  • SERMS
  • one of the active compounds described herein is administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist.
  • an androgen (such as testosterone) inhibitor including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist.
  • the prostate or testicular cancer is androgen-resistant.
  • anti-androgen compounds are provided in WO 2011/156518 and US Patent Nos. 8,455,534 and 8,299,112.
  • anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.
  • a treatment regimen comprising the administration of a compound of the present invention in combination with at least one additional chemotherapeutic agent.
  • the combinations disclosed herein can be administered for beneficial, additive, or synergistic effect in the treatment of abnormal cellular proliferative disorders.
  • the treatment regimen includes the administration of a compound of the present invention in combination with at least one kinase inhibitor.
  • the at least one kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
  • PI3K phosphoinositide 3-kinase
  • BTK Bruton’s tyrosine kinase
  • Syk spleen tyrosine kinase
  • Additional anti-cancer agents include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY- 142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK- 0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bc1-2 inhibitor, an HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kinase
  • anti-HIV agent or“additional anti-HIV agent” includes, for example, nucleoside reverse transcriptase inhibitors (NRTI), other non-nucloeoside reverse transcriptase inhibitors (i.e., those which are not representative of the present invention), protease inhibitors, fusion inhibitors, among others, exemplary compounds of which may include, for example, 3TC (Lamivudine), AZT (Zidovudine), ( ⁇ )-FTC, ddl (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritona
  • NNRTI's i.e., other than the NNRTI's according to the present invention
  • NNRTI's may be selected from the group consisting of nevirapine (BI- R6-587), delavirdine (U-90152S/T), efavirenz (DMP-266), UC-781 (N-[4-chloro-3-(3-methyl-2- butenyloxy)phenyl]-2methyl3-furancarbothiamide), etravirine (TMC125), Trovirdine (Ly300046.HCl), HI-236, HI-240, HI-280, HI-281, rilpivirine (TMC-278), MSC-127, HBY 097, DMP266, Baicalin (TJN-151) ADAM-II (Methyl 3′,3′-dichloro-4′,4′′-dimethoxy-5′,5′′
  • a combination described herein can be further combined with an additional therapeutic to treat the cancer.
  • the second therapy can be an immunotherapy.
  • the compound of the present invention can be conjugated to an antibody, radioactive agent, or other targeting agent that directs the compound to the diseased or abnormally proliferating cell.
  • the combination is used in combination with another pharmaceutical or a biologic agent (for example an antibody) to increase the efficacy of treatment with a combined or a synergistic approach.
  • combination can be used with T-cell vaccination, which typically involves immunization with inactivated autoreactive T cells to eliminate a cancer cell population as described herein.
  • the combination is used in combination with a bispecific T-cell Engager (BiTE), which is an antibody designed to simultaneously bind to specific antigens on endogenous T cells and cancer cells as described herein, linking the two types of cells.
  • BiTE bispecific T-cell Engager
  • the additional therapy is a monoclonal antibody (MAb).
  • MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs“coat” the cancer cell surface, triggering its destruction by the immune system.
  • bevacizumab targets vascular endothelial growth factor(VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels.
  • VEGF vascular endothelial growth factor
  • cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2).
  • MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells.
  • MAbs are the immunoconjugates. These MAbs, which are sometimes called immunotoxins or antibody-drug conjugates, consist of an antibody attached to a cell-killing substance, such as a plant or bacterial toxin, a chemotherapy drug, or a radioactive molecule. The antibody latches onto its specific antigen on the surface of a cancer cell, and the cell-killing substance is taken up by the cell. FDA-approved conjugated MAbs that work this way include ado-trastuzumab emtansine, which targets the HER-2 molecule to deliver the drug DM1, which inhibits cell proliferation, to HER-2 expressing metastatic breast cancer cells.
  • FDA-approved conjugated MAbs that work this way include ado-trastuzumab emtansine, which targets the HER-2 molecule to deliver the drug DM1, which inhibits cell proliferation, to HER-2 expressing metastatic breast cancer cells.
  • Immunotherapies with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) are approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells.
  • a compound described herein can be combined with at least one immunosuppressive agent.
  • the immunosuppressive agent is preferably selected from the group consisting of a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g.
  • Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g.
  • Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx- 247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1
  • a compound described herein is administered to the subject prior to treatment with another chemotherapeutic agent, during treatment with another chemotherapeutic agent, after administration of another chemotherapeutic agent, or a combination thereof.
  • the compound of the present invention can be administered to the subject such that the other chemotherapeutic agent can be administered either at higher doses (increased chemotherapeutic dose intensity) or more frequently (increased chemotherapeutic dose density).
  • Dose-dense chemotherapy is a chemotherapy treatment plan in which drugs are given with less time between treatments than in a standard chemotherapy treatment plan.
  • Chemotherapy dose intensity represents unit dose of chemotherapy administered per unit time. Dose intensity can be increased or decreased through altering dose administered, time interval of administration, or both.
  • pharmaceutically acceptable salt is used throughout the specification to describe, where applicable, a salt form of one or more of the compounds described herein which are presented to increase the solubility of the compound in the gastic juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of the phosphates according to the present invention.
  • Enzymatic resolutions a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme
  • Enzymatic asymmetric synthesis a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer
  • Chemical asymmetric synthesis a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries
  • Diastereomer separations a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or
  • Kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions;
  • Enantiospecific synthesis from non-racemic precursors a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis;
  • Chiral liquid chromatography a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including via chiral HPLC).
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;
  • Chiral gas chromatography a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;
  • Extraction with chiral solvents a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent;
  • Transport across chiral membranes a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non- racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.
  • a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non- racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.
  • Simulated moving bed chromatography is used in one embodiment.
  • a wide variety of chiral stationary phases are commercially available.
  • compounds for use in the present invention can be prepared by chemically combining a Degron and a Linker followed by subsequent addition of a Targeting Ligand.
  • compounds for use in the present invention are prepared by chemically combing a Targeting Ligand and Linker first, followed by subsequent addition of a Degron.
  • compounds for use in the present invention can readily be synthesized by one skilled in the art in a variety of methods and chemical reactions.
  • Step 1 a nucleophilic Degron displaces a leaving group on the Linker to make a Degron Linker fragment.
  • Step 2 the protecting group is removed by methods known in the art to free a nucleophilic site on the Linker.
  • Step 3 the nucleophilic Degron Linker fragment displaces a leaving group on the Targeting Ligand to form a compound for use in the present invention.
  • Step 1 and/or Step 2 is accomplished by a coupling reaction instead of a nucleophilic attack.
  • Step 1 a nucleophilic Targeting Ligand displaces a leaving group on the Linker to make a Targeting Ligand Linker fragment.
  • Step 2 the protecting group is removed by methods known in the art to free a nucleophilic site on the Linker.
  • Step 3 the nucleophilic Targeting Ligand Linker fragment displaces a leaving group on the Degron to form a compound for use in the present invention.
  • Step 1 and/or Step 2 is accomplished by a coupling reaction instead of a nucleophilic attack.
  • R is the point of attachment to the linker.
  • a solution of 3-nitrophthalic anhydride (1 equiv.) in acetone is subjected to catalytic reduction under hydrogen (60 psi) in the presence of Raney nickel and anhydrous magnesium sulfate. After 2-3 hours, the solution is warmed to 50 °C, treated with Norite, filtered, and concentrated in vacuo at room temperature. The residue is treated with ethyl acetate, chilled and collected to give 3-aminophthalic anhydride.15 N sulfuric acid is cooled to 0 °C, 3-aminophthalic anhydride (1 equiv.) is added gradually with good stirring. After one hour, a solution of sodium nitrite (1 equiv.) in water is added slowly while maintaining the temperature below 5 °C.
  • 1-(3-Hydroxy-1H-pyrazol-1-yl)ethanone (1 equiv.) is dissolved in DMF. NaH (1.5 equiv.) is added slowly and stirred at rt for 30 min. 4-Fluorothalidomide (1 equiv.) is added and the solution is stirred at rt or 90 °C until the consumption of the starting materials. The reaction is quenched with methanol and extracted with EtOAc. The organic layer is washed with brine, dried (Na 2 SO 4 ), and concentrated.
  • tert-butyl 3-(4-((1-acetyl-1H-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6- dioxopiperidine-1-carboxylate (1 equiv.) is dissolved in a mixture of MeOH/THF (2:3). 10% NaOH is added, and the solution is stirred at rt for 5 h. Then all the volatiles are removed in vacuo. The residue is diluted with EtOAc and water. The aqueous phase was extracted with EtOAc. The combined organic layers are washed with water and brine and dried (Na2SO4).
  • tert-butyl 3-(4-((1H-pyrazol-3-yl)oxy)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidine-1- carboxylate (1 equiv.) is dissolved in DMF and K2CO3 (2 equiv.) is added, followed by alkyl halide (1.2 equiv.). The mixture is stirred at rt overnight. The reaction is poured into water and extracted with EtOAc. The organic layer is washed with water and brine, dried (Na 2 SO 4 ), and concentrated.
  • N-pyridyl-Boc-lenalidomide (1 equiv.) in TFA/DCM (1:1) is stirred at rt overnight. Solvent is evaporated and the residue is purified by column chromatography on silica gel to give N-pyridyl-lenalidomide.
  • General procedure to re are O-ar l lenalidomide:
  • Oxidation of ruthenium dioxide to ruthenium tetraoxide is carried out with aqueous sodium hypochlorite (household bleach, 5.25 % concentration).
  • aqueous sodium hypochlorite household bleach, 5.25 % concentration.
  • carbon tetrachloride RuO .
  • the product in ether solution is again taken to complete dryness and dissolved in acetone.
  • the acetone solution is concentrated and water is added to retain any remaining undesired salts.
  • the 4-methyl-3- nitrophthalic acid product is allowed to precipitate from the acetone-water solution.
  • 5-methylpomalidomide (1 equiv.) is dissolved in DMF and K2CO3 (2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture is stirred at rt until the consumption of the starting material. The mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography to give N-linked 5-methylpomalidomide derivatives.
  • 5-methyl-4-hydroxythalidomide (1 equiv.) is dissolved in DMF and K 2 CO 3 (2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture is stirred at rt until the consumption of the starting material. The mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried (Na 2 SO 4 ), and concentrated. The residue is purified by column chromatography to give O-linked 5-methylthalidomide derivatives. 6-Methylthalidomide derivatives:
  • 1,4-Dioxane is added to a mixture of Pd(OAc)2 (10 mol%), 2-fluoro-4-methylbenzoic acid (1 equiv.), Ag2CO3 (2 equiv.) and NaOAc (2 equiv.) in a Schlenk tube containing a Hi-Vac valve.
  • the Schlenk tube is degassed under high vacuum and filled with carbon monoxide at room temperature.
  • the reaction mixture is heated at 130 °C with vigorous stirring. After 18-48 h, the reaction is cooled to room temperature, acidified with 2 N HCl and thoroughly extracted with ethyl acetate.
  • 1,4-Dioxane is added to a mixture of Pd(OAc)2 (10 mol%), 2-fluoro-5-methylbenzoic acid (1 equiv.), Ag 2 CO 3 (2 equiv.) and NaOAc (2 equiv.) in a Schlenk tube containing a Hi-Vac valve.
  • the Schlenk tube is degassed under high vacuum and filled with carbon monoxide at room temperature.
  • the reaction mixture is heated at 130 °C with vigorous stirring. After 18-48 h, the reaction is cooled to room temperature, acidified with 2 N HCl and thoroughly extracted with ethyl acetate.
  • An oven-dried vial is equipped with Ru(phen)3Cl2 (1–2 mol%), dry K2HPO4 (3 equiv.), 1- fluoro-2,3-dimethylbenzene (1 equiv.) and MeCN (0.125 M), and degassed by alternating vacuum evacuation and argon backfill at -78 °C.
  • the triflyl chloride (1–4 equiv.) is then added and the solution is stirred at room temperature adjacent to a 26-W compact fluorescent light bulb.
  • reaction mixture is purified by column chromatography on silica gel to furnish 2-fluoro-3,4- dimethyl-1-(trifluoromethyl)benzene and 1-fluoro-2,3-dimethyl-4-(trifluoromethyl)benzene. The former one is taken to proceed to the next steps. (Nature 2011, 480, 224) 3-Fluoro-4-trifluorometh l hthalic acid
  • 1,2-Dimethyl-3-nitro-5-(trifluoromethyl)benzene (1 equiv.) is dissolved in acetic acid glacial (0.045 M).
  • sulfuric acid about 96% is added (1/5 volume of AcOH) and the mixture is cooled to approximately 15 °C in an ice bath, under stirring.
  • Chromium(VI) trioxide (4.6 equiv.) is added stepwise within approximately 30 min.
  • the ice bath is removed and the mixture is allowed to warm to approximately room temperature and then is heated to about 35 °C for about 20 h. Further, the mixture is diluted approximately 1.5 fold with water and methanol is added cautiously in order to destroy the excess CrO3.
  • An oven-dried vial is equipped with Ru(phen)3Cl2 (1–2 mol%), dry K2HPO4 (3 equiv.), 1- fluoro-2,3-dimethylbenzene (1 equiv.) and MeCN (0.125 M), and degassed by alternating vacuum evacuation and argon backfill at -78 °C.
  • the triflyl chloride (1–4 equiv.) is then added and the solution is stirred at room temperature adjacent to a 26-W compact fluorescent light bulb.
  • ⁇ -D N-Boc-pomalidomide (1 equiv.) is dissolved in DMF and K2CO3 (2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture is stirred at rt until the consumption of the starting material. The mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography to give ⁇ -D N-Boc-pomalidomide derivatives.
  • ⁇ -D N-Boc-4-hydroxythalidomide (1 equiv.) is dissolved in DMF and K2CO3 (2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture is stirred at rt until the consumption of the starting material. The mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography to give ⁇ -D N-Boc-4-hydroxythalidomide derivatives.
  • ⁇ -F N-Boc-pomalidomide (known compound reported in BMCL, 2003, 13, 3415) (1 equiv.) is dissolved in DMF and K2CO3 (2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture is stirred at rt until the consumption of the starting material. The mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography to give ⁇ -F N-Boc-pomalidomide derivatives.
  • ⁇ -F N-Boc-4-hydroxythalidomide (1 equiv.) is dissolved in DMF and K2CO3 (2 equiv.) is added, followed by alkyl halides (1.2 equiv.). The mixture is stirred at rt until the consumption of the starting material. The mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried (Na 2 SO 4 ), and concentrated. The residue is purified by column chromatography to give ⁇ -F N-Boc-4-hydroxythalidomide derivatives.
  • N-Boc 4-fluorothalidomide (1 equiv.) in DMF is added sodium hydride (2 equiv.) slowly at 0 °C.
  • the mixture is stirred at 0 °C for 30 min and methyl iodide (1.1 equiv.) is added dropwise.
  • the mixture is stirred at rt until the consumption of the starting material and then quenched with methanol.
  • the mixture is diluted with saturated NaHCO 3 , extracted with EtOAc, dried (Na 2 SO 4 ), and concentrated. The residue is purified by column chromatography on silica gel to obtain N-Boc 4-fluoro- ⁇ -methylthalidomide.
  • N-Boc 4-fluoro- ⁇ -methylthalidomide (1 equiv.), alkyl amine (1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90 °C for 12 h.
  • the mixture is cooled to room temperature, poured into water and extracted with ethyl acetate.
  • the combined organic phases are washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude residue is purified by column chromatography on silica gel to provide N-Boc ⁇ - methylpomalidomide derivatives. (ref: Chem Biol.2015 Jun 18;22(6):755-63.)
  • N-Boc ⁇ -methylpomalidomide derivatives (1 equiv.) in TFA/DCM (1:1) is stirred at rt overnight. Solvent is evaporated and the residue is purified by column chromatography on silica gel to give N-linked ⁇ -methylpomalidomide derivatives. 5’-Hydroxyl, alkoxy, amino, sulfonamide substituted glutarimide
  • 5'-Hydroxy pomalidomide derivatives (1 equiv.) is dissolved in anhydrous 1,4-dioxane under nitrogen.1.4 M n-butyllithium hexane solution (5 equiv.) diluted with 1,4-dioxane is added, and stirred for 10 minutes at room temperature. A solution of p-toluene sulfonyl chloride in 1,4- dioxane is added and stirred for 1 hour. After reaction completion, it is quenched with aqueous ammonia chloride, and extracted with EtOAc.
  • N-(3-(3-Amino-3-cyanopropyl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (1 equiv.) is dissolve in 12 M HCl (excess) and stirred for 48 hours at 100 °C in a closed vial. Solvent is then removed in vacuo to provide 2-amino-4-(3-aminooxetan-3-yl)butanoic acid. (Angew. Chem. Int. Ed.2014, 53, 557) 7-amino-2-oxa-5-azaspiro 3.5 nonan-6-one
  • a mixture of ethyl 2-nitroacetate (2 equiv.), potassium carbonate (1 equiv.) and 18-crown- 6 (0.5 equiv.) in toluene is heated to 90 °C and phenyl vinylsulfonate (1 equiv.) in toluene is added dropwise over one hour.
  • the mixture is heated for 16 hours, cooled to ambient temperature and diluted with ethyl acetate.
  • the mixture is washed with saturated brine.
  • the organic layer is separated and the aqueous layer is extracted with ethyl acetate.
  • the combined organic layers are dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • 6’-Sulfonyl pomalidomide derivatives A mixture of alkyl amine (1 equiv.), 4-fluoro-6’-sulfonyl-thalidomide (1 equiv.) and DIEA (2 equiv.) in dry DMF is stirred at 90 °C for 12 h. The mixture is cooled to room temperature, poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue is purified by column chromatography on silica gel to give 6’-sulfonyl pomalidomide derivatives. (Chem Biol.2015, 22, 755-763) 2’-Sulfonyl glutarimide

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Abstract

La présente invention concerne un dégronimère qui possède une fraction ciblant l'ubiquitine Ligase E3 (Degron) qui peut être liée à un Ligand de ciblage pour une protéine de bromodomaine sélectionnée pour une dégradation in vivo en vue d'obtenir un effet thérapeutique, et des méthodes d'utilisation, des compositions de ceux-ci ainsi que des procédés pour leur préparation.
PCT/US2017/032053 2016-05-10 2017-05-10 Dégronimères ciblant un bromodomaine pour la dégradation de protéines cibles WO2017197056A1 (fr)

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