EP4164690A1 - Inhibiteurs de ve-ptp à petites molécules - Google Patents

Inhibiteurs de ve-ptp à petites molécules

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Publication number
EP4164690A1
EP4164690A1 EP21825008.2A EP21825008A EP4164690A1 EP 4164690 A1 EP4164690 A1 EP 4164690A1 EP 21825008 A EP21825008 A EP 21825008A EP 4164690 A1 EP4164690 A1 EP 4164690A1
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European Patent Office
Prior art keywords
substituted
compound according
unsubstituted
previous
immediately previous
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German (de)
English (en)
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Michael RYCZKO
Amy Ripka
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Mannin Research Inc
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to compounds capable of inhibiting vascular endothelial protein tyrosine phosphatase (VE-PTP). These compounds are also capable of activating Tie2 receptor-mediated signaling. Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP.
  • the present disclosure also relates to pharmaceutically acceptable salts of said compounds, to pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof, and to the use of such compounds, pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions comprising the same in treating diseases and/or conditions mediated by VE- PTP signaling, such as those mediated by Angiopoietin/Tie2 signaling.
  • VE-PTP Vascular endothelial tyrosine phosphatase
  • ⁇ - ⁇ vascular endothelial tyrosine phosphatase beta
  • VE-PTP knockout mice have defective blood vessel remodeling (Dominguez, MG et al.
  • VE-PTP Vascular endothelial tyrosine phosphatase
  • Phosphotyrosine phosphatase R3 receptors Origin, evolution and structural diversification, PLoS ONE, 12(3), e0172887.; Matozaki, T et al. (2010 Dec) Expression, localization, and biological function of the R3 subtype of receptor-type protein tyrosine phosphatases in mammals, Cell Signal. 22(12):1811-7).
  • One of the substrates for VE-PTP is Tie2, an endothelial tyrosine kinase receptor that regulates angiogenesis and lymphangiogenesis and can support the integrity of endothelial junctions (Eklund, L et al.
  • VE-PTP Antibodies against the extracellular domain of VE-PTP dissociate the phosphatase from Tie2, leading to Tie2 phosphorylation and activated signaling (Winderlich, M et al. (2009 May) VE-PTP controls blood vessel development by balancing Tie-2 activity, J Cell Biol. 185(4):657-71). Pharmacological inhibition of VE-PTP activity also activates Tie2 and is capable of suppressing ocular neovascularization and VEGF-mediated vascular leakage (Goel, S et al. (2013 Aug) Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression.
  • the Angiopoietin-Tie2 signaling pathway is a major regulator of vascular development, vascular permeability, vessel remodeling, and post-natal angiogenesis, and altered expression of the Angiopoietin ligands or activity of the Tie2 receptor has been linked to a variety of lymphatic and blood vasculature pathologies including cancer, sepsis, diabetes, atherosclerosis, and ocular diseases (Eklund, L et al. (2017 Jan) Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems, Clin Sci.
  • Angiopoietin2 In blood vascular endothelium, Angiopoietin2 (Angpt2 or Ang2) is reported to function as a competitive antagonist of Angiopoietinl /Tie2 signaling, inhibiting Angiopoietin 1 (Angptl or Angl>mediated phosphorylation of Tie2 (Thurston, G et al. (2012 Sep) The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway, Cold Spring Harb Perspect Med. 2(9):a006550.; Saharinen, P et al. (2017 Sep) Therapeutic targeting of the angiopoietin-TIE pathway, Nat Rev Drug Discov.
  • Tie2 receptor activators include, for example, Angptl recombinant proteins, vascular endothelial protein tyrosine phosphatase (VE-PTP) inhibitors, and Tie2-peptidomimetics (Saharinen, P et al. (2017 Sep) Therapeutic targeting of the angiopoietin-TIE pathway, Nat Rev Drug Discov. 16(9):635-661.; Shen, J et al. (2014 Oct) Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature, J Clin Invest. 124(10):4564-76.; Souma, T et al.
  • angiopoietin 2 Context-dependent Junctions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP, Proc Natl Acad Sci U S A. pii: 1714446115).
  • Angiopoietin- 1 decreases endothelial cell permeability and increases vascular stabilization via recruitment of pericytes and smooth muscle cells to growing blood vessels, while Angiopoietin-2 mediates angiogenic sprouting and vascular regression (Eklund, L et al. (2017 Jan) Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems, Clin Sci.
  • angiopoietin 2 Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP, Proc Natl Acad Sci U S A. pii: 1714446115).
  • Angpt2 deficiency in knockout mice resulted in widespread lymphatic dysfunction due to abnormal remodeling of the developing lymphatic vessels, resulting in lymphedema (Dellinger, M et al. (2008 Jul) Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice, Dev Biol. 319(2):309-20.; Eklund, L et al.
  • Both Angptl/Angpt2 double knockout mice and Tie2 knockout mice have a defective Schlemm’s canal, leading to impaired drainage of aqueous humour, increased intraocular pressure (IOP) and glaucoma (Souma, T et al. (2016 Jul) Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity, J Clin Invest. 126(7):2575-87.; Thomson, BR et al. (2014 Oct) A lymphatic defect causes ocular hypertension and glaucoma in mice, J Clin Invest. 124(10):4320-4.; Thomson, BR et al.
  • VE-PTP inhibitors particularly some that could have improved physicochemical properties, and are potent Tie2 activators.
  • Such therapeutic agents can be useful in the treatment of cancer, glaucoma, occlusive cardiovascular disease, vascular leaking syndromes, and other vascular-related diseases (Parikh, SM (2017 Jul) The Angiopoietin-Tie2 Signaling Axis in Systemic Inflammation, J Am Soc Nephrol. 28(7): 1973- 1982.; Saharinen, P et al. (2017 Sep) Therapeutic targeting of the angiopoietin-TIE pathway, Nat Rev Drug Discov. 16(9):635-661.; Schmittnaegel, M et al. (2017 Dec) Reprogramming Tumor Blood Vessels for Enhancing Immunotherapy, Trends Cancer. 3(12):809-812).
  • the present disdosure relates to compounds and pharmaceutically acceptable salts thereof that are capable of inhibiting vascular endothelial protein tyrosine phosphatase (VE- PTP). These compounds are capable of activating the Tie-2 receptor.
  • VE- PTP vascular endothelial protein tyrosine phosphatase
  • the present disclosure also relates to pharmaceutical compositions comprising such compounds and/or pharmaceutically acceptable salts thereof.
  • the present disclosure also relates to the use of such compounds, pharmaceutically acceptable salts thereof, and/or pharmaceutical compositions in treating diseases and/or conditions mediated by VE-PTP activity, including those that are linked to Ang/Tie2-mediated signaling.
  • the present disclosure is directed to:
  • Ri is chosen from wherein
  • R 2 is chosen from substituted or unsubstituted heteroaiyl and substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more halogen atoms.
  • R 3 is chosen from substituted or unsubstituted heteroaiyl, substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 3 -C 6 cyclic alkyl; n is an integer chosen from 1, 2, 3, 4, 5, and 6;
  • R t is chosen from substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted Ci-C 6 branched alkyl, and substituted or unsubstituted C 3 -C 6 cyclic alkyl;
  • R is chosen from H, substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 3 -C 6 cyclic alkyl; and each of Xi, X2, and X3 is independently chosen from CH and N, with the proviso that Xi, X2, and X3 are not simultaneously CH.
  • R2 is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more halogen atoms.
  • R 2 is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more fluorine atoms.
  • R 3 is chosen from substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C3- Ce cyclic alkyl.
  • R 3 is chosen from substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 3 -C 6 cyclic alkyl.
  • R 3 is chosen from substituted or unsubstituted C 1 -C 6 linear alkyl and substituted or unsubstituted C 3 -C 6 cyclic alkyl.
  • n is an integer chosen from 1 , 2, and 3.
  • n is an integer chosen from 1 and 2.
  • Re is substituted or unsubstituted heteroaryl, mis an integer chosen from 1, 2, 3, 4, 5, and 6;
  • R 7 is chosen from substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 1 -C 6 cyclic alkyl;
  • Re is chosen from H, substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 1 -C 6 cyclic alkyl; and each of Rg and Rio is independently selected from H, substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 1 -C 6 cyclic alkyl.
  • Rn is chosen from substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, substituted or unsubstituted C 3 -C 6 cyclic alkyl, and substituted or unsubstituted heterocyclyl; a is an integer chosen from 0, 1, 2, 3, 4, 5, and 6;
  • R12 is chosen from substituted or unsubstituted heteroaiyl and substituted or unsubstituted aiyl.
  • a method for inhibiting VE-PTP in a mammalian subject in need thereof comprising administering to the subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 149, or a pharmaceutically acceptable salt thereof, whereby VE-PTP activity is inhibited.
  • a compound according to any one of embodiments 1 to 149, or a pharmaceutically acceptable salt thereof whereby VE-PTP activity is inhibited.
  • 151. The method of embodiment 150, wherein the subject suffers from one or more of cancer, ocular disorders, occlusive cardiovascular disease, a vascular leaking syndrome, or another vascular-related disease.
  • a method for reducing VE-PTP-mediated signaling in a mammalian subject in need thereof comprising administering to the mammalian subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 149, or a pharmaceutically acceptable salt thereof, whereby VEPTP-mediated signaling is reduced.
  • a method for increasing Tie2-mediated signaling in a mammalian subject in need thereof comprising administering to the mammalian subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 149, or a pharmaceutically acceptable salt thereof, whereby Tie2-mediated signaling is increased.
  • FIG. 1. depicts Western blot results of Human Umbilical Vein Endothelial Cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had an IC50 for VE-PTP in the activity range of 0.1 to 5 nM.
  • VEC Human Umbilical Vein Endothelial Cells
  • FIG. 2. depicts further Western blot results of Human Umbilical Vein Endothelial Cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had an IC50 for VE-PTP in the activity range of 0.1 to 5 nM.
  • VEC Human Umbilical Vein Endothelial Cells
  • FIG. 3. depicts still further Western blot results of Human Umbilical Vein Endothelial Cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had an IC50 for VE-PTP in the activity range of 0.1 to 5 nM.
  • HUVEC Human Umbilical Vein Endothelial Cells
  • FIG. 4. depicts yet further Western blot results of Human Umbilical Vein Endothelial Cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had an IC50 for VE-PTP in the activity range of 0.1 to 5 nM.
  • VEC Human Umbilical Vein Endothelial Cells
  • FIG. 5 depicts additional Western blot results of Human Umbilical Vein Endothelial Cells (HUVEC) treated with the indicated concentrations of compounds of the disclosure that had an IC50 for VE-PTP in the activity range of 0.1 to 5 nM.
  • HUVEC Human Umbilical Vein Endothelial Cells
  • FIG. 6. depicts results of dose response titration experiments with compounds of the disclosure having an IC50 for VE-PTP in the activity range of 0.1 to 5 nM over a range of 0.2 to 50 ⁇ and illustrates a clear dose response relationship.
  • Angiopoietin 1 is the cognate ligand for Tie2 receptor, used to activate the Tie2 signaling pathway.
  • numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions and results, and so forth, used to describe and claim certain embodiments of the presort disclosure are to be understood as being modified in some instances by the term “about.”
  • the term “about” is used to indicate that a value includes the standard deviation of the mean for tire device or method being employed to determine the value.
  • the numerical parameters set forth in the specification are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment.
  • the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the present disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • administering refers to the placement of a compound and/or a pharmaceutical composition comprising the compound into a mammalian tissue or a subject by a method or route that results in at least partial localization of the compound and/or composition at a desired site or tissue location.
  • Effectiveness can be established in vitro (biochemical and/or biological in cultured cells) and/or in vivo. Effectiveness in vitro may be used to extrapolate or predict some degree of effectiveness in vivo, in an animal or in a human subject. A reference or standard or comparison may be used.
  • the term “effective” at inhibiting or activating an enzyme (VE-PTP and/or Tie2, respectively), and/or signaling mediated by the enzyme in the context of this disclosure and claims means reducing/activating the activity of the enzyme and/or the activation and propagation of the signaling pathway in terms of activation of a downstream molecule or known biological effect by a detectable or measurable amount relative to the baseline activity.
  • the reduction or activation is measured in terms of percentage reduction or activation, relative to the activity in the absence of exposure to the compound of the disclosure, including, for example, at least 5%, at least 10%, 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or about 100%.
  • the activity might also fall within a range, e.g., about 5-10%, about 10-20%, and any other range interval between about 1% and 100%.
  • An amount is “effective” in vivo if it produces any benefit to the subject to which the compound is administered.
  • disease or “disorder” are used interchangeably herein and refer to any alteration in state of the body or of some of the organs, interrupting or disturbing the performance of the functions and/or causing symptoms such as discomfort, dysfunction, distress, or even death to the person afflicted or those in contact with a person.
  • a disease or disorder can also relate to a distemper, ailing, ailment, malady, sickness, illness, complaint, indisposition, or affection.
  • VE-PTP-mediated disorder or a “Tie-2 mediated disorder” is any disease or deleterious condition in which VE-PTP or Tie2 play a role. Non-limiting examples of such disorders are provided elsewhere in the disclosure.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Drug-approval agencies e.g., EMA, US-FDA
  • Examples are listed in Pharmacopeias.
  • phrases “pharmaceutically acceptable excipient” is employed herein to refer to a pharmaceutically acceptable material chosen from a solvent, dispersion media, diluent, dispersion, suspension aid, surface active agent, isotonic agent, thickening or emulsifying agent, preservative, polymer, peptide, protein, cell, hyaluronidase, and mixtures thereof.
  • the solvent is an aqueous solvent.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or can be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • subject is meant a mammal, including, but not limited to, a human or non- human mammal, such as a bovine, equine, canine, ovine, or feline.
  • Ranges provided herein are understood to be shorthand for all of the values within the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • the same rule applies for any other ranges described herein, even if the values within the range are not specifically called out in this disclosure.
  • alkyl refers to a saturated monovalent hydrocarbon radical comprising one to twelve carbon atoms (C 1 -C 12 ).
  • Alkyl groups may be linear, branched, or cyclic. Alkyl groups may be unsubstituted, or they may be substituted as described elsewhere herein.
  • an alkyl group comprises one to eight carbon atoms (Ci-Cg). In some embodiments, an alkyl group comprises one to six carbon atoms (C 1 -C 6 ). In some embodiments, an alkyl group comprises one to four carbon atoms (Ci-C*).
  • a cyclic alkyl group comprises three to six carbon atoms (C 1 -C 6 ).
  • substituted and unsubstituted linear, branched, or cyclic alkyl groups include methyl, ethyl, «-propyl, iso-propyl, cyclopropyl, «-butyl, sec-butyl, iso-butyl, ieri-butyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, chloromethyl, fluoromethyl, trifluoromethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4- dimethylaminobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, trifluoroethy
  • alkylene alkylene unit
  • alkylene group refers to a saturated divalent hydrocarbon radical comprising one to twelve carbon atoms (Ci-Cu).
  • Alkylene groups may be linear, branched, or cyclic. Alkylene groups may be unsubstituted, or they may be substituted as described elsewhere herein.
  • an alkylene group comprises one to eight carbon atoms (C 1 -C 6 ).
  • an alkylene group comprises one to six carbon atoms (C 1 -C 6 ).
  • an alkylene group comprises one to four carbon atoms (C1-C4).
  • Non-limiting examples of alkylene groups include methylene and ethylene.
  • alkenyl refers to a monovalent hydrocarbon radical comprising two to eight carbon atoms (C2- Cs) with at least one site of unsaturation (i.e., an sp 2 carbon-carbon double bond).
  • Alkenyl groups may be linear, branched, or cyclic. Alkenyl groups max' be unsubstituted, or they may be substituted as described elsewhere herein. In some embodiments, an alkenyl group comprises two to six carbon atoms (Cz-Ce). In some embodiments, an alkenyl group comprises two to four carbon atoms (C2-C4). Alkenyl groups max' have E or Z orientations. Non-limiting examples of alkenyl groups include ethenyl (also called vinyl), 1-propenyl, iso- propenyl, and 2-chloroethenyl.
  • alkenylene refers to a divalent hydrocarbon radical comprising two to eight carbon atoms (C2-C8) with at least one site of unsaturation (e.g., an sp 2 carbon-carbon double bond).
  • Alkenylene groups may be linear, branched, or cyclic. Alkenylene groups may be unsubstituted, or they may be substituted as described elsewhere herein.
  • an alkylene group comprises two to six carbon atoms (C2-Ce).
  • an alkylene group comprises two to four carbon atoms (C2-C4).
  • alkylene groups may have E ox Z orientations.
  • Non-limiting examples of alkenyl groups include ethenylene (also called vinylene).
  • alkynyl refers to a monovalent hydrocarbon radical comprising two to eight carbon atoms (C2- Cs) with at least one site of unsaturation ⁇ i.e., an sp carbon-carbon triple bond).
  • Alkynyl groups may be linear or branched. Alkynyl groups may be unsubstituted, or they may be substituted as described elsewhere herein.
  • an alkynyl group comprises two to six carbon atoms (Ca-Ce).
  • an alkynyl group comprises two to four carbon atoms (C2-C4) ⁇
  • Non-limiting examples of alkynyl groups include ethynyl.
  • alkynylene refers to a divalent hydrocarbon radical comprising two to eight carbon atoms (Ca-Cg) with at least one site of unsaturation (i.e., an sp carbon-carbon triple bond).
  • Alkynylene groups may be linear or branched. Alkynylene groups may be unsubstituted, or they may be substituted as described elsewhere herein.
  • an alkynylene group comprises two to six carbon atoms (C2-C6).
  • an alkynylene group comprises two to four carbon atoms (C 2 -C 4 ).
  • Non-limiting examples of alkynylene groups incl ude ethynylene.
  • aryl refers to a monovalent aromatic hydrocarbon radical comprising 6-20 carbon atoms (C6-C20) that is derived by removing a hydrogen atom from an aromatic ring.
  • Aryl groups can be unsubstituted, or they can substituted with one or more substituents as described elsewhere herein.
  • Non-limiting examples of unsubstituted and substituted aryl groups include phenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4- methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-dilorophenyl, 2,6-dichlorophenyl, 3,4- difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 2- cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3- dimethylaminophenyl, 4-dimethylaminophenyl, 3-methylsulfonylphenyl, 4- methylsulfonylphenyl
  • arylene refers to a divalent aromatic hydrocarbon radical comprising 6-20 carbon atoms (Ce- C20) that is derived by removing two hydrogen atoms from an aromatic ring.
  • Arylene groups can be unsubstituted, or they can be substituted with one or more substituents as described elsewhere herein.
  • Non-limiting examples of arylene groups include phenylene.
  • heterocycle refers to a saturated or partially unsaturated ring system comprising 3 to 20 atoms, wherein at least one of the ring atoms is a heteroatom chosen from nitrogen, oxygen, phosphorous, and sulfur.
  • a heterocyclic group may be unsubstituted or may be substituted with one or more substituents as described elsewhere herein.
  • a heterocyclic group comprises 3 to 10 atoms.
  • a heterocyclic group comprises 3 to 7 atoms.
  • a heterocyclic group is monocyclic.
  • a heterocyclic group is bicyclic.
  • a heterocyclic group comprises fused rings.
  • unsubstituted and substituted heterocyclic groups include pyrrolidinyl, JV-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3- methoxypyrrolidinyl.
  • heteroaryl group refers to a monovalent aromatic radical comprising one or more 5-, 6-, or 7-membered rings and comprising one or more heteroatoms independently chosen from nitrogen, oxygen, phosphorous, and sulfur.
  • a heteroaryl group may be unsubstituted or may be substituted with one or more substituents as described elsewhere herein.
  • a heteroaryl group comprises 5 to 20 atoms.
  • a heteroaryl group comprises 5 to 9 atoms.
  • a heteroaryl group comprises 5 atoms.
  • a heteroaryl group comprises 6 atoms.
  • a heteroaryl group comprises 7 atoms. In some embodiments, a heteroaryl group is monocyclic. In some embodiments, a heteroaryl group is bicyclic. In some embodiments, a heteroaryl group comprises fused rings.
  • heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl- 1,2,4- oxadiazolyl, 3-phenyl-l,2,4-oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, thiadiazolyl, furazanyl, benzofurazany
  • heteroaryl groups include:
  • substituted refers to the replacement of one or more hydrogen atoms on one or more of a hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group with one or more substituents.
  • a substituted hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaryl group any number of hydrogen atoms may be replaced by substituents.
  • Non-limiting examples of substituents that replace a single hydrogen atom include halogen, hydroxyl, and amino.
  • Non-limiting examples of substituents that replace two hydrogen atoms include carbonyl.
  • Non-limiting examples of substituents that replace three hydrogen atoms include cyano.
  • Non-limiting examples of substituents that can substitute for hydrogen atoms on one or more of a hydrocarbon radical, alkyl group, alkylene group, alkenyl group, alkenylene group, alkynyl group, alkynylene group, aryl group, heterocyclic group, or heteroaiyl group include:
  • Ci-C 6 linear, branched, or cyclic alkyl groups non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl sec-butyl, iso- butyl, tert- butyl, cyclobutyl, cyclopentyl, and cyclohexyl;
  • substituted or unsubstituted aryl groups non-limiting examples of which include phenyl, 2-fluorophenyl, 3-methylphenyl, 4-chlorophenyl, 2,6- dichlorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-cyanophenyl, 2- dimethylaminophenyl, 3-metiiylsulfonylphenyl, 4-trifluorometiiylphenyl, 3- isopropylphenyl, 1 -naphthyl, and 2-naphthyl;
  • substituted or unsubstituted heterocyclic groups include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3- methoxypyrrolidinyl;
  • substituted or unsubstituted heteroaryl groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, frnyl, 2-thienyl, 3- thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-l,2,4-oxadiazolyl, 3- phenyl-l,2,4-oxadiazolyl, indolyl, benzothiazolyl, and l//-pyrrolo[2,3- 6]pyridinyl;
  • -(CR a R b ) z S0 3 R c non-limiting examples of which include -S0 3 H, -S0 3 CH 3 , -CH 2 S0 3 H, -CH 2 S0 3 CH 3 , -S0 3 C 6 H 5 , and -CH 2 S0 3 C 6 H 5 ; wherein each of R a and R b is independently chosen from hydrogen and substituted or unsubstituted C 1 -C 6 linear, branched, or cyclic alkyl, each of R c and R d is independently chosen from hydrogen, substituted or unsubstituted Ci-C 6 linear, branched, or cyclic alkyl, and aryl, or wherein R c and R d together form a ring system comprising 3 to 7 atoms, and z is chosen from 0, 1, 2, 3, and 4.
  • Compounds of the disclosure may contain one or more chiral centers. Compounds of tiie disclosure thus may exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds described herein, including, as non-limiting examples, diastereomers, enantiomers, and mixtures thereof (including, as a non-limiting example, racemic mixtures) form parts of the disclosure.
  • a compound of the disclosure is a compound of Formula I Formula I wherein
  • Ri is chosen from wherein
  • R 2 is chosen from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted linear alkenyl, substituted or unsubstituted branched alkenyl, substituted or unsubstituted cyclic alkenyl, substituted or unsubstituted linear alkynyl, and substituted or unsubstituted branched alkynyl;
  • R 3 is chosen from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted linear alkenyl, substituted or unsubstituted branched alkenyl, substituted or unsubstituted cyclic alkenyl, substituted or unsubstituted linear alkynyl, and substituted or unsubstituted branched alkynyl; n is an integer chosen from 1, 2, 3, 4, 5, and 6;
  • R 4 is chosen from substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl;
  • R is chosen from H, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl; and each of Xi, X 2 , and X 3 is independently chosen from CH and N, with the proviso that Xi, X 2 , and X 3 are not simultaneously CH.
  • R 2 is chosen from substituted or unsubstituted heteroaryl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl. In some embodiments, R 2 is substituted or unsubstituted heteroaryl. In some embodiments, R 2 is substituted heteroaryl. In some embodiments, R 2 is unsubstituted heteroaryl. In some embodiments, R 2 is 2-thienyl. In some embodiments, R 2 is 3-thienyl.
  • R 2 is not substituted or unsubstituted heteroaryl. In some embodiments, R 2 is not substituted heteroaryl. In some embodiments, R 2 is not unsubstituted heteroaryl. In some embodiments, R 2 is not 2-thienyl. In some embodiments, R 2 is not 3- thienyl.
  • R 2 is substituted or unsubstituted linear alkyl. In some embodiments, R 2 is substituted or unsubstituted Ci-C 6 linear alkyl. In some embodiments, R 2 is unsubstituted C 1 -C 6 linear alkyl. In some embodiments, R 2 is substituted C 1 -C 6 linear alkyl. In some embodiments, R 2 is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more halogen atoms.
  • R 2 is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more fluorine atoms.
  • R 2 is a trifluoroalkyl group. In some embodiments, R 2 is trifluoroethyl.
  • R 2 is not substituted or unsubstituted linear alkyl. In some embodiments, R 2 is not substituted or unsubstituted branched alkyl. In some embodiments, R 2 is not substituted or unsubstituted cyclic alkyl. In some embodiments, R 2 is not substituted or unsubstituted C 1 -C 6 linear alkyl. In some embodiments, R2 is not unsubstituted C 1 -C 6 linear alkyl. In some embodiments, R2 is not substituted C 1 -C 6 linear alkyl. In some embodiments, R 2 is not methyl. In some embodiments, R 2 is not ethyl. In some embodiments, R 2 is not isopropyl. In some embodiments, R 2 is not cyclopropyl.
  • R 3 is chosen from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl. In some embodiments, R 3 is substituted or unsubstituted heteroaryl. In some embodiments, R 3 is substituted heteroaryl. In some embodiments, R 3 is unsubstituted heteroaryl. In some embodiments, R 3 is 2-thienyl. In some embodiments, R 3 is 3-thienyl.
  • R 3 is not substituted or unsubstituted ary-l. In some embodiments, R 3 is not substituted aryl. In some embodiments, R 3 is not unsubstituted aryl. In some embodiments, R 3 is not phenyl. In some embodiments, R 3 is not substituted or unsubstituted heteroaryl. In some embodiments, R 3 is not substituted heteroaryl. In some embodiments, R 3 is not unsubstituted heteroaryl. In some embodiments, R 3 is not 2-thienyl. In some embodiments, R 3 is not 3-thienyl.
  • R 3 is chosen from substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl. In some embodiments, R 3 is chosen from substituted or unsubstituted Ci-C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 3 -C 6 cyclic alkyl. In some embodiments, R 3 is chosen from substituted C 1 -C 6 linear alkyl, substituted C 1 -C 6 branched alkyl, and substituted C 3 -C 6 cyclic alkyl.
  • R 3 is chosen from unsubstituted C 1 -C 6 linear alkyl, unsubstituted C 1 -C 6 branched alkyl, and unsubstituted C 3 -C 6 cyclic alkyl.
  • R 3 is not substituted or unsubstituted linear alkyl. In some embodiments, R 3 is not substituted or unsubstituted branched alkyl. In some embodiments, R 3 is not substituted or unsubstituted cyclic alkyl. In some embodiments, R 3 is not substituted or unsubstituted C 1 -C 6 linear alkyl. In some embodiments, R 3 is not substituted C 1 -C 6 linear alkyl. In some embodiments, R 3 is not unsubstituted C 1 -C 6 linear alkyl. In some embodiments, R 3 is not methyl. In some embodiments, R 3 is not ethyl. In some embodiments, R 3 is not isopropyl. In some embodiments, R 3 is not cyclopropyl.
  • R 3 is unsubstituted C 1 -C 6 linear alkyl. In some embodiments, R 3 is substituted C 1 -C 6 linear alkyl. In some embodiments, R 3 is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with a C 5 -C 20 heteroaryl group. In some embodiments, R 3 is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more halogen atoms.
  • R 3 is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more fluorine atoms.
  • R 3 is a trifluoroalkyl group.
  • R 3 is trifluoroethyl.
  • R 3 is trifluoropropyl.
  • R 3 is substituted or unsubstituted C 3 -C 6 cyclic alkyl. In some embodiments, R 3 is unsubstituted C 3 -C 6 cyclic alkyl. In some embodiments, R 3 is cyclopropyl.
  • R 3 is chosen from 2-thienyl, trifluoroethyl, trifluoropropyl, cyclopropyl,
  • R 3 is 2-thienyl. In some embodiments, In some embodiments, R 3 is
  • R 4 is chosen from substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 3 - C 6 cyclic alkyl. In some embodiments, R 4 is chosen from substituted Ci-C 6 linear alkyl, substituted C 1 -C 6 branched alkyl, and substituted C 3 -C 6 cyclic alkyl.
  • R 4 is chosen from unsubstituted C 1 -C 6 linear alkyl, unsubstituted C 1 -C 6 branched alkyl, and unsubstituted C 3 -C 6 cyclic alkyl. In some embodiments, R 4 is unsubstituted C 1 -C 6 linear alkyl. In some embodiments, R 4 is methyl.
  • R 5 is H. hi some embodiments, R 5 is chosen from substituted or unsubstituted Ci-C 6 linear alkyl, substituted or unsubstituted C]-C 6 branched alkyl, and substituted or unsubstituted C 3 -C 6 cyclic alkyl. In some embodiments, R 5 is substituted C 1 -C 6 linear alkyl. In some embodiments, Rs is unsubstituted C 1 -C 6 linear alkyl. In some embodiments, R 5 is methyl.
  • R 5 is not substituted C 1 -C 6 linear alkyl. In some embodiments, R 5 is not unsubstituted C 1 -C 6 linear alkyl. In some embodiments, Rs is not methyl. In some embodiments, R $ is not H.
  • Xi and X 2 are CH and X 3 is N. In some embodiments, Xi and X 3 are CH and X 2 is N. In some embodiments, X 2 and X 3 are CH and Xi is N. In some embodiments, Xi is CH and X 2 and X 3 are N. In some embodiments, X 2 is CH and Xi and X 3 are N. For the avoidance of doubt, it is meant to be understood that, in some embodiments, > > ,
  • n is an integer chosen from 1, 2, and 3. In some embodiments, n is an integer chosen from 1 and 2. In some embodiments, n is 1.
  • a compound of the disclosure is a compound of Formula ⁇
  • Re is substituted or unsubstituted heteroaryl, mis an integer chosen from 1, 2, 3, 4, 5, and 6;
  • R ? is chosen from substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl;
  • Rg is chosen from H, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl; and each of Rg and Rio is independently selected from H, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl.
  • Re is substituted heteroaryl. In some embodiments, Re is unsubstituted heteroaryl. In some embodiments, Re is 2-thienyl. In some embodiments, Re is 3-thienyl.
  • R 7 is chosen from substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C3- Ce cyclic alkyl. In some embodiments, R 7 is substituted C 1 -C 6 linear alkyl. In some embodiments, R 7 is unsubstituted Ci-C 6 linear alkyl. In some embodiments, R 7 is methyl.
  • Rg is H. In some embodiments, Rg is chosen from substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted C 1 -C 6 branched alkyl, and substituted or unsubstituted C 3 -C 6 cyclic alkyl. In some embodiments, Rg is substituted C 1 -C 6 linear alkyl. In some embodiments, Rg is unsubstituted C 1 -C 6 linear alkyl. In some embodiments, Rg is methyl.
  • each of Rg and Rio is independently selected from H and substituted or unsubstituted linear alkyl. In some embodiments, each of Rg and Rio is independently selected from H and substituted or unsubstituted linear C 1 -C 6 alkyl. In some embodiments, Rg is H. In some embodiments, Rio is H. In some embodiments, each of Rg and Rio is H. In some embodiments, each of Rg and Rio is independently substituted C 1 -C 6 linear alkyl. In some embodiments, each of Rg and Rio is independently unsubstituted Ci-C 6 linear alkyl. In some embodiments, Rg is methyl. In some embodiments, Rio is methyl. In some embodiments, each ofRg and Rio is methyl.
  • m is an integer chosen from 2, 3, 4, 5, and 6. In some embodiments, m is an integer chosen from 2, 3, 4, and 5. In some embodiments, m is an integer chosen from 2, 3, and 4. In some embodiments, m is an integer chosen from 3 and 4. In some embodiments, m is 3. In some embodiments, m is 4.
  • a compound of the disclosure is a compound of Formula III
  • Rn is chosen from substituted or unsubstituted aiyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cyclic alkyl, substituted or unsubstituted linear alkenyl, substituted or unsubstituted branched alkenyl, substituted or unsubstituted cyclic alkenyl, substituted or unsubstituted linear alkynyl, and substituted or unsubstituted branched alkynyl; a is an integer chosen from 0, 1 , 2, 3, 4, 5, and 6;
  • R12 is chosen from substituted or unsubstituted heteroaiyl and substituted or unsubstituted aryl.
  • Rn is chosen from substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted linear alkyl, substituted or unsubstituted branched alkyl, and substituted or unsubstituted cyclic alkyl. In some embodiments, Rn is chosen from substituted or unsubstituted C 1 -C 6 linear alkyl, substituted or unsubstituted branched C 1 -C 6 alkyl, and substituted or unsubstituted C 3 -C 6 cyclic alkyl.
  • Ru is substituted or unsubstituted heteroaryl. In some embodiments, Ru is substituted heteroaiyl. In some embodiments, Ru is unsubstituted heteroaryl. In some embodiments, Ru is 2-thienyl. In some embodiments, Ru is 3-thienyl.
  • Ru is not substituted or unsubstituted heteroaiyl. In some embodiments, Rn is not substituted heteroaryl. In some embodiments, Ru is not unsubstituted heteroaiyl. In some embodiments, Ru is not 2-thienyl. In some embodiments, Rn is not 3-thienyl.
  • Rn is not substituted aryl. In some embodiments, Rn is not unsubstituted aiyl. In some embodiments, Rn is not phenyl.
  • Rn is not substituted or unsubstituted linear alkyl. In some embodiments, Rn is not substituted or unsubstituted branched alkyl. In some embodiments, Rn is not substituted or unsubstituted cyclic alkyl. In some embodiments, Rn is not substituted or unsubstituted C 1 -C 6 linear alkyl. In some embodiments, Rn is not substituted C 1 -C 6 linear alkyl. In some embodiments, Rn is not unsubstituted C 1 -C 6 linear alkyl. In some embodiments, Rn is not methyl. In some embodiments, Rn is not ethyl. In some embodiments, Rn is not isopropyl. In some embodiments, Rn is not cyclopropyl.
  • Rn is substituted or unsubstituted linear alkyl. In some embodiments, Rn is substituted or unsubstituted C 1 -C 6 linear alkyl. In some embodiments, Rn is unsubstituted C 1 -C 6 linear alkyl. In some embodiments, Rn is substituted C 1 -C 6 linear alkyl.
  • Rn is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more halogen atoms. In some embodiments, Rn is substituted C1-C6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with one or more fluorine atoms. In some embodiments, Rn is a trifluoroalkyl group. In some embodiments, Rn is trifluoroethyl. In some embodiments, Rn is trifluoropropyl.
  • Rn is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with a C 3 -C 6 cyclic alkyl group.
  • Rn is substituted Ci-C 6 linear alkyl, wherein said substituted Ci-C 6 linear alkyl is substituted with cyclopropyl group.
  • Rn is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with cyclopentyl group.
  • Rn is cyclopropylmethyl.
  • Rn is cyclopentylmethyl.
  • Rn is substituted C 1 -C 6 linear alkyl, wherein said substituted Ci-C 6 linear alkyl is substituted with a heteroaryl group. In some embodiments, Rn is substituted Ci-C 6 linear alkyl, wherein said substituted Ci-C 6 linear alkyl is substituted with an imidazolyl group.
  • Rn is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with -N(R c )(R d ), wherein each of R c and R d are independently chosen from hydrogen, substituted or unsubstituted linear, branched, or cyclic alkyl, and aryl, or wherein R c and R d together form a ring system comprising 3 to 7 atoms.
  • Rn is substituted Ci-C 6 linear alkyl, wherein said substituted Ci-C 6 linear alkyl is substituted with -N(R c )(R d ), wherein each of R c and R d are independently chosen from H and substituted or unsubstituted C 1 -C 6 linear alkyl.
  • Rn is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with -NfR ⁇ OR 11 ), wherein each of R c and R d are independently chosen from substituted or unsubstituted C 1 -C 6 linear alkyl.
  • Rn is substituted C 1 -C 6 linear alkyl, wherein said substituted C1-C6 linear alkyl is substituted with -N(R c )(R d ), wherein each of R c and R d are independently chosen from unsubstituted C 1 -C 6 linear alkyl.
  • Rn is substituted C 1 -C 6 linear alkyl, wherein said substituted C 1 -C 6 linear alkyl is substituted with an amino group, a dimethylamino group, a diethylaminogroup, a di-n- propylamino group, or a di-n-butylamino group.
  • Rn is a dimethylaminomethyl group.
  • Rn is substituted or unsubstituted C 3 -C 6 cyclic alkyl. In some embodiments, Rn is substituted C 3 -C 6 cyclic alkyl. In some embodiments, Rn is unsubstituted C 3 -C 6 cyclic alkyl. In some embodiments, Rn is cyclopropyl.
  • Rn is substituted or unsubstituted heterocyclyl. In some embodiments, Rn is unsubstituted heterocyclyl. In some embodiments, Rn is substituted heterocyclyl. In some embodiments, Rn is chosen from pyrrolidinyl, 3-hydroxypyrrolidinyl, and 3-methoxypyrroIidinyl.
  • Rn is chosen from 2-thienyl, trifluoroethyl, trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclopentylmethyl,
  • R12 is substituted or unsubstituted heteroaiyl.
  • Rn is substituted heteroaryl.
  • R12 is unsubstituted heteroaryl.
  • Rn is pyridinyl.
  • R12 is substituted or unsubstituted aryl.
  • R12 is substituted aryl.
  • Rn is monosubstituted aryl. In some embodiments, Rn is monosubstituted phenyl. In some embodiments, Rn is unsubstituted aryl. In some embodiments, Rn is phenyl. In some embodiments, Rn is chosen from 1-naphthyl and 2-naphthyl. In some embodiments, Rn is 1- naphthyl. In some embodiments, Rn is 2-naphthyl.
  • a is an integer chosen from 0, 1, 2, and 3. In some embodiments, a is an integer chosen from 0, 1, and 2. In some embodiments, a is an integer chosen from 0 and 1. In some embodiments, a is 2. In some embodiments, a is 1. In some embodiments, a is 0.
  • b is an integer chosen from 0, 1, 2, and 3. In some embodiments, b is an integer chosen from 0, 1, and 2. In some embodiments, b is an integer chosen from 0 and 1. In some embodiments, b is 2. In some embodiments, b is 1. In some embodiments, b is 0.
  • a compound of the disclosure is a compound of Formula III wherein Y1-Y2 is nothing and a and b are not simultaneously 0. It is thus to be understood that, in some embodiments, a compound of the disclosure is a compound having the structure . It is also thus to be understood that, in some embodiments, a compound of the disclosure is a compound having the structure
  • compounds of the disclosure are chosen from the compounds recited in Table I, below:
  • a compound of the disclosure is in the form of a
  • pharmaceutically acceptable salt refers to a salt that is pharmaceutically acceptable as defined herein and that has the desired pharmacological activity of the parent compound.
  • pharmaceutically acceptable salts include those derived from inorganic acids, non-limiting examples of which include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and those derived from organic acids, non-limiting examples of which include acetic acid, trifluoroacetic add, propionic acid, glycolic acid, pyruvic acid, oxalic acid, stearic acid, malic acid, maldc acid, malonic acid, salicylic add, succinic acid, fumaric add, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid,
  • Additional non-limiting examples of pharmaceutically acceptable salts include those formed when an acidic proton in a parent compound is replaced by a metal ion, non-limiting examples of which include an alkali metal ion and an alkaline earth metal ion, and those formed when an acidic proton present in a parent compound is replaced by a ammonium ion, a primary ammonium ion, a secondary ammonium ion, a tertiary ammonium ion, or a quaternary ammonium ion.
  • Non-limiting examples of alkali metals and alkaline earth metals include sodium, potassium, lithium, calcium, aluminum, magnesium, copper, zinc, iron, and manganese.
  • Additional non-limiting examples of pharmaceutically acceptable salts include those comprising one or more counterions and zwitterions.
  • compositions can be used therapeutically as pharmaceutical compositions.
  • pharmaceutical composition refers to a preparation that is in such form as to permit the biological activity of the active ingredient to be effective, and that contains no additional components that are unacceptably toxic to a subject to which the composition would be administered.
  • such compositions may be sterile.
  • the components of the composition may be in solution, emulsions, or suspension (for example, incorporated into microparticles, nanoparticles, or liposomes). Colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions can also be used.
  • an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to render the formulation isotonic.
  • pharmaceutically acceptable carriers include, but are not limited to, saline, Ringer’s solution and dextrose solution.
  • the pH of the solution is preferably from about 5 to about 8, and more preferably from about 7 to about 7.5.
  • Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, and surface-active agents.
  • Further carriers include sustained release preparations such as semi-permeable matrices of solid hydrophobic polymers containing the compound of the disclosure, which matrices are in the form of shaped particles, e.g., films, liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of the composition being administered. Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, and anesthetics.
  • compositions comprising said compounds and/or pharmaceutically acceptable salts thereof can be administered as therapeutic treatments.
  • Said compounds, pharmaceutically acceptable salts, and/or pharmaceutical compositions can be administered in unit forms of administration to mammalian subjects, including human beings.
  • Suitable unit forms of administration include, as non-limiting examples, forms administered orally and forms administered via a parenteral/systemic route, non-limiting examples of which including inhalation, subcutaneous administration, intramuscular administration, intravenous administration, intradermal administration, intravitreal administration, as well as topical and local ocular (i.e, subconjunctival, intravitreal, retrobulbar, intracameral) modes of administration.
  • compositions for oral administration can be in tiie form of tablets, pills, powders, hard gelatine capsules, soft gelatine capsules, and/or granules.
  • a compound of the disclosure and/or a pharmaceutically acceptable salt of a compound of the disclosure is (or are) mixed with one or more inert diluents, non-limiting examples of which including starch, cellulose, sucrose, lactose, and silica.
  • such pharmaceutical compositions may further comprise one or more substances other than diluents, such as (as non-limiting examples), lubricants, coloring agents, coatings, or varnishes.
  • compositions for parenteral administration can be in the form of aqueous solutions, non-aqueous solutions, suspensions, emulsions, drops (including, as a non-limiting example, eye drops), or any combination(s) thereof.
  • such pharmaceutical compositions may comprise one or more of water, pharmaceutically acceptable glycol(s), pharmaceutically acceptable oil(s), pharmaceutically acceptable organic esters, or other pharmaceutically acceptable solvents.
  • a variety of vehicles suitable for administering compounds to the eye are known in the art. Specific nonlimiting examples are described in U.S. Pat. No. 6,261,547; U.S. Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No.
  • compounds of the disclosure, pharmaceutically acceptable salts of said compounds, and/or pharmaceutical compositions comprising said compounds and/or pharmaceutically acceptable salts thereof can be administered to a mammalian subject in need thereof to inhibit VE-PTP. In some embodiments, compounds of the disclosure, pharmaceutically acceptable salts of said compounds, and/or pharmaceutical compositions comprising said compounds and/or pharmaceutically acceptable salts thereof can be administered to a mammalian subject in need thereof to reduce or activate VE-PTP-mediated signaling.
  • compounds of the disclosure, pharmaceutically acceptable salts of said compounds, and/or pharmaceutical compositions comprising said compounds and/or pharmaceutically acceptable salts thereof can be administered to a mammalian subject in need thereof to increase Tie2-mediated signaling. In some embodiments, compounds of the disclosure, pharmaceutically acceptable salts of said compounds, and/or pharmaceutical compositions comprising said compounds and/or pharmaceutically acceptable salts thereof can be administered to a mammalian subject in need thereof to treat a Tie2-mediated disorder or a VEPTP-mediated disorder.
  • compounds of the disclosure, pharmaceutically acceptable salts of said compounds, and/or pharmaceutical compositions comprising said compounds and/or pharmaceutically acceptable salts thereof can be administered as therapeutic treatments for one or more of cancer, ocular disorders, occlusive cardiovascular disease, vascular leaking syndrome(s), and/or other vascular-related disease(s).
  • compounds of the disclosure, pharmaceutically acceptable salts of said compounds, and/or pharmaceutical compositions comprising said compounds and/or pharmaceutically acceptable salts thereof can be administered as therapeutic treatments for ocular disorders.
  • the mode (or modes) of administration, dosage (or dosages), and optimized pharmaceutical form (or forms) can be determined according to criteria generally considered during the establishment of a treatment of a patient, such as, by way of non-limiting examples, the potency of the compound(s) and/or pharmaceutically acceptable salts of the compound(s), the age of the patient, the body weight of the patient, the severity of the patient’s condition (or conditions), the patient’s tolerance to the treatment, and secondary effects observed in treatment. Determination of dosages effective to provide therapeutic benefit for specific modes and frequency of administration is within the capabilities of those skilled in the art.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 2,000 pg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 1,000 pg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 500 pg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 250 pg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 100 pg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 pg to 50 pg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 5,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 3,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 2,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is presort in a pharmaceutical composition in an amount from about 1 mg to about 1,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 500 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 250 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 100 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 1 mg to about 50 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 2,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 1,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 500 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 250 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 100 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 5 mg to 50 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 2,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 1,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 500 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 250 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 10 mg to 100 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is presort in a pharmaceutical composition in an amount from about 10 mg to 50 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 2,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 1,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 500 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 250 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 25 mg to 100 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is presort in a pharmaceutical composition in an amount from about 25 mg to 50 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 2,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 1,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 500 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 250 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 50 mg to 100 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 100 mg to 2,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 100 mg to 1,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 100 mg to 500 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is presort in a pharmaceutical composition in an amount from about 100 mg to 250 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 250 mg to 2,000 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 250 mg to 1,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 250 mg to 500 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 500 mg to 2,000 mg. In some embodiments, a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount from about 500 mg to 1,000 mg.
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount of about 1 pg, about 2 pg, about 3 pg, about 4 pg, about 5 pg, about 10 pg, about 15 pg, about 20 pg, about 25 pg, about 30 pg, about 35 pg, about 40 pg, about 45 pg, about 50 pg, about 60 pg, about 70 pg, about 80 pg, about 90 pg, about 100 pg, about 125 pg, about 150 pg, about 175 pg, about 200 pg, about 225 pg, about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg, about 550 pg, about 600 pg, about 650 pg, about 700 pg, about 750 pg, about 800 pg, about 850
  • a compound of the disclosure or pharmaceutically acceptable salt thereof is present in a pharmaceutical composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 1,000 mg, about 1,100 mg, about 1,200 mg, about 1,300 mg, about 1,400 mg, about 1,500 mg, about 1,600 mg, about
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mgZmL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/mL to about 10 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/mL to about 5 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/mL to about 3 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/mL to about 2 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/mL to about 1 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 0.1 mg/mL to about 0.5 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 1 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 1 mg/mL to about 80 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 1 mg/mL to about 60 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 1 mg/mL to about 40 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 1 mg/mL to about 30 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 1 mg/mL to about 20 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 1 mg/mL to about 10 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 1 mg/mL to about 5 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 5 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 5 mg/mL to about 80 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 5 mg/mL to about 60 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 5 mg/mL to about 40 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 5 mg/mL to about 30 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 5 mg/mL to about 20 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 5 mg/mL to about 10 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 10 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 10 mg/mL to about 80 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 10 mg/mL to about 60 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 10 mg/mL to about 40 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 10 mg/mL to about 30 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 10 mg/mL to about 20 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 20 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 20 mg/mL to about 80 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 20 mg/mL to about 60 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 20 mg/mL to about 40 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 20 mg/mL to about 30 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 30 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 30 mg/mL to about 80 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 30 mg/mL to about 60 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 30 mg/mL to about 40 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 40 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 40 mg/mL to about 80 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 40 mg/mL to about 60 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 50 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 50 mg/mL to about 80 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 50 mg/mL to about 60 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 60 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 60 mg/mL to about 80 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 70 mg/mL to about 100 mg/mL. In some embodiments, a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount from about 70 mg/mL to about 80 mg/mL.
  • a pharmaceutical composition comprises a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount of about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.5 mg/mL, about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, or about 100 mg/mL.
  • Effective amounts and dosages can be estimated initially from in vitro assays.
  • an initial dosage for use in animals can be formulated to achieve a circulating blood or serum concentration of active compound that is at or above an ICjo of the particular compound as measured in an in vitro assay. Calculating dosages to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound is well within the capabilities of skilled artisans. For guidance, the reader is referred to Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, latest edition, Pergamagon Press, and the references cited therein, which methods are incorporated herein by reference in their entirety.
  • Initial dosages can also be estimated from in vivo data, such as animal models. Animal models useful for testing the efficacy of compounds to treat or prevent the various diseases described in this disclosure are well-known in the art.
  • dosage amounts will be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher or lower, depending upon, among other factors, the activity of the compound, its bioavailability, the mode of administration and various factors discussed above. Dosage amount and interval can be adjusted individually to provide plasma levels of the compound(s) which are sufficient to maintain therapeutic or prophylactic effect.
  • the compounds can be administered once per week, several times per week (e.g., every other day), once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician.
  • the effective local concentration of active compound(s) may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • a therapeutic treatment comprises administration of a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount of 5 pg,
  • a therapeutic treatment comprises administration of a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount of 5 pg, 7.5 pg, 10 pg, 12.5 pg, 15 pg, 17.5 pg, 20 pg, 22.5 pg, 25 pg, 27.5 pg, or 30 pg.
  • a therapeutic treatment comprises administration of a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount of 5 pg, 7.5 pg, 10 pg, 12.5 pg, 15 pg, 17.5 pg, 20 pg, 22.5 pg, 25 pg, 27.5 pg, or 30 pg once daily.
  • a therapeutic treatment comprises administration of a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount of 5 pg, 7.5 pg, 10 pg,
  • a therapeutic treatment comprises administration of a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount of 5 mg,
  • a therapeutic treatment comprises administration of a a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount of 5 mg, 7.5 mg, 10 mg,
  • a therapeutic treatment comprises administration of a a compound of the disclosure or pharmaceutically acceptable salt thereof in an amount of 5 mg, 7.5 mg, 10 mg,
  • Phosphatase hydrolyzes phospho-substrate (DiFMUP) to release a fluorophore (DiFMU).
  • the fluorophore-DiFMU can be detected using FlexStation multi-mode microplate reader with excitation at 360 nm and emission at 460 nm.
  • the fluorescence intensity represents the reaction activity.
  • Buffer Preparation pH 7.4 buffer Potassium Phosphate, Monobasic 0.2 M. Dissolve 27.22 g of monobasic potassium phosphate (KH2PO4) in water, and dilute with water to 1000 mL. Place 50 mL of the monobasic potassium phosphate solution in a 200 mL volumetric flask, add 40 mL of sodium hydroxide solution, then add water to achieve desired volume and adjust pH to
  • HUVEC human umbilical vein endothelial cells
  • HUVEC AKT is a verified downstream signaling effector of Tie2 receptor tyrosine kinase, whose phosphorylation increases upon binding of Angiopoietin ligand to the receptor or by inhibiting VE-PTP, the negative inhibitor of the activated receptor (Souma, T et al. (2018 Jan)
  • Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP, Proc Natl Acad Sci U S A. pii: 1714446115).
  • HUVEC-C Human Umbilical Vein/Vascular Endothelium cells
  • ATCC American Type Culture Collection
  • CRL-1730 Human Umbilical Vein/Vascular Endothelium cells
  • HUVEC ells were grown using EndoGro LS Complete Media Kit (Millipore, SCMEOOl) supplemented with Penicillin-Streptomycin cocktail (Coming, 30-002-CI) in an incubator at 37°C in 5%CC> 2 . Few days prior to the experiment, cells were counted using a hematocytometer and subcultured so as to reach 60-80% confluency on the day of the experiment.
  • DMSO dimethyl sulfoxide
  • the obtained whole cell lysate was spinned down for 5 minutes at 13,300 rpm, 4°C to remove cellular debris.
  • the supernatant was mixed with 4x Laemmli sample buffer (Bio-Rad, #161- 0747) to final lx concentration.
  • Subsequently samples were boiled at 95°C for 5 minutes and either used directly in polyacrylamide gel electrophoresis or stored at -20°C.
  • the PVDF membrane was washed once in lx TBS-T, followed by blocking with 5% BSA in TBS-T for 1 hour at room temperature with gentle shaking. The blocked membrane was cut according to the visible marker lanes to probe simultaneously but separately for different proteins of interest.
  • the resulting PVDF membrane stripes were incubated with either primary Phospho-AKT (Ser473) (D9E) XP® Rabbit mAb (Cell Signaling Technology', 4060) or with primary GAPDH (D16H11) XP® Rabbit mAb (Cell Signaling Technology, 5174) overnight, gently shaking at 4°C. Next day, membrane stripes were washed three times with lx TBS-T for 5 minutes, gently shaking at room temperature.
  • Radio immune precipitation assay buffer 50 mM Tris-Cl (pH 8.0)
  • Tween-20 Tris buffered saline-Tween-20 (TBS-T): 50 mM Tris pH 7.4,150 mM NaCl, and 0.01% (v/v) Tween-20
  • FIG. 1 to FIG. 6 depict Western blot analyses performed in accordance with the above- described protocol.
  • Compounds with IC50 for VE-PTP in the activity' range of 0.1 to 5 nM were dissolved in DMSO and used to treat Human Umbilical Vein Endothelial Cells
  • HUVEC cells treated for 10 minutes with indicated concentration of specific compound were used in whole cell lysate Western blot analysis to determine the effectiveness of compound at inhibiting VE-PTP and activating Tie2 signaling cascade, culminating in increase in downstream phosphorylation of serine/threonine-specific protein kinase AKT/PKB.
  • the glycolytic enzyme Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as loading control.
  • Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as loading control.
  • FIG. 1 to FIG. 5 show two biological replicates for each compound.
  • certain compounds are much more effective at inducing phosphorylation of AKT than others, despite being in the same ICso activity range for VE-PTP.
  • tire Western blots some compounds had tire same or slightly higher level of pAKT induction as DMSO at the concentrations tested, while others generated a more pronounced response.
  • FIG. 6 depicts dose response titration experiments with selected compounds over a range of 0.2 to 50 ⁇ and illustrates a clear dose response relationship.
  • Angiopoietin 1 600 ng/mL is the cognate ligand for Tie2 receptor, used to activate the Tie2 signaling pathway.
  • the ocular penetration study was performed to ascertain whether potent and soluble compounds 1, 2, 3 (diastereomer 1), 3 (diastereomer 2), 5, 16 and 17 administered topically as a single dose to the rat’s eye are present in the aqueous humor 30 minutes post-treatment.
  • Compounds 1, 2, 3, 5, 16 and 17 were dissolved in 50 mM PBS pH 7.4 at maximum formulatable concentration, ranging from 5 to 15 mg/mL, and dose volume delivered topically as 6 uL per eye.
  • Four rats per group were used, receiving bilateral doses to the central cornea using a calibrated micropipette, with a total of eight eyes per group collected post euthanasia. Rats were held such that the treatment remained in the eye for a period of few seconds before letting go of the animal. After receiving a single dose per eye the eyes and aqueous humour were collected 30 minutes post-dose and frozen immediately.
  • rats were euthanized by CO2 inhalation followed by thoracotomy performed in accordance with the accepted American Veterinary Medical Association guidelines. Immediately following confirmation of death the eye was washed with balanced salt solution. Aqueous humor was collected from both eyes of each animal, flash frozen in liquid nitrogen and stored in a -80 degree Celsius freezer. All tissues where then shipped on dry ice for bioanalysis. Mass spectrometry and chromatography methods were established to separate, detect and quantify each compound used in the study. Aqueous humor samples were analysed to detect and calculate the concentration of each analyte, which were then averaged and represented as ng/mL per group per compound.
  • the crude was purified by prep-HPLC (column: Phenomenex Gemini C18 250*50 10u;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 12%-42%,20min) to yield ammonium (4-((2S)-2-(2- methoxycarbonyl)(methyl)amino)-3-(pyridin-3-yl)propanamido)-2-(2-(thiophen-2- yl)thiazol-4-yl)ethyl)phenyl)sulfamate diastereomer 2 (101.50 mg, 34%) was obtained as a white solid.
  • reaction was bubbled withNHs (2.59 g, 152.24 mmol, 1.00 eq) at 0 °C, the mixture was stirred at 0 °C for 0.5 h.
  • the reaction was monitored by LCMS and TLC and when complete, the solution was washed with aq. HC1 (5%, 500 mL), HzO (2 x 400 mL) and aq. NaHCOs (5%, 500mL).
  • the combined organic layer was washed with brine (300 mL), dried with anhydrous NazSO*, filtered and concentrated in vacuo.
  • the mixture was stirred at 25 °C for 13 h.
  • the reaction was monitored by LCMS and when complete, the reaction mixture was diluted with ice water 20 mL and extracted with ethyl acetate 30 mL (3 x 10 mL). The combined organic layer was washed with brine (30 mL), dried with Na 2 SC> 4 , filtered and concentrated under vacuo.
  • reaction was monitored by LCMS and when complete, the reaction mixture was concentrated in vacuo, and the residue was diluted with water 20 mL and extracted with DCM 60 mL (3 x 20 mL). The combined organic layer was washed with brine (50 mL), dried with NaaSO*, filtered and concentrated in vacuo.
  • Diastereoisomer 1 To a solution of 18_diastereoisomer 1 (0.12 g, 232.70 umol, 1 eq) in pyridine (1 mL) andMeCN (1 mL) was cooled to 0 °C, then the sulfur trioxide pyridine complex (111.11 mg, 698.09 umol, 3 eq) was added at 0 °C and the reaction mixture was stirred at 0 °C for 0.17 h.
  • reaction was monitored by TLC and when complete, the reaction mixture was filtered, the filtrate was added diazomethane (12.75 g, 303.51 mmol, 7.09 eq) in ether (300 mL) and then the olution was stirred at 0 °C for 3 h.
  • the reaction was monitored by TLC and when complete, the eaction mixture was to yield intermediate 4 (14.31 g, crude) in THF (100 mL) was obtained as ellow liquid.
  • reaction was monitored by TLC and LCMS and when complete, the reaction mixture was poured nto water (700 mL) and then the filter cake was dissolved into ethyl acetate (1000 mL) and washed with water (3 x 500 mL). Then the organic phase was washed with HC1 (5 %, 2 x 500 mL), water (2 x 400 mL) and NaHCCb (3 x 500 mL), then the organic phase was dried with nhydrous Na 2 SC> 4 and concentrated in vacuo.
  • reaction was monitored by TLC nd when complete, the reaction mixture was filtered, the filtrate was added ice-water (300 mL), nd then the mixture was extracted with ethyl acetate (3 x 300 mL), the organic phase was eutralized with aq. NaHCO .3 (5%, 3 x 200 mL). Then the combined organic phase was washed with brine (300 mL), dried with anhydrous Na2SC>4 and concentrated in vacuo.
  • ntermediate IB (20 g, 212.51 mmol, 1 eq), intermediate 1C (33.83 g, 318.76 mmol, 32.22 mL, .5 eq) and ZnCh (11.59 g, 85.00 mmol, 0.4 eq) were stirred at 160 °C for 5 h.
  • the reaction was monitored by TLC and when complete, the reaction mixture was concentrated in vacuo.
  • ntermediate 2A (7 g, 38.41 mmol, 1 eq) was dissolved in dioxane (140 mL) and HiO (47 mL) was added OsC>4 (0.1 M, 5.88 mL, 1.53e '2 eq) and NaI04 (16.68 g, 77.98 mmol, 2.03 eq), and hen stirred at 25 °C for 6 h.
  • reaction was monitored y LCMS and when complete, the reaction mixture was diluted with water (30 mL) and xtracted with ethyl acetate (3 x 15 mL). The combined organic layer was washed with brine (30 mL), dried with anhydrous NazSC ⁇ , filtered and concentrated in vacuo to give a residue.

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Abstract

La présente invention concerne des composés pouvant inhiber la protéine tyrosine phosphatase endothéliale vasculaire (VE-PTP). Ces composés peuvent également activer une signalisation médiée par le récepteur Tie2. La présente invention concerne également des sels pharmaceutiquement acceptables desdits composés, des compositions pharmaceutiques comprenant de tels composés et/ou leurs sels pharmaceutiquement acceptables, et l'utilisation de tels composés, et/ou de leurs sels pharmaceutiquement acceptables, et/ou des compositions pharmaceutiques les comprenant pour le traitement de maladies et/ou de pathologies médiées par une signalisation de VE-PTP, telles que celles médiées par une signalisation d'angiopoïétine/Tie2.
EP21825008.2A 2020-06-16 2021-06-16 Inhibiteurs de ve-ptp à petites molécules Pending EP4164690A1 (fr)

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