WO2023211889A1 - Polymorphic compounds and uses thereof - Google Patents

Polymorphic compounds and uses thereof Download PDF

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Publication number
WO2023211889A1
WO2023211889A1 PCT/US2023/019743 US2023019743W WO2023211889A1 WO 2023211889 A1 WO2023211889 A1 WO 2023211889A1 US 2023019743 W US2023019743 W US 2023019743W WO 2023211889 A1 WO2023211889 A1 WO 2023211889A1
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WIPO (PCT)
Prior art keywords
compound
cancer
increased
tead
activity
Prior art date
Application number
PCT/US2023/019743
Other languages
French (fr)
Inventor
Xiongwei Cai
James Nolan
Chao MENG
Mingxin Wei
Jin Wang
Hongtao FENG
Jianxin Yang
Kyle W. ROWINSKI
Sarah J. Bethune
Stephan BOERRIGTER
Stephan Parent
Original Assignee
Ikena Oncology, Inc.
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Application filed by Ikena Oncology, Inc. filed Critical Ikena Oncology, Inc.
Publication of WO2023211889A1 publication Critical patent/WO2023211889A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid

Definitions

  • the present disclosure relates to N-methyl-3-(l-methyl-lH-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide (Compound A) and salts thereof, their various crystalline forms, and compositions and methods thereof useful for inhibition of Transcriptional Enhancer Associate Domain (TEAD) and treatment of various diseases, disorders, and conditions associated with TEAD.
  • TEAD Transcriptional Enhancer Associate Domain
  • Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with TEAD transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers.
  • Compounds provided by this disclosure are also useful for the study of TEAD in biological and pathological phenomena; the study of intracellular signal transduction pathways; and the comparative evaluation of new TEAD inhibitors in vitro or in vivo.
  • FIG. 1 depicts the XRPD pattern of Compound A, Form A.
  • FIG. 2 depicts a DSC trace of Compound A, Form A.
  • FIG. 3 depicts the XRPD pattern of Compound A, Form B.
  • FIG. 4 depicts a DSC trace of Compound A, Form B.
  • FIG 5 depicts the XRPD pattern of a mixture of Form A and Form B Compound A.
  • FIG 6 depicts the TGA/DSC trace of a mixture of Form A and Form B Compound A.
  • FIG. 7 depicts the XRPD pattern of Compound 1, Form A.
  • FIG. 8 depicts a TGA/DSC trace of Compound 1, Form A.
  • FIG. 9 depicts the XRPD pattern of Compound 1, Form B with trace amount Form A.
  • FIG. 10 depicts the TGA/DSC trace of Compound 1, Form B with trace amount Form A.
  • FIG. 11 depicts the XRPD pattern of Compound 2, Form A.
  • FIG. 12 depicts the TGA/DSC trace of Compound 2, Form A.
  • FIG. 13 depicts the XRPD pattern of Compound 3, Form A.
  • FIG. 14 depicts the TGA/DSC trace of Compound 3, Form A.
  • FIG. 15 depicts the XRPD pattern of Compound 4, Form A.
  • FIG. 16 depicts the TGA/DSC trace of Compound 4, Form A.
  • FTG. 17 depicts the XRPD pattern of Compound 5, Form A.
  • FIG. 18 depicts the TGA/DSC trace of Compound 5, Form A.
  • FIG. 19 depicts the XRPD pattern of Compound 6, Form A.
  • FIG. 20 depicts the TGA/DSC trace of Compound 6, Form A.
  • compound A can exist in a variety of physical forms.
  • compound A can be in solution, suspension, or in solid form.
  • compound A is in solid form.
  • the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides a form of compound A substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include different forms of compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound A.
  • at least about 95% by weight of a form of compound A is present.
  • at least about 99% by weight of a form of compound A is present
  • a form of compound A is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • a form of compound A contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • a form of compound A contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for a form of compound A is also meant to include all tautomeric forms of compound A. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C -enriched carbon are within the scope of this disclosure.
  • compound A can exist in a variety of solid forms.
  • Exemplary forms include polymorphs such as those described herein.
  • the term “polymorph” refers to the different crystal structures into which a compound, or a salt or solvate thereof, can crystallize.
  • compound A is a crystalline solid.
  • compound A is a crystalline solid substantially free of amorphous compound A.
  • substantially free of amorphous compound A means that the compound contains no significant amount of amorphous compound A. In certain embodiments, at least about 95% by weight of crystalline compound A is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound A is present.
  • compound A can exist in at least two distinct polymorphic forms.
  • the present disclosure provides a polymorphic form of compound A referred to herein as Form A. In certain embodiments, the present disclosure provides a polymorphic form of compound A referred to herein as Form B. In certain embodiments, the present disclosure provides a mixture of Form A and Form B of compound A.
  • compound A is amorphous. In some embodiments, compound A is amorphous, and is substantially free of crystalline compound A.
  • Form A of compound A has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 1 below.
  • Form A of compound A is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 17.2, about 19.2 and about 26.7 degrees 2-theta. Tn some embodiments, Form A of compound A is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 17.2, about 19.2 and about 26.7 degrees 2-theta. In some embodiments, Form A of compound A is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 17.2, about 19.2 and about 26.7 degrees 2-theta.
  • the X-ray powder diffraction pattern of Form A of compound A is substantially similar to the XRPD provided in FIG. 1.
  • the Differential Scanning Calorimetry (DSC) of Form A of compound A is substantially similar to the DSC provided in FIG. 2.
  • Form B of compound A has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 2 below.
  • Form B of compound A is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 13.7, about 18.3 and about 19.8 degrees 2-theta. In some embodiments, Form B of compound A is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 13.7, about 18.3 and about 19.8 degrees 2-theta. In some embodiments, Form B of compound A is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 13.7, about 18.3 and about 19.8 degrees 2-theta.
  • the X-ray powder diffraction pattern of Form B of compound A is substantially similar to the XRPD provided in FIG. 3.
  • the DSC of Form B of compound A is substantially similar to the DSC provided in FIG. 4.
  • the present disclosure provides a mixture of Form A and Form B of compound A, which has an X-ray powder diffraction pattern substantially similar to the XRPD provided in FIG. 5.
  • a mixture of Form A and Form B of compound A has a TGA/DSC substantially similar to the TGA/DSC provided in FIG. 6.
  • the present disclosure provides compound A:
  • the present disclosure provides compound A, wherein the compound is substantially free of amorphous compound A.
  • the present disclosure provides compound A, wherein the compound is substantially free of impurities.
  • the present disclosure provides compound A, wherein the compound has an XRPD substantially similar to that depicted in FIG. 1.
  • the present disclosure provides compound A, wherein the compound has an XRPD substantially similar to that depicted in FIG. 3.
  • the present disclosure provides compound A, wherein the compound has an XRPD substantially similar to that depicted in FIG. 5.
  • the present disclosure provides a composition comprising compound A and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound A or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound A or composition thereof.
  • the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound A or composition thereof.
  • the TEAD-mediated disorder is a proliferative disease such as cancer.
  • an acid and compound A are ionically bonded to form one of compounds 1 through 6, described below.
  • compounds 1 through 6 can exist in a variety of physical forms.
  • compounds 1 through 6 can be in solution, suspension, or in solid form.
  • compounds 1 through 6 are in solid form.
  • the compounds may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms of compounds 1 through 6 are described below.
  • the present disclosure provides a maleate salt of compound A, represented by compound 1 :
  • compound 1 can exist in a variety of physical forms.
  • compound 1 can be in solution, suspension, or in solid form.
  • compound 1 is in solid form.
  • the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides compound 1 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter.
  • Such extraneous matter may include excess maleic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 1.
  • at least about 95% by weight of compound 1 is present. In still other embodiments of the disclosure, at least about 99% by weight of compound 1 is present.
  • compound 1 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 1 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 1 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 1 is also meant to include all tautomeric forms of compound 1. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • compound 1 can exist in a variety of solid forms. Exemplary forms include polymorphs such as those described herein.
  • compound 1 is a crystalline solid. In other embodiments, compound 1 is a crystalline solid substantially free of amorphous compound 1. As used herein, the term "substantially free of amorphous compound 1" means that the compound contains no significant amount of amorphous compound 1. In certain embodiments, at least about 95% by weight of crystalline compound 1 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 1 is present.
  • compound 1 can exist in at least two distinct polymorphic forms.
  • the present disclosure provides a polymorphic form of compound 1 referred to herein as Form A.
  • the present disclosure provides a polymorphic form of compound 1 referred to herein as Form B.
  • compound 1 is amorphous. In some embodiments, compound 1 is amorphous, and is substantially free of crystalline compound 1.
  • Form A of compound 1 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 3 below.
  • Form A of compound 1 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 12.0 and about 20.7 degrees 2-theta. In some embodiments, Form A of compound 1 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 12.0 and about 20.7 degrees 2-theta. In some embodiments, Form A of compound 1 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 12.0 and about 20.7 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 7.
  • the DSC is substantially similar to the DSC provided in FIG. 8.
  • the TGA is substantially similar to the TGA provided in FIG. 8.
  • Form B of compound 1 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 4 below.
  • the position 20 is within ⁇ 0.2.
  • Form B of compound 1 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 18.9 and about 21.8 degrees 2-theta. In some embodiments, Form B of compound 1 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 18.9 and about 21.8 degrees 2-theta. In some embodiments, Form B of compound 1 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 18.9 and about 21.8 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 9.
  • the DSC is substantially similar to the DSC provided in FIG. 10.
  • the TGA is substantially similar to the TGA provided in FIG. 10.
  • the present disclosure provides compound 1: [0078] In some embodiments, the present disclosure provides compound 1, wherein the compound is crystalline.
  • the present disclosure provides compound 1, wherein the compound is a crystalline solid substantially free of amorphous compound 1.
  • the present disclosure provides compound 1, wherein the compound is substantially free of impurities.
  • the present disclosure provides compound 1, wherein the compound has one or more peaks in its XRPD selected from those at 7.8, about 12.0 and about 20.7 degrees 2-theta. In some embodiments, the present disclosure provides compound 1, wherein the compound has at least two peaks in its XRPD selected from those at about 7.8, about 12.0 and about 20.7 degrees 2-theta. In some embodiments, the present disclosure provides compound 1, wherein the compound is of Form A.
  • the present disclosure provides compound 1, wherein the compound has an XRPD substantially similar to that depicted in FIG. 7.
  • the present disclosure provides compound 1, wherein the compound has one or more peaks in its XRPD selected from those at 13.3, about 18.9 and about 21.8 degrees 2-theta. In some embodiments, the present disclosure provides compound 1, wherein the compound has at least two peaks in its XRPD selected from those at about 13.3, about 18.9 and about 21.8 degrees 2-theta. In some embodiments, the present disclosure provides compound 1, wherein the compound is of Form B.
  • the present disclosure provides compound 1, wherein the compound has an XRPD substantially similar to that depicted in FIG. 9.
  • the present disclosure provides a composition comprising compound 1 and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 1 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 1 or composition thereof.
  • the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 1 or composition thereof.
  • the TEAD-mediated disorder is a proliferative disease such as cancer.
  • the present disclosure provides a maleate hemi-salt of compound A, represented by compound 2:
  • compound 2 can exist in a variety of physical forms.
  • compound 2 can be in solution, suspension, or in solid form.
  • compound 2 is in solid form.
  • the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides compound 2 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess maleic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 2.
  • at least about 95% by weight of compound 2 is present. In still other embodiments of the disclosure, at least about 99% by weight of compound 2 is present.
  • compound 2 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 2 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 2 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 2 is also meant to include all tautomeric forms of compound 2. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • compound 2 can exist in at least one distinct polymorphic form.
  • the present disclosure provides a polymorphic form of Compound 2 referred to herein as Form A.
  • Form A of Compound 2 comprises compound A and maleic acid in a ratio of about 2: 1.
  • compound 2 is a crystalline solid. In other embodiments, compound 2 is a crystalline solid substantially free of amorphous compound 2. As used herein, the term "substantially free of amorphous compound 2" means that the compound contains no significant amount of amorphous compound 2. In certain embodiments, at least about 95% by weight of crystalline compound 2 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 2 is present.
  • compound 2 can exist in at least one distinct polymorphic form.
  • the present disclosure provides a polymorphic form of Compound 2 referred to herein as Form A.
  • compound 2 is amorphous. In some embodiments, compound 2 is amorphous, and is substantially free of crystalline compound 2.
  • Form A of compound 2 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 5 below.
  • the position 20 is within ⁇ 0.2.
  • Form A of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.3, about 11.3 and about 16.0 degrees 2-theta. In some embodiments, Form A of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.4, about 12.3 and about 17.8 degrees 2-theta. In some embodiments, Form A of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 7.4, about 12.3 and about 17.8 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 11.
  • the DSC is substantially similar to the DSC provided in FIG. 12.
  • the TGA is substantially similar to the TGA provided in FIG. 12.
  • the present disclosure provides compound 2:
  • the present disclosure provides compound 2, wherein the compound is crystalline.
  • the present disclosure provides compound 2, wherein the compound is a crystalline solid substantially free of amorphous compound 2.
  • the present disclosure provides compound 2, wherein the compound is substantially free of impurities.
  • the present disclosure provides compound 2, wherein the compound has one or more peaks in its XRPD selected from those at about 7.4, about 12.3 and about 17.8 degrees 2-theta. In some embodiments, the present disclosure provides compound 2, wherein the compound has at least two peaks in its XRPD selected from those at about 7.4, about 12.3 and about 17.8 degrees 2-theta. In some embodiments, the present disclosure provides compound 2, wherein the compound is of Form A. In some embodiments, Form A of Compound 2 comprises compound A and maleic acid in a ratio of about 2: 1.
  • the present disclosure provides compound 2, wherein the compound has an XRPD substantially similar to that depicted in FIG. 11.
  • the present disclosure provides a composition comprising compound 2 and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 2 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 2 or composition thereof.
  • the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 2 or composition thereof.
  • the TEAD-mediated disorder is a proliferative disease such as cancer.
  • the present disclosure provides a mesylate salt of compound A, represented by compound 3:
  • compound 3 can exist in a variety of physical forms.
  • compound 3 can be in solution, suspension, or in solid form.
  • compound 3 is in solid form.
  • the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides compound 3 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess methanesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 3.
  • extraneous matter may include excess methanesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 3.
  • at least about 95% by weight of compound 3 is present.
  • at least about 99% by weight of compound 3 is present.
  • compound 3 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 3 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 3 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 3 is also meant to include all tautomeric forms of compound 3. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • compound 3 can exist in at least one distinct polymorphic form.
  • the present disclosure provides a polymorphic form of Compound 3 referred to herein as Form A.
  • compound 3 is a crystalline solid. In other embodiments, compound 3 is a crystalline solid substantially free of amorphous compound 3. As used herein, the term "substantially free of amorphous compound 3" means that the compound contains no significant amount of amorphous compound 3. In certain embodiments, at least about 95% by weight of crystalline compound 3 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 3 is present.
  • compound 3 is amorphous. In some embodiments, compound 3 is amorphous, and is substantially free of crystalline compound 3.
  • Form A of compound 3 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 6 below.
  • Form A of compound 3 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 13.
  • the DSC is substantially similar to the DSC provided in FIG. 14.
  • the TGA is substantially similar to the TGA provided in FIG. 14.
  • the present disclosure provides compound 3: 3
  • the present disclosure provides compound 3, wherein the compound is crystalline.
  • the present disclosure provides compound 3, wherein the compound is a crystalline solid substantially free of amorphous compound 3.
  • the present disclosure provides compound 3, wherein the compound is substantially free of impurities.
  • the present disclosure provides compound 3, wherein the compound has one or more peaks in its XRPD selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta. In some embodiments, the present disclosure provides compound 3, wherein the compound has at least two peaks in its XRPD selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta. In some embodiments, the present disclosure provides compound 3, wherein the compound is of Form A.
  • the present disclosure provides compound 3, wherein the compound has an XRPD substantially similar to that depicted in FIG. 13.
  • the present disclosure provides a composition comprising compound 3 and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 3 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 3 or composition thereof.
  • the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 3 or composition thereof.
  • the TEAD-mediated disorder is a proliferative disease such as cancer.
  • the present disclosure provides a tosylate salt of compound A, represented by compound 4:
  • compound 4 can exist in a variety of physical forms.
  • compound 4 can be in solution, suspension, or in solid form.
  • compound 4 is in solid form.
  • the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides compound 4 substantially free of impurities.
  • the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess / oluenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 4.
  • extraneous matter may include excess / oluenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 4.
  • at least about 95% by weight of compound 4 is present.
  • at least about 99% by weight of compound 4 is present.
  • compound 4 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 4 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 4 contains no more than about 1 .0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 4 is also meant to include all tautomeric forms of compound 4. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • compound 4 can exist in at least one distinct solid form.
  • Exemplary forms include polymorphs such as those described herein.
  • compound 4 can exist in at least one distinct polymorphic form.
  • the present disclosure provides a polymorphic form of Compound 4 referred to herein as Form A.
  • compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound contains no significant amount of amorphous compound 4. In certain embodiments, at least about 95% by weight of crystalline compound 4 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 4 is present.
  • compound 4 is amorphous. In some embodiments, compound 4 is amorphous, and is substantially free of crystalline compound 4.
  • Form A of compound 4 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 7 below.
  • Form A of compound 4 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta. In some embodiments, Form A of compound 4 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta. In some embodiments, Form A of compound 4 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 15.
  • the DSC is substantially similar to the DSC provided in FIG. 16.
  • the TGA is substantially similar to the TGA provided in FIG. 16.
  • the present disclosure provides compound 4:
  • the present disclosure provides compound 4, wherein the compound is crystalline. [00146] In some embodiments, the present disclosure provides compound 4, wherein the compound is a crystalline solid substantially free of amorphous compound 4.
  • the present disclosure provides compound 4, wherein the compound is substantially free of impurities.
  • the present disclosure provides compound 4, wherein the compound has one or more peaks in its XRPD selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta. In some embodiments, the present disclosure provides compound 4, wherein the compound has at least two peaks in its XRPD selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta. In some embodiments, the present disclosure provides compound 4, wherein the compound is of Form A.
  • the present disclosure provides compound 4, wherein the compound has an XRPD substantially similar to that depicted in FIG. 15.
  • the DSC is substantially similar to the DSC provided in FIG. 16.
  • the TGA is substantially similar to the TGA provided in FIG. 16.
  • the present disclosure provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 4 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 4 or composition thereof.
  • the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 4 or composition thereof.
  • the TEAD-mediated disorder is a proliferative disease such as cancer.
  • the present disclosure provides a bis-tosylate salt of compound A, represented by compound 5:
  • compound 5 can exist in a variety of physical forms.
  • compound 5 can be in solution, suspension, or in solid form.
  • compound 5 is in solid form.
  • the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides compound 5 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess p-toluenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 5.
  • extraneous matter may include excess p-toluenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 5.
  • at least about 95% by weight of compound 5 is present.
  • at least about 99% by weight of compound 5 is present.
  • compound 5 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 5 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 5 contains no more than about 1 .0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 5 is also meant to include all tautomeric forms of compound 5. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • compound 5 can exist in at least one distinct polymorphic form.
  • the present disclosure provides a polymorphic form of Compound 5 referred to herein as Form A.
  • compound 5 is a crystalline solid. In other embodiments, compound 5 is a crystalline solid substantially free of amorphous compound 5. As used herein, the term "substantially free of amorphous compound 5" means that the compound contains no significant amount of amorphous compound 5. In certain embodiments, at least about 95% by weight of crystalline compound 5 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 5 is present.
  • compound 5 is amorphous. In some embodiments, compound 5 is amorphous, and is substantially free of crystalline compound 5.
  • Form A of compound 5 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 8 below.
  • Form A of compound 5 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 18.8 and about 19.3 degrees 2-theta. In some embodiments, Form A of compound 5 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 18.8 and about 19.3 degrees 2-theta. In some embodiments, Form A of compound 5 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 18.8 and about 19.3 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 17.
  • the DSC is substantially similar to the DSC provided in FIG. 18.
  • the TGA is substantially similar to the TGA provided in FIG. 18.
  • the present disclosure provides compound 5:
  • the present disclosure provides compound 5, wherein the compound is crystalline.
  • the present disclosure provides compound 5, wherein the compound is a crystalline solid substantially free of amorphous compound 5.
  • the present disclosure provides compound 5, wherein the compound is substantially free of impurities.
  • the present disclosure provides compound 5, wherein the compound has one or more peaks in its XRPD selected from those at about 5.6, about 18.8 and about 19.3 degrees 2-theta. In some embodiments, the present disclosure provides compound 5, wherein the compound has at least two peaks in its XRPD selected from those at about 5.6, about
  • the present disclosure provides compound 5, wherein the compound is of Form A.
  • the present disclosure provides compound 5, wherein the compound has an XRPD substantially similar to that depicted in FIG. 17.
  • the present disclosure provides a composition comprising compound 5 and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 5 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 5 or composition thereof.
  • the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 5 or composition thereof.
  • the TEAD-mediated disorder is a proliferative disease such as cancer.
  • the present disclosure provides an HCl salt of compound A, represented by compound 6:
  • x is about 0.5, about 1, or about 2.
  • compound A and hydrochloric acid are ionically bonded to form compound 6.
  • compound A and hydrochloric acid are in a ratio of about 1 : 1.
  • compound A and hydrochloric acid are in a ratio of about 2: 1.
  • compound A and hydrochloric acid are in a ratio of about 1:2.
  • compound 6 can exist in a variety of physical forms.
  • compound 6 can be in solution, suspension, or in solid form.
  • compound 6 is in solid form.
  • the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
  • the present disclosure provides compound 6 substantially free of impurities.
  • the term "substantially free of impurities” means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess hydrochloric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 6.
  • extraneous matter may include excess hydrochloric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 6.
  • at least about 95% by weight of compound 6 is present.
  • at least about 99% by weight of compound 6 is present.
  • compound 6 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent where the percentages are based on the total weight of the composition.
  • compound 6 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram.
  • compound 6 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
  • the structure depicted for compound 6 is also meant to include all tautomeric forms of compound 6. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • compound 6 can exist in at least one distinct polymorphic form.
  • the present disclosure provides a polymorphic form of Compound 6 referred to herein as Form A.
  • compound 6 is a crystalline solid. In other embodiments, compound 6 is a crystalline solid substantially free of amorphous compound 6. As used herein, the term "substantially free of amorphous compound 6" means that the compound contains no significant amount of amorphous compound 6. In certain embodiments, at least about 95% by weight of crystalline compound 6 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 6 is present.
  • compound 6 is amorphous. In some embodiments, compound 6 is amorphous, and is substantially free of crystalline compound 6.
  • Form A of compound 6 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 9 below.
  • the position 20 is within ⁇ 0.2.
  • Form A of compound 6 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta. In some embodiments, Form A of compound 6 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta. In some embodiments, Form A of compound 6 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta.
  • the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 19.
  • the DSC is substantially similar to the DSC provided in FIG. 20.
  • the TGA is substantially similar to the TGA provided in FIG. 20.
  • the present disclosure provides compound 6: 6 wherein x is about 0.5, about 1, or about 2.
  • the present disclosure provides compound 6, wherein the compound is crystalline.
  • the present disclosure provides compound 6, wherein the compound is a crystalline solid substantially free of amorphous compound 6.
  • the present disclosure provides compound 6, wherein the compound is substantially free of impurities.
  • the present disclosure provides compound 6, wherein the compound has one or more peaks in its XRPD selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta. Tn some embodiments, the present disclosure provides compound 6, wherein the compound has at least two peaks in its XRPD selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta. In some embodiments, the present disclosure provides compound 6, wherein the compound is of Form A. In some embodiments, Form A of Compound 6 comprises compound A and hydrochloric acid in a ratio of about 1 :1. In some embodiments, Form A of Compound 6 comprises compound A and hydrochloric acid in a ratio of about 1 :2. In some embodiments, Form A of Compound 6 comprises compound A and hydrochloric acid in a ratio of about 2: 1.
  • the present disclosure provides compound 6, wherein the compound has an XRPD substantially similar to that depicted in FIG. 19.
  • the present disclosure provides a composition comprising compound 6 and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 6 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 6 or composition thereof.
  • the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 6 or composition thereof.
  • the TEAD-mediated disorder is aproliferative disease such as cancer.
  • the present disclosure provides a compound selected from: compound A, Form A; compound A, Form B; compound 1, Form A; compound 1, Form B; compound 2, Form A; compound 3, Form A; compound 4, Form A; compound 5, Form A; and compound 6, Form A.
  • the present disclosure provides a composition comprising one of the above compound forms and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient a compound of the present disclosure or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient a compound of the present disclosure or composition thereof.
  • the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof a compound of the present disclosure or composition thereof.
  • the TEAD-mediated disorder is a proliferative disease such as cancer.
  • Compound A is prepared according to the methods described in detail herein.
  • the present disclosure provides a method for preparing compound A as shown in the scheme: intermediate 4 Compound A
  • the present disclosure provides a method for preparing
  • the present disclosure provides a method for preparing
  • the present disclosure provides a method for preparing
  • Compound A is prepared according to the methods described in detail herein.
  • Salt compounds of general formula X which formula encompasses, inter alia, salt compounds 1 through 6, and/or particular forms thereof, are prepared from compound A, according to the general Scheme below.
  • each of compounds 1 through 6, and forms thereof are prepared from compound A by combining compound A with an appropriate acid to form a salt of that acid.
  • another aspect of the present disclosure provides a method for preparing compounds 1 through 6, and forms thereof.
  • the present disclosure provides a method for preparing a salt compound of the general formula X: salt compound X comprising steps of: combining compound A: with a suitable acid and optionally a suitable solvent under conditions suitable for forming a salt compound of general formula X.
  • a suitable acid is maleic acid.
  • the present disclosure provides a method of making a maleate salt of compound A.
  • the maleate salt of compound A is compound 1.
  • the maleate salt of compound A is Form A of compound 1.
  • the maleate salt of compound A is Form B of compound 1.
  • the maleate salt of compound A is hemimaleate salt compound 2.
  • the hemi-maleate salt of compound A is Form A of compound 2.
  • a suitable acid is methanesulfonic acid.
  • the present disclosure provides a method of making a mesylate salt of compound A.
  • the mesylate salt of compound A is compound 3.
  • the mesylate salt of compound A is Form A of compound 3.
  • a suitable acid is p-toluenenesulfonic acid.
  • the present disclosure provides a method of making a tosylate salt of compound A.
  • the tosylate salt of compound A is compound 4.
  • the tosylate salt of compound A is Form A of compound 4.
  • the tosylate salt of compound A is bis-tosylate salt compound 5.
  • the bis-tosylate salt of compound A is Form A of compound 5.
  • a suitable acid is hydrochloric acid.
  • the present disclosure provides a method of making an HC1 salt of compound A.
  • the HO salt of compound A is compound 6.
  • the HC1 salt of compound A is Form A of compound 6.
  • a suitable solvent may be any solvent system (e.g., one solvent or a mixture of solvents) in which compound A and/or an acid are soluble, or are at least partially soluble.
  • suitable solvents useful in the present disclosure include, but are not limited to protic solvents, aprotic solvents, polar aprotic solvent, or mixtures thereof.
  • suitable solvents include an ether, an ester, an alcohol, a ketone, or a mixture thereof.
  • the solvent is one or more organic alcohols.
  • the solvent is chlorinated.
  • the solvent is an aromatic solvent.
  • a suitable solvent is methanol, ethanol, isopropanol, or acetone wherein the solvent is anhydrous or in combination with water or heptane.
  • suitable solvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile.
  • a suitable solvent is ethanol.
  • a suitable solvent is anhydrous ethanol.
  • the suitable solvent is MTBE.
  • a suitable solvent is ethyl acetate.
  • a suitable solvent is a mixture of methanol and methylene chloride.
  • a suitable solvent is a mixture of acetonitrile and water.
  • a suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran.
  • a suitable solvent is diethylether.
  • a suitable solvent is water.
  • a suitable solvent is methyl ethyl ketone.
  • a suitable solvent is toluene.
  • the present disclosure provides a method for preparing a salt compound of the general formula X, comprising one or more steps of removing a solvent and adding a solvent
  • an added solvent is the same as the solvent removed.
  • an added solvent is different from the solvent removed.
  • Means of solvent removal are known in the synthetic and chemical arts and include, but are not limited to, any of those described herein and in the Exemplification.
  • a method for preparing a salt compound of the general formula X comprises one or more steps of heating or cooling a preparation.
  • a method for preparing a salt compound of the general formula X comprises one or more steps of agitating or stirring a preparation.
  • a method for preparing a salt compound of the general formula X comprises a step of adding a suitable acid to a solution or slurry of compound A.
  • a method for preparing a salt compound of the general formula X comprises a step of heating.
  • a salt compound of formula X precipitates from the mixture. In another embodiment, a salt compound of formula X crystallizes from the mixture. In other embodiments, a salt compound of formula X crystallizes from solution following seeding of the solution (i.e., adding crystals of a salt compound of formula X to the solution).
  • a salt compound of formula X can precipitate out of the reaction mixture, or be generated by removal of part or all of the solvent through methods such as evaporation, distillation, fdtration (ex. nanofdtration, ultrafdtration), reverse osmosis, absorption and reaction, by adding an anti-solvent such as heptane, by cooling or by different combinations of these methods.
  • a salt compound of formula X is optionally isolated. It will be appreciated that a salt compound of formula X may be isolated by any suitable physical means known to one of ordinary skill in the art.
  • precipitated solid salt compound of formula X is separated from the supernatant by filtration. In other embodiments, precipitated solid salt compound of formula X is separated from the supernatant by decanting the supernatant.
  • a salt compound of formula X is separated from the supernatant by filtration.
  • an isolated salt compound of formula X is dried in air. In other embodiments, isolated salt compound of formula X is dried under reduced pressure, optionally at elevated temperature.
  • the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of this disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this disclosure is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient.
  • the amount of compound in compositions of this disclosure is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient.
  • a composition of this disclosure is formulated for administration to a patient in need of such composition.
  • a composition of this disclosure is formulated for oral administration to a patient.
  • patient or “subject” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this disclosure refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropy
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.
  • inhibitors as used herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of TEAD, or a variant or mutant thereof.
  • compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this disclosure can be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • compositions of this disclosure can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.
  • compositions of this disclosure can be administered in the form of suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this disclosure can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.
  • compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.
  • compositions of this disclosure can also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this disclosure are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.
  • compositions of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form varies depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present disclosure in the composition also depends upon the particular compound in the composition.
  • the Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation.
  • the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1).
  • YAP transcriptional co-activators Yes-associated protein
  • TEZ transcriptional co-activator with PDZ-binding motif
  • the Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control.
  • YAP also known as YAP1 or YAP65
  • TAZ TEAD family of transcription factors toupregulate genes that promote proliferation and migration, and inhibit apoptosis.
  • unregulated upregulation of these genes involved in proliferation, migration, and antiapoptosis leads to development of cancer.
  • overexpression of YAP/TAZ is associated with cancer.
  • Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Latsl/2 (homologues of Warts/Wts), and their adaptor proteins Savl (homologue of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively.
  • MST1/2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl/2 kinase.
  • Latsl/2 is also activated by the scaffold protein Mob.
  • the activated Latsl/2 then phosphorylates and inactivates YAP or its paralog TAZ.
  • the phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.
  • Latsl/2 phosphorylates YAP at the [HXRXXS] (SEQ ID NO: 21) consensus motifs.
  • YAP comprises five [HXRXXS] (SEQ ID NO: 21) consensus motifs, wherein X denotes any amino acid residue.
  • Latsl/2 phosphorylates YAP at one or more of the consensus motifs.
  • Latsl/2 phosphorylates YAP at all five of the consensus motifs.
  • Latsl/2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP.
  • Latsl/2 phosphorylates TAZ at the [HXRXXS] (SEQ ID NO: 21) consensus motifs.
  • TAZ comprises four [HXRXXS] (SEQ ID NO: 21) consensus motifs, wherein X denotes any amino acid residues.
  • Latsl/2 phosphorylates TAZ at one or more of the consensus motifs.
  • Latsl/2 phosphorylates TAZ at all four of the consensus motifs.
  • Latsl/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
  • phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCFk
  • the Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skpl, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme.
  • the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, PTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2).
  • the SCF complex e.g. SCF pTrCP1
  • an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate.
  • Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1.
  • Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1.
  • the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome.
  • the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.
  • un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus.
  • YAP/TAZ interacts with the TEAD family of transcription factors (e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID QI 5561 (SEQ ID NO: 4)) to activate genes involved in anti-apoptosis and proliferation, such as for example CTFG, Cyr61, and FGF1.
  • TEAD1 UniProt KB ID P28347-1 (SEQ ID NO: 1)
  • human TEAD2 UniProtKB ID Q15562 (SEQ ID NO: 2)
  • human TEAD3 UniProtKB ID Q99594 (SEQ ID NO: 3)
  • human TEAD4 Uni
  • TEAD TEAD
  • C327S and C359S Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation.
  • C53S, C327S and C359S Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation.
  • C359S mutant showed the greatest loss of palmitoylation, and C327S and C53S also showed decreased palmitoylation.
  • the compounds disclosed herein modulate the interaction between YAP/TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEAD. [00251] In some embodiments, the compounds described herein reversibly inhibit a TEAD transcription factor. In some embodiments, the transcription factor is TEAD1. In some embodiments, the transcription factor is TEAD2. In some embodiments, the transcription factor is TEAD3. In some embodiments, the transcription factor is TEAD4. In some embodiments, the compounds described herein reversibly inhibit the activity of a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • TEAD1, TEAD2, TEAD3, and/or TEAD4 e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD2 and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the compounds disclosed herein bind to TEAD3 and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD4 and disrupt or inhibit the interaction between YAP and TEAD4.
  • the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C405, and disrupt or inhibit the interaction between YAP and TEAD 1.
  • the compounds disclosed herein bind to TEAD1 at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD I . In some embodiments, the compounds disclosed herein bind to TEAD I at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEADl. In some embodiments, the compounds disclosed herein bind to TEADl at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEADl.
  • the compounds disclosed herein bind to TEAD1 at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEADl at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEADl palmitoylation at C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359 and C327.
  • the compounds disclosed herein bind to TEADl and prevent TEAD1 palmitoylation at C359 and C53. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEAD1 palmitoylation at C53 and C327. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359 and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C53 and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C327 and C405.
  • the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359, C327, and C53. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359, C327, and C405. In some embodiments, the compounds disclosed herein bind to TEAD l and prevent TEAD l palmitoylation at C359, C353, and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C327, C53, and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359, C327, C53, and C405.
  • the compounds disclosed herein bind to TEAD, prevent TEAD palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD. In some embodiments, the compounds disclosed herein bind to TEADI and prevent TE ADI palmitoylation at C359, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
  • the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEADI and prevent TEADI palmitoylation at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEADI.
  • the compounds disclosed herein bind to TEADI and prevent TEADI palmitoylation at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEADI . In some embodiments, the compounds disclosed herein bind to TEADI and prevent TEADI palmitoylation at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEADI. [00256] In some embodiments, the compounds disclosed herein bind to TEAD2 at C380, and disrupt or inhibit the interaction between YAP and TEAD2.
  • the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380.
  • the compounds disclosed herein bind to TEAD2, prevent TEAD2 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380, and disrupt or inhibit the interaction between YAP and TEAD2.
  • the compounds disclosed herein bind to TEAD3 at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3.
  • the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368 and C371.
  • the compounds disclosed herein bind to TEAD3, prevent TEAD3 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3.
  • the compounds disclosed herein bind to TEAD4 at C367, and disrupt or inhibit the interaction between YAP and TEAD4. [00263] In some embodiments, the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367.
  • the compounds disclosed herein bind to TEAD4, prevent TEAD4 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD4. In some embodiments, the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367, and disrupt or inhibit the interaction between YAP and TEAD4.
  • the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins.
  • G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs.
  • monomeric small GTPases and heterotrimeric G protein complexes.
  • the latter class of complexes comprise of alpha (G a ), beta (Gp), and gamma (G Y ) subunits.
  • G a subunits G q /na, Giz/ , Gi/ O a (G inhibitory, G other), and G s a (G stimulatory).
  • Gia G inhibitory
  • G o a G other
  • G q /l la G12/13a coupled GPCRs activate YAP/TAZ and promote nuclear translocation.
  • G s a G stimulatory coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.
  • Gia G inhibitory
  • G o a G other
  • G q /na Gn/ua coupled GPCRs activate YAP/TAZ through repression of Latsl/2 activities.
  • G s a in some embodiments, induces Latsl/2 activity, thereby promoting YAP/TAZ degradation.
  • G q a also known as G q /n protein
  • IP3 inositol trisphosphate
  • PLC phospholipase C
  • PLC phospholipase C
  • PIP2 phosphatidylinositol 4,5-bisphosphate
  • DAG diacyl glycerol
  • IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca 2+ channel.
  • the binding triggers the opening of the Ca 2+ channel, and thereby increases the release of Ca 2+ into the cytoplasm.
  • the GPCRs that interact with G q a include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT? and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and M5; and trace amine-associated receptor 1.
  • 5-HT receptor 5-hydroxytryptamine receptor
  • G q a there are several types of G q a: G q , G q /n, G q /i4, and G q /is.
  • the G q protein is encoded by GNAQ.
  • G q /n is encoded by GNA11.
  • G q /i4 is encoded by GNA14.
  • G q /is is encoded by GNA15.
  • G q a genes have been associated with cancer. Indeed, studies have shown that mutations in G q a promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.
  • mutations or modifications of the G q a genes have been associated with congenital diseases.
  • mutations of G q a have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome.
  • congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome.
  • Port-Wine Stain and/or Sturge-Weber Syndrome.
  • about 92% of Port-Wine stain cases harbors a mutation in GNAQ.
  • about 88% of Sturge- Weber Syndrome harbors a mutation in GNAQ.
  • Gi2/i3a modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs).
  • GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways.
  • small GTPases include the Ras-related GTPase superfamily (e.g, Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.
  • the GPCRs that interact with Gi2/i3a include, but are not limited to, purinergic receptors (e.g, P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1 -phosphate (e.g., SIP2, SIP3, SIP4 and SIP5); lysophosphatidic acid (e.g., LPAi, LPA2, LPA3); angiotensin II (ATI); serotonin (5-HT2 C and 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; D5 dopamine receptors; fMLP formy
  • purinergic receptors e
  • G12/1301 is further subdivided into G12 and GB types which are encoded by GNA12 and GNA13, respectively.
  • Gi/od G inhibitory, G other
  • Gi/G 0 or Gi protein suppresses the production of 3’, 5 ’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.
  • cAMP cyclic AMP
  • the GPCRs that interact with Gi a include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HTs; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as d2A, d2B, and a 2c ; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GABAB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8
  • 5-HT receptor 5-hydroxytry
  • Gial is encoded by GNAII.
  • Gia2 is encoded by GNAI2.
  • Gia3 is encoded by GNAI3.
  • G o a the a 0 subunit, is encoded by GNA01.
  • Gt is encoded by GNAT1 and GNAT2.
  • Ggust is encoded by GNAT3.
  • G z is encoded by GNAZ.
  • G s a also known as G stimulatory, G s alpha subunit, or G s protein activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3 ’,5 ’-cyclic AMP (cAMP) and pyrophosphate
  • the GPCRs that interact with G s a include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HTe, and 5-HT?; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and Ait,; arginine vasopressin receptor 2 (AVPR2); 0-adrenergic receptors Pi, P2, and P3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor
  • 5-HT receptor 5-hydroxytry
  • G s there are two types of G s a: G s and G o ir.
  • G s is encoded by GNAS.
  • Goif is encoded by GN AL.
  • the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex.
  • the Crumbs complex is a key regulator of cell polarity and cell shape.
  • the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity.
  • CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components.
  • AMOT Angiomotin
  • the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family.
  • MST kinases monitor actin cytoskeletal integrity.
  • the regulators include TAO kinases and cell polarity kinase PAR-1.
  • the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction.
  • E-Cadherin suppresses YAP nuclear localization and activity through regulating MST activity.
  • E-cad- associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm.
  • Ajuba protein family members interact with Latsl/2 kinase activity, thereby preventing inactivation of YAP/TAZ.
  • additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.
  • the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP).
  • the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP).
  • the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR.
  • an inhibitor of the Hippo pathway is an inhibitor of a G-protein.
  • an inhibitor of the Hippo pathway is an inhibitor of the G q a family proteins such as Gq, Gq/n, Gq/14, and Gq/15; the Gn/na family of proteins such as G12 and G13; or the Gia family of proteins such as Gial, G,a2, G,a3, Gta4, G o a, Gt, Ggust, and G z .
  • an inhibitor of the Hippo pathway is an inhibitor of G q .
  • an inhibitor of the Hippo pathway is an inhibitor of G q /n.
  • an inhibitor of the Hippo pathway is an inhibitor of Gq/14.
  • an inhibitor of the Hippo pathway is an inhibitor of Gq/15.
  • an inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gial . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gta3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G o a. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust Tn some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G z .
  • an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of Savl.
  • an inhibitor of the Hippo pathway is an inhibitor of Mob.
  • an inhibitor of the Hippo pathway is an inhibitor of YAP.
  • an inhibitor of the Hippo pathway is an inhibitor of TAZ.
  • an inhibitor of the Hippo pathway is an inhibitor of TEAD.
  • an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway.
  • an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g, 26S proteasome).
  • an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.
  • Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.
  • GEFs guanine nucleotide exchange factors
  • an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme.
  • an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease.
  • an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease.
  • USP47 is a member of the ubiquitin-specific protease (USP/UBP) superfamily of cysteine proteases.
  • the compounds disclosed herein are inhibitors of USP47.
  • the present disclosure provides a use of a compound, or a pharmaceutical salt or composition thereof, for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.
  • TEAD1, TEAD2, TEAD3, and/or TEAD4 The activity of a compound utilized in this disclosure as an inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, can be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof.
  • Alternate in vitro assays quantitate the ability of the inhibitor to bind to TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • TEAD4 e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment can be administered after one or more symptoms have developed.
  • treatment can be administered in the absence of symptoms.
  • treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.
  • the provided compounds are inhibitors of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) and are therefore useful for treating one or more disorders associated with activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • the present disclosure provides a method for treating a TEAD-mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof.
  • TEAD-mediated disorders, diseases, and/or conditions means any disease or other deleterious condition in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, is known to play a role. Accordingly, another aspect or embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are known to play a role.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • a therapeutically effective amount of refers to the amount of a TEAD inhibitor or a pharmaceutically acceptable salt thereof, which is effective to reduce or attenuate the biological activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof, provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition in a biological sample or in a patient.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • a therapeutically effective amount of refers to the amount of a TEAD inhibitor or a pharmaceutically acceptable salt thereof that measurably decreases the binding or signaling activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, or any TEAD-mediated activity.
  • the term “therapeutically effective amount” can encompass, in some embodiments, an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for inhibition of a TEAD transcription factor.
  • a therapeutically effective amount is an amount sufficient for treating a proliferative disease.
  • TEAD1, TEAD2, TEAD3, and/or TEAD4 expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • TEAD1, TEAD2, TEAD3, and/or TEAD4 activity comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof.
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4
  • provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of the Hippo pathway is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof.
  • the present disclosure provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a TEAD inhibitor compound as described herein, or a pharmaceutical salt or composition thereof.
  • a cellular proliferative disorder is cancer.
  • the cancer is characterized by increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity.
  • an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.
  • the terms “increased expression” and/or “increased activity” of a substance, such as TEAD, in a sample or cancer or patient refers to an increase in the amount of the substance, such as TEAD, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50- fold, about 100-fold, or higher, relative to the amount of the substance, such as TEAD, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g.,
  • a subject can also be determined to have an “increased expression” or “increased activity” of TEAD if the expression and/or activity of TEAD is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of TEAD in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples.
  • control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.
  • a proliferative disease refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990).
  • a proliferative disease can be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes, such as the matrix metalloproteinases (e.g, collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis.
  • Exemplary proliferative diseases include cancers (i.e. /‘malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
  • the cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
  • a cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcription coactivator (TAZ/YAP).
  • a cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD (e.g, TEAD1, TEAD2, TEAD3, and/or TEAD4).
  • the cancer is characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g, TEAD1, TEAD2, TEAD3, and/or TEAD4) activity.
  • TEAD e.g., TEAD1, TEAD2, TEAD3, and/or TEAD
  • the cancer is a cancer in which YAP is localized in the nucleus of the cancer cells.
  • a cancer is characterized by a mutant Ga-protein.
  • a mutant Ga-protein is selected from G12, G13, Gq, Gi l, Gi, Go, and Gs.
  • a mutant Ga-protein is G12.
  • a mutant Ga-protein is G13.
  • a mutant Ga-protein is Gq.
  • a mutant Ga-protein is Gl 1.
  • a mutant Ga-protein is Gi.
  • a mutant Ga-protein is Go.
  • Gs Ga-protein
  • a cancer is treated by inhibiting or reducing or decreasing or arresting further growth or spread of the cancer or tumor.
  • a cancer is treated by inhibiting or reducing the size (e.g, volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90% or at least 99% relative to the size of the cancer or tumor prior to treatment.
  • a cancer is treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90% or at least 99% relative to the quantity of the cancers or tumors prior to treatment.
  • the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma.
  • the cancer is mesothelioma, such as malignant mesothelioma.
  • cancer includes, without limitation, leukemias (e.g, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g, Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial s,
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma schwannoma
  • neurofibrosarcoma meningioma, melanoma
  • neuroblastoma
  • the cancer is acoustic neuroma, astrocytoma (e. , Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • astrocytoma e. , Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - G
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
  • Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymph
  • the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/ stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPN
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma.
  • Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas.
  • the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomy
  • the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastom
  • HCC hepatocellular
  • the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer
  • the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). Tn some embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments
  • the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
  • MPNST peripheral nerve sheath tumors
  • the cancer is neurofibromatosis- 1 associated MPNST.
  • the cancer is Waldenstrom
  • a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papillomavirus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma.
  • HCV human immunodeficiency virus
  • HPV human papillomavirus
  • a cancer is melanoma cancer.
  • a cancer is breast cancer.
  • a cancer is lung cancer.
  • a cancer is small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the compounds and compositions, according to the method of the present disclosure can be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer.
  • the exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like.
  • Compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure is decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.
  • patient or “subject,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated.
  • the compounds of the disclosure can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • Solid compositions of a similar type can also be employed as fdlers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
  • the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • additional therapeutic agents that are normally administered to treat that condition can also be present in the compositions of this disclosure.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated.”
  • the present disclosure provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • a compound of the current disclosure can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • a compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds.
  • a compound of the current disclosure can besides, or in addition, be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible, as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • One or more other therapeutic agent(s) can be administered separately from a compound or composition of the disclosure, as part of a multiple dosage regimen.
  • one or more other therapeutic agents can be part of a single dosage form, mixed together with a compound of this disclosure in a single composition.
  • one or more other therapeutic agent(s) and a compound or composition of the disclosure can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent(s) and a compound or composition of the disclosure are administered as a multiple dosage regimen within greater than 24 hours apart.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a compound of the present disclosure can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of the disclosure should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the disclosure can be administered.
  • compositions which comprise one or more other therapeutic agent(s) can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 pg/kg body weight/day of the one or more other therapeutic agent(s) can be administered.
  • the amount of one or more other therapeutic agent(s) present in the compositions of this disclosure may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent.
  • the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.
  • the compounds of this disclosure, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • Vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Implantable devices coated with a compound of this disclosure are another embodiment of the present disclosure.
  • one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor.
  • PARP Poly ADP ribose polymerase
  • a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).
  • one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor.
  • HDAC histone deacetylase
  • an HDAC inhibitor is selected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®, Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (EPIDAZA®, HBI-8000, Chipscreen Biosciences, China).
  • one or more other therapeutic agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor.
  • a CDK 4/6 inhibitor is selected from palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
  • one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor.
  • PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).
  • one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins.
  • Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells.
  • a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi -Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).
  • one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division.
  • a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis/Celgene), cabazitaxel (JEVTANA®, Sanofi -Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).
  • one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
  • a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals, MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene
  • one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist.
  • Approved VEGF inhibitors and kinase inhibitors useful in the present disclosure include: bevacizumab (AVASTIN®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/Sanofi).
  • VEGFR inhibitors such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFTNLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech/Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib
  • kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present disclosure include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S.
  • ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib ( Amgen/T akeda) .
  • one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake.
  • an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).
  • one or more other therapeutic agent is a proteasome inhibitor.
  • Approved proteasome inhibitors useful in the present disclosure include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda).
  • one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).
  • Approved PDGF antagonists which may be used in the present disclosure include olaratumab (LARTRUVO®; Eli Lilly).
  • Approved EGFR antagonists which may be used in the present disclosure include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).
  • one or more other therapeutic agent is an aromatase inhibitor.
  • an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).
  • one or more other therapeutic agent is an antagonist of the hedgehog pathway.
  • Approved hedgehog pathway inhibitors which may be used in the present disclosure include sonidegib (0D0MZ0®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma.
  • one or more other therapeutic agent is a folic acid inhibitor.
  • Approved folic acid inhibitors useful in the present disclosure include pemetrexed (ALIMTA®, Eli Lilly).
  • one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor.
  • CCR4 inhibitors being studied that may be useful in the present disclosure include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan).
  • one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor.
  • IDH inhibitors being studied which may be used in the present disclosure include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).
  • one or more other therapeutic agent is an arginase inhibitor.
  • Arginase inhibitors being studied which may be used in the present disclosure include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).
  • one or more other therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present disclosure include CB-839 (Calithera Biosciences).
  • one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells.
  • Approved antibodies that bind to tumor antigens which may be used in the present disclosure include rituximab (RITUXAN®, Genentech/Biogenldec); ofatumumab (anti-CD20, ARZERRA®, GlaxoSmithKline), obinutuzumab (anti-CD20, GAZYVA®, Genentech), ibritumomab (anti- CD20 and Yttrium-90, ZEVALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab em
  • one or more other therapeutic agent is a topoisomerase inhibitor.
  • Approved topoisomerase inhibitors useful in the present disclosure include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline).
  • Topoisomerase inhibitors being studied which may be used in the present disclosure include pixantrone (PIXUVRI®, CTI Biopharma).
  • one or more other therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2.
  • Approved anti-apoptotics which may be used in the present disclosure include venetoclax (VENCLEXTA®, AbbVie/Genentech); and blinatumomab (BLINCYTO®, Amgen).
  • Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present disclosure include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).
  • one or more other therapeutic agent is an androgen receptor inhibitor.
  • Approved androgen receptor inhibitors useful in the present disclosure include enzalutamide (XTANDI®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals).
  • one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens.
  • Approved SERMs useful in the present disclosure include raloxifene (EVISTA®, Eli Lilly).
  • one or more other therapeutic agent is an inhibitor of bone resorption.
  • An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases.
  • Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).
  • one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2.
  • Inhibitors of p53 suppression proteins being studied include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53.
  • ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).
  • one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGF13).
  • TGF-beta or TGF13 transforming growth factor-beta
  • Inhibitors of TGF-beta proteins being studied which may be used in the present disclosure include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165).
  • the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787).
  • the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) IntT J. Biological Sciences 8:964-978.
  • M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PD- Ll/TGFB trap compound (NCT02699515); and (NCT02517398).
  • M7824 is comprised of a fully human IgGl antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF
  • one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti -gly coprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE.
  • gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.
  • one or more other therapeutic agents is an antiproliferative compound.
  • antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of
  • aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole.
  • Exemestane is marketed under the trade name AROMASINTM.
  • Formestane is marketed under the trade name LENTARONTM. Fadrozole is marketed under the trade name AFEMATM. Anastrozole is marketed under the trade name ARTMTDEXTM Letrozole is marketed under the trade names FEMARATM or FEMArTM. Aminoglutethimide is marketed under the trade name ORIMETENTM.
  • a combination of the disclosure comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
  • antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen is marketed under the trade name NOLVADEXTM.
  • Raloxifene hydrochloride is marketed under the trade name EVISTATM.
  • Fulvestrant can be administered under the trade name FASLODEXTM.
  • a combination of the disclosure comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
  • anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEXTM).
  • CASODEXTM bicalutamide
  • gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name ZOLADEXTM.
  • topoisomerase I inhibitor includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148.
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSARTM.
  • Topotecan is marketed under the trade name HYCAMPTINTM.
  • topoisomerase II inhibitor includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CAELYXTM), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide is marketed under the trade name ETOPOPHOSTM.
  • Teniposide is marketed under the trade name VM 26-Bristol
  • Doxorubicin is marketed under the trade name ACRIBLASTINTM or ADRIAMYCINTM.
  • microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.
  • Paclitaxel is marketed under the trade name TAXOLTM Docetaxel is marketed under the trade name TAXOTERETM. Vinblastine sulfate is marketed under the trade name VINBLASTIN R.PTM. Vincristine sulfate is marketed under the trade name FARMISTINTM.
  • alkylating agent includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CYCLOSTINTM. Ifosfamide is marketed under the trade name HOLOXANTM
  • histone deacetylase inhibitors or "HDAC inhibitors” relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
  • SAHA suberoylanilide hydroxamic acid
  • antimetabolite includes, but is not limited to, 5 -fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed.
  • Capecitabine is marketed under the trade name XELODATM.
  • Gemcitabine is marketed under the trade name GEMZARTM.
  • platinum compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLATTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATINTM.
  • the term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds” as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factorreceptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor T (T
  • PI3K inhibitor includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to PI3Ka, PI3Ky, PI3K5, PI3K , PI3K-C2a, PI3K-C2 , PI3K- C2y, Vps34, pl lO-a, pl 10-p, pl lO-y, pl 10-8, p85-a, p85-P, p55-y, pl50, pl 01, and p87.
  • PI3K inhibitors useful in this disclosure include but are not limited to ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
  • Bcl-2 inhibitor includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see W02008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see W02004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ, of Michigan), and venetoclax.
  • the Bcl-2 inhibitor is a small molecule therapeutic.
  • the Bcl-2 inhibitor is a small molecule therapeutic.
  • BTK inhibitor includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
  • SYK inhibitor includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.
  • SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this disclosure can be found in W02003063794, W02005007623, and W02006078846, the entirety of which are incorporated herein by reference.
  • PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this disclosure can be found in W02004019973, W02004089925, W02007016176, US8138347, W02002088112, W02007084786,
  • W02007129161, W02006122806, W02005113554, and W02007044729 the entirety of which are incorporated herein by reference.
  • JAK inhibitory compounds and conditions treatable by such compounds in combination with compounds of this disclosure can be found in W02009114512, W02008109943, W02007053452, W02000142246, and W02007070514, the entirety of which are incorporated herein by reference.
  • Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. , unrelated to protein or lipid kinase inhibition e.g. , thalidomide (THALOMIDTM) and TNP-470.
  • TAALOMIDTM thalidomide
  • TNP-470 TNP-470.
  • proteasome inhibitors useful for use in combination with compounds of the disclosure include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.
  • Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
  • Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- y- or 8- tocopherol or a- y- or 8-tocotrienol.
  • cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREXTM), rofecoxib (VIOXXTM), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • CELEBREXTM celecoxib
  • VIOXXTM rofecoxib
  • etoricoxib etoricoxib
  • valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
  • bisphosphonates includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
  • Etridonic acid is marketed under the trade name DIDRONELTM.
  • Clodronic acid is marketed under the trade name BONEFOSTM.
  • Tiludronic acid is marketed under the trade name SkelidTM.
  • Pamidronic acid is marketed under the trade name AREDIATM.
  • Alendronic acid is marketed under the trade name FOSAMAXTM.
  • Ibandronic acid is marketed under the trade name BONDRANATTM.
  • Risedronic acid is marketed under the trade name ACTONELTM.
  • Zoledronic acid is marketed under the trade name ZOMETATM.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (RAPAMUNE®), everolimus (CERTICANTM), CCI-779 and ABT578.
  • heparanase inhibitor refers to compounds which target, decrease or inhibit heparin sulfate degradation.
  • the term includes, but is not limited to, PI-88.
  • biological response modifier refers to a lymphokine or interferons.
  • inhibitor of Ras oncogenic isoforms such as H-Ras, K-Ras, or N-Ras
  • a "famesyl transferase inhibitor” such as L-744832, DK8G557 or R115777 (ZARNESTRATM).
  • telomerase inhibitor refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.
  • methionine aminopeptidase inhibitor refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase.
  • Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
  • proteasome inhibitor refers to compounds which target, decrease or inhibit the activity of the proteasome.
  • Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VELCADETM) and MLN 341.
  • matrix metalloproteinase inhibitor or (“MMP” inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
  • MMP matrix metalloproteinase inhibitor
  • FMS-like tyrosine kinase inhibitors which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-P-D-arabinofuransyl cytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
  • FMS-like tyrosine kinase receptors are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
  • HSP90 inhibitors includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway.
  • Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.
  • antiproliferative antibodies includes, but is not limited to, trastuzumab (HERCEPTINTM), Trastuzumab-DMl, erbitux, bevacizumab (AVASTINTM), rituximab (RITUXAN®), PRO64553 (anti-CD40) and 2C4 Antibody.
  • HERCEPTINTM trastuzumab
  • Trastuzumab-DMl Trastuzumab-DMl
  • AVASTINTM bevacizumab
  • RITUXAN® bevacizumab
  • PRO64553 anti-CD40
  • 2C4 Antibody 2C4 Antibody.
  • antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.
  • AML acute myeloid leukemia
  • compounds of the current disclosure can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML
  • compounds of the current disclosure can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • drugs useful for the treatment of AML such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
  • anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate.
  • Compounds which target, decrease or inhibit activity of histone deacetylase (HD AC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases.
  • HD AC histone deacetylase
  • SAHA suberoylanilide hydroxamic acid
  • HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl) ⁇ 2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt.
  • Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230.
  • Tumor cell damaging approaches refer to approaches such as ionizing radiation.
  • the term "ionizing radiation” referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1 , pp.
  • EDG binders and ribonucleotide reductase inhibitors.
  • EDG binders refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720.
  • ribonucleotide reductase inhibitors refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5 -fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin.
  • Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.
  • VEGF vascular endothelial growth factor
  • compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATINTM; ENDOSTATINTM; anthranilic acid amides; ZD4190; Zd 6 474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (AVASTINTM).
  • VEGF aptamer such as Macugon
  • Photodynamic therapy refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers.
  • Examples of photodynamic therapy include treatment with compounds, such as VISUDYNETM and porfimer sodium.
  • Angiostatic steroids refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • angiogenesis such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
  • Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
  • chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
  • one or more other therapeutic agent is an immuno-oncology agent.
  • an immuno-oncology agent refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject.
  • the administration of an immuno-oncology agent with a compound of the disclosure has a synergic effect in treating a cancer.
  • An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule.
  • biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • an antibody is a monoclonal antibody.
  • a monoclonal antibody is humanized or human.
  • an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses.
  • Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF).
  • B7 family includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6 includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.
  • TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/ Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI/TL I A, TRAMP/DR3, EDAR, EDAI, XEDAR, EDA2, TNFR1, Lymphotoxin a/TNFP, TNFR2, TNFot, LTPR, Lymphotoxin aip2, FAS
  • an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL- 10, TGF-P, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
  • T cell activation e.g., IL-6, IL- 10, TGF-P, VEGF, and other immunosuppressive cytokines
  • an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM- 4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, TCOS-L, 0X40, OX40L, GTTR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
  • an antagonist of a protein that inhibits T cell activation e.g., immune checkpoint inhibitors
  • an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonists of activating receptors on NK cells.
  • an immuno-oncology agent is an antagonist of KIR, such as lirilumab.
  • an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
  • CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
  • an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
  • block inhibitory receptor engagement e.g., PD-L1/PD-1 interactions
  • Tregs e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex
  • an immuno-oncology agent is a CTLA-4 antagonist.
  • a CTLA-4 antagonist is an antagonistic CTLA-4 antibody.
  • an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.
  • an immuno-oncology agent is a PD-1 antagonist.
  • a PD-1 antagonist is administered by infusion.
  • an immuno- oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity.
  • a PD-1 antagonist is an antagonistic PD-1 antibody.
  • an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493).
  • an immuno-oncology agent may be pidilizumab (CT- 011).
  • an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP -224.
  • an immuno-oncology agent is a PD-L1 antagonist.
  • a PD-L1 antagonist is an antagonistic PD-L1 antibody.
  • a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS- 936559 (W02007/005874), and MSB0010718C (WO2013/79174).
  • an immuno-oncology agent is a LAG-3 antagonist.
  • a LAG-3 antagonist is an antagonistic LAG-3 antibody.
  • a LAG3 antibody is BMS-986016 (W010/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).
  • an immuno-oncology agent is a CD137 (4-1BB) agonist.
  • a CD137 (4-1BB) agonist is an agonistic CD137 antibody.
  • a CD137 antibody is urelumab or PF-05082566 (WO12/32433).
  • an immuno-oncology agent is a GITR agonist
  • a GITR agonist is an agonistic GITR antibody.
  • a GITR antibody is BMS-986153, BMS-986156, TRX-518 (W0006/105021, WG009/009116), or MK- 4166 (WO 11/028683).
  • an immuno-oncology agent is an indoleamine (2,3)- dioxygenase (IDO) antagonist.
  • IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (W009/73620, WO009/1156652, WO11/56652, WO12/142237).
  • an immuno-oncology agent is an 0X40 agonist.
  • an 0X40 agonist is an agonistic 0X40 antibody.
  • an 0X40 antibody is MEDL6383 or MEDI-6469.
  • an immuno-oncology agent is an OX40L antagonist.
  • an OX40L antagonist is an antagonistic 0X40 antibody.
  • an OX40L antagonist is RG-7888 (WO06/029879).
  • an immuno-oncology agent is a CD40 agonist.
  • a CD40 agonist is an agonistic CD40 antibody.
  • an immuno- oncology agent is a CD40 antagonist.
  • a CD40 antagonist is an antagonistic CD40 antibody.
  • a CD40 antibody is lucatumumab or dacetuzumab.
  • an immuno-oncology agent is a CD27 agonist.
  • a CD27 agonist is an agonistic CD27 antibody.
  • a CD27 antibody is varlilumab.
  • an immuno-oncology agent is MGA271 (to B7H3) (WO 11/109400).
  • an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab
  • an immuno-oncology agent is an immunostimulatory agent.
  • antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor- reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou e/c//. (2016) Sci. Transl. Med. 8.
  • the anti-PD-1 antibody nivolumab (OPDIVO®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti -angiogenic therapy.
  • the immunomodulatory therapeutic specifically induces apoptosis of tumor cells.
  • Approved immunomodulatory therapeutics which may be used in the present disclosure include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma).
  • an immuno-oncology agent is a cancer vaccine.
  • the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex/ Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma.
  • sipuleucel-T PROVENGE®, Dendreon/Valeant Pharmaceuticals
  • IMLYGIC® BioVex/ Amgen, previously known as T-VEC
  • an immuno-oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS -activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCTO 1166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC)
  • an immuno-oncology agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5- fluorocytosine to the cytotoxic drug 5 -fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3-E2F-delta24-hTNFa-IRES- hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which
  • an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR.
  • the T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.
  • CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes.
  • TCR T-cell receptor
  • the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al , hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD 19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta).
  • an antigen binding domain such as a domain that binds to CD 19
  • CD3 zeta intracellular signaling domain of the T cell antigen receptor complex zeta chain
  • the CAR When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD 19, the antigen is expressed on malignant B cells.
  • an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor y (RORyt).
  • RORyt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Thl7) and CD8+ (Tcl7) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells.
  • an activator of RORyt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).
  • an immunostimulatory agent is an agonist or activator of a tolllike receptor (TLR).
  • TLR tolllike receptor
  • Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax).
  • SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772).
  • Agonists or activators of TLR8 which may be used in the present disclosure include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).
  • immuno-oncology agents that can be used in the present disclosure include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol- Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (ZPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti -KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.
  • BMS-663513 Bristol-Myers Squib
  • an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORyt.
  • an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15).
  • rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453).
  • an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12).
  • an IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/ Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the soluble IL- 15 binding protein IL- 15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268).
  • a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.
  • an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages 603-622, the content of which is incorporated herein by refenrece in its entirety.
  • an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams el al.
  • an immuno-oncology agent is a small molecule targeting an immuno-oncoloby target selected from those listed in Table 2 of Jerry L. Adams et al.
  • an immuno-oncology agent is a small molecule agent selectd from those listed in Table 2 of Jerry L.
  • an immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the content of which is incorporated herein by refenrece in its entirety.
  • an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.
  • an immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BITE® ) antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390, the conten of which is incorporated herein by reference in its entirety.
  • an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct is a CD19/CD3 bispecific antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct is an EGFR/CD3 bispecific antibody construct.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.
  • a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis.
  • the bystander cells are in solid tumors.
  • the bystander cells being lysed are in proximity to the BITE®-acticvated T cells.
  • the bystander cells comprise tumor-associated antigen (TAA) negatgive cancer cells.
  • TAA tumor-associated antigen
  • the bystander cells comprise EGFR-negative cancer cells.
  • an immuno- oncology agent is an antibody which blocks the PD-L1/PD1 axis and/or CTLA4.
  • an immuno-oncology agent is an ex vivo expanded tumor-infdtrating T cell.
  • an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs).
  • an immuno-oncology agent is an immune checkpoint inhibitor as described herein.
  • checkpoint inhibitor as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient.
  • T-cell exhaustion One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.
  • PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.
  • CTL-4 cytotoxic T-lymphocyte antigen 4
  • BTLA B and T Lymphocyte Attenuator
  • Tim-3 T cell Immunoglobulin and Mucin domain-3
  • Lag-3 Lymphocyte Activation Gene-3
  • checkpoint regulators act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.
  • an immune checkpoint inhibitor is an antibody to PD-1.
  • PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti -tumor immune response.
  • PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti -tumor immune response.
  • the checkpoint inhibitor is a biologic therapeutic or a small molecule.
  • the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof.
  • the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof.
  • the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof.
  • the interleukin is IL-7 or IL- 15.
  • the interleukin is glycosylated IL-7.
  • the vaccine is a dendritic cell (DC) vaccine.
  • DC dendritic cell
  • Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system.
  • Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands.
  • Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, y5, and memory CD8 + (( 3) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands.
  • CTLA-4 CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, y5, and memory CD8 + (( 3) T cells), CD160 (also referred to as BY55
  • B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7- H4, B7-H5, B7-H6 and B7-H7.
  • Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049.
  • Illustrative immune checkpoint inhibitors include, but are not limited to, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS- 936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor).
  • Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3.
  • the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-Ll antagonist, and a CTLA-4 antagonist.
  • the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®).
  • the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, EMFINZI®, AstraZeneca); and atezolizumab (anti-PD-Ll antibody, TECENTRIQ®, Genentech).
  • nivolumab anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb
  • pembrolizumab anti-PD-1 antibody, KEYTRUDA®, Merck
  • ipilimumab anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb
  • durvalumab anti-PD-Ll antibody, EMFINZI®,
  • the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab.
  • MK-3475 lambrolizumab
  • BMS-936558 nivolumab
  • CT-011 pidilizumab
  • AMP-224 pidilizumab
  • MDX-1105 MEDI4736
  • MPDL3280A MPDL3280A
  • BMS-936559 ipilimumab
  • lirlumab IPH2101, pembrolizumab (KEYTRUDA®)
  • tremelimumab tremelimum
  • an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT- 011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or P
  • Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma.
  • AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).
  • a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3).
  • TIM-3 inhibitors that may be used in the present disclosure include TSR-022, LY3321367 and MBG453.
  • TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633).
  • LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109).
  • MBG453 Novartis
  • NCT02608268 is an anti- TIM-3 antibody which is being studied in advanced malignancies
  • a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells.
  • TIGIT inhibitors that may be used in the present disclosure include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428) [00461]
  • a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3).
  • LAG-3 inhibitors that may be used in the present disclosure include BMS- 986016 and REGN3767 and IMP321.
  • BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981).
  • REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782).
  • IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).
  • Checkpoint inhibitors that can be used in the present disclosure include 0X40 agonists.
  • 0X40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MED 10562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155
  • Checkpoint inhibitors that can be used in the present disclosure include CD137 (also called 4-1BB) agonists.
  • CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).
  • Checkpoint inhibitors that can be used in the present disclosure include CD27 agonists.
  • CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).
  • Checkpoint inhibitors that can be used in the present disclosure include glucocorticoid- induced tumor necrosis factor receptor (GITR) agonists.
  • GITR glucocorticoid- induced tumor necrosis factor receptor
  • GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgGl Fc domain, in advanced solid tumors (NCT02583165).
  • TRX518 Leap Therapeutics
  • Checkpoint inhibitors that can be used in the present disclosure include inducible T- cell co-stimulator (ICOS, also known as CD278) agonists.
  • ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).
  • Checkpoint inhibitors that can be used in the present disclosure include killer IgG-like receptor (KIR) inhibitors.
  • KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti -KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).
  • KIR3DL2 killer IgG-like receptor
  • Checkpoint inhibitors that can be used in the present disclosure include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa).
  • CD47/SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgGl, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC- 90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002);
  • Checkpoint inhibitors that can be used in the present disclosure include CD73 inhibitors.
  • CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).
  • Checkpoint inhibitors that can be used in the present disclosure include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173).
  • STING stimulator of interferon genes protein
  • Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU- S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).
  • Checkpoint inhibitors that can be used in the present disclosure include CSF1R inhibitors.
  • CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-lR antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((lR,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2- carboxylic
  • Checkpoint inhibitors that can be used in the present disclosure include NKG2A receptor inhibitors.
  • NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH220I, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).
  • the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
  • XRPD patterns were collected using a PANalytical XPert Pro or Empyrian diffractometer.
  • the specimen was analyzed using Cu radiation produced using an Optix long fine- focus source.
  • An elliptically graded multilayer mirror was used to focus the Cu Ka X-rays of the source through the specimen and onto the detector.
  • the specimen was sandwiched between 3- micron thick films, analyzed in transmission geometry, and rotated parallel to the diffraction vector to optimize orientation statistics.
  • a beam-stop and helium purge was used to minimize the background generated by air scattering.
  • Soller slits were used for the incident and diffracted beams to minimize axial divergence.
  • Diffraction patterns were collected using a scanning positionsensitive detector (X'Celerator) located 240 mm from the specimen. The data- acquisition parameters of each diffraction pattern are displayed above the image of each pattern in the data section. Prior to the analysis a silicon specimen (NIST standard reference material 640c) was analyzed to verify the position of the silicon 111 peak.
  • X'Celerator scanning positionsensitive detector
  • PXRD was carried out via Bruker D8 XRD. Approximately 2-50 mg of material (pending the availability of sample amount) was transferred to a zero background sample holder coated with a thin layer of petroleum jelly and leveled with a glass plate. Samples were characterized via reflectance geometry. The following table 10 describes experimental parameters.
  • DSC was carried out via TA Instruments DSC Q2000 V24. l l Build 124. Approximately 2mg to 6mg of sample was weighed into Aluminum hermetically sealed pans. Samples were heated at a ramp rate of 10°C/min under a Nitrogen atmosphere. Initial and final temperature ranges varied by experiment; generally samples were ramped from 25°C to approximately 250°C. Specific initial and final temperatures for individual experiments are visible in DSC thermograms.
  • TG analyses were performed using a TA Instruments thermogravimetric analyzer. Temperature calibration was performed using nickel and AlumelTM Each sample was placed in a platinum pan. The sample was hermetically sealed, the lid pierced, then inserted into the TG furnace. The furnace was heated under nitrogen. The data acquisition parameters are displayed in the image of each thermogram.
  • the method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., 00-350-10 means "from ambient to 350 °C, at l0 °C/min".
  • TGA was carried out via TA Instruments TGA Q50 V20.13 Build 39. Approximately 2-8mg of sample was placed onto a platinum pan. Samples were heated at a ramp rate of 10°C/min from 25°C to 35O°C under a Nitrogen atmosphere. Nuclear Magnetic Resonance (NMR) Spectroscopy
  • Form A of Compound A [0001] Form A of compound A was prepared as described above.
  • FIG. 1 depicts an XRPD pattern of Form A of compound A.
  • FIG. 2 depicts a TGA/DTA trace of Form A of compound A.
  • Form B of compound A was prepared as described above.
  • the position 20 is within ⁇ 0.2.
  • FIG. 3 depicts an XRPD pattern of Form B of compound A.
  • FIG. 4 depicts a TGA/DSC trace of Form B of compound A.
  • FIG. 7 depicts an XRPD pattern of Form A of compound 1.
  • FIG. 8 depicts a TGAZDSC trace of Form A of compound 1.
  • Form B of compound 1 was prepared as described above. [0016] Table 4, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form B of compound 1.
  • FIG. 9 depicts an XRPD pattern of Form B of compound 1 with trace amount Form A.
  • FIG. 10 depicts a TGA/DSC trace of Form B of compound 1 with trace amount Form
  • Form A of Compound 2 [0019] Form A of compound 2 was prepared as described above.
  • FIG. 11 depicts an XRPD pattern of Form A of compound 2.
  • FIG. 12 depicts a TGA/DSC trace of Form A of compound 2.
  • FIG. 13 depicts an XRPD pattern of Form A of compound 3.
  • FIG. 14 depicts a TGA/DSC trace of Form A of compound 3.
  • the position 26 is within ⁇ 0.2.
  • FIG. 15 depicts an XRPD pattern of Form A of compound 4.
  • FIG. 16 depicts a TGA/DSC trace of Form A of compound 4.
  • FIG. 17 depicts an XRPD pattern of Form A of compound 5.
  • FIG. 18 depicts a TGA/DSC trace of Form A of compound 5.
  • FIG. 19 depicts an XRPD pattern of Form A of compound 6.
  • FIG. 20 depicts a TGA/DSC trace of Form A of compound 6.

Abstract

The present disclosure provides crystalline forms of the free base and of various salts of the compound of formula A and compositions and methods thereof, useful for treating various conditions in which the Transcriptional Enhancer Associate Domain (TEAD) is implicated, by the administration of small molecule therapeutics which act as inhibitors of TEAD.

Description

POLYMORPHIC COMPOUNDS AND USES THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of International Patent Application No. PCT/CN2022/088996, filed April 25, 2022, the contents of which is herein incorporated by reference in its entirety.
TECHNICAL FIELD OF THE DISCLOSURE
[0002] The present disclosure relates to N-methyl-3-(l-methyl-lH-imidazol-4-yl)-4-((4- (trifluoromethyl)benzyl)amino)benzenesulfonamide (Compound A) and salts thereof, their various crystalline forms, and compositions and methods thereof useful for inhibition of Transcriptional Enhancer Associate Domain (TEAD) and treatment of various diseases, disorders, and conditions associated with TEAD.
BACKGROUND OF THE DISCLOSURE
[0003] Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are transcriptional co-activators of the Hippo pathway network and regulate cell proliferation, migration, and apoptosis. Inhibition of the Hippo pathway promotes YAP/TAZ translocation to the nucleus, wherein YAP/TAZ interact with TEAD transcription factors and coactivate the expression of target genes and promote cell proliferation. Hyperactivation of YAP and TAZ and/or mutations in one or more members of the Hippo pathway network have been implicated in numerous cancers.
SUMMARY OF THE DISCLOSURE
[0004] Compounds of the present disclosure, and pharmaceutically acceptable salts and compositions thereof, are useful for treating a variety of diseases, disorders or conditions associated with TEAD. In general, salt forms or freebase forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of diseases or disorders as described in detail herein. Such compounds are represented by the chemical structure below, denoted as compound A:
Figure imgf000003_0001
[0005] Compounds of the present disclosure, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with TEAD. Such diseases, disorders, or conditions include those described herein.
[0006] Compounds provided by this disclosure are also useful for the study of TEAD in biological and pathological phenomena; the study of intracellular signal transduction pathways; and the comparative evaluation of new TEAD inhibitors in vitro or in vivo.
BRIEF DESCRIPTION OF THE FIGURES
[0007] FIG. 1 depicts the XRPD pattern of Compound A, Form A.
[0008] FIG. 2 depicts a DSC trace of Compound A, Form A.
[0009] FIG. 3 depicts the XRPD pattern of Compound A, Form B.
[0010] FIG. 4 depicts a DSC trace of Compound A, Form B.
[0011] FIG 5 depicts the XRPD pattern of a mixture of Form A and Form B Compound A.
[0012] FIG 6 depicts the TGA/DSC trace of a mixture of Form A and Form B Compound A.
[0013] FIG. 7 depicts the XRPD pattern of Compound 1, Form A.
[0014] FIG. 8 depicts a TGA/DSC trace of Compound 1, Form A.
[0015] FIG. 9 depicts the XRPD pattern of Compound 1, Form B with trace amount Form A.
[0016] FIG. 10 depicts the TGA/DSC trace of Compound 1, Form B with trace amount Form A.
[0017] FIG. 11 depicts the XRPD pattern of Compound 2, Form A.
[0018] FIG. 12 depicts the TGA/DSC trace of Compound 2, Form A.
[0019] FIG. 13 depicts the XRPD pattern of Compound 3, Form A.
[0020] FIG. 14 depicts the TGA/DSC trace of Compound 3, Form A.
[0021] FIG. 15 depicts the XRPD pattern of Compound 4, Form A.
[0022] FIG. 16 depicts the TGA/DSC trace of Compound 4, Form A. [0023] FTG. 17 depicts the XRPD pattern of Compound 5, Form A.
[0024] FIG. 18 depicts the TGA/DSC trace of Compound 5, Form A.
[0025] FIG. 19 depicts the XRPD pattern of Compound 6, Form A.
[0026] FIG. 20 depicts the TGA/DSC trace of Compound 6, Form A.
DETAILED DESCRIPTION OF THE DISCLOSURE
General Description of Certain Aspects of the Disclosure
[0027] United States Patent Publication No. 2020-0407327 ("the '327 publication," the entireties of which are incorporated herein by reference), describes certain TEAD inhibiting compounds. Such compounds include compound A:
Figure imgf000004_0001
[0028] Compound A, N-methyl-3-(l-methyl-lH-imidazol-4-yl)-4-((4-
(trifluoromethyl)benzyl)amino)benzenesulfonamide, is designated as compound 1-32 in the '327 publication.
[0029] It would be desirable to provide a solid form of compound A (e.g., as a freebase thereof or salt thereof) that imparts characteristics such as improved aqueous solubility, stability and ease of formulation. Accordingly, the present disclosure provides both free base forms and salt forms of compound A:
Figure imgf000004_0002
Free Base Forms o f Compound A [0030] It is contemplated that compound A can exist in a variety of physical forms. For example, compound A can be in solution, suspension, or in solid form. In certain embodiments, compound A is in solid form. When compound A is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
[0031] In some embodiments, the present disclosure provides a form of compound A substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include different forms of compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound A. In certain embodiments, at least about 95% by weight of a form of compound A is present. In still other embodiments of the disclosure, at least about 99% by weight of a form of compound A is present
[0032] According to one embodiment, a form of compound A is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition. According to another embodiment, a form of compound A contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. In other embodiments, a form of compound A contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
[0033] The structure depicted for a form of compound A is also meant to include all tautomeric forms of compound A. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C -enriched carbon are within the scope of this disclosure.
[0034] It has been found that compound A can exist in a variety of solid forms. Exemplary forms include polymorphs such as those described herein.
[0035] As used herein, the term "polymorph" refers to the different crystal structures into which a compound, or a salt or solvate thereof, can crystallize. [0036] In certain embodiments, compound A is a crystalline solid. Tn other embodiments, compound A is a crystalline solid substantially free of amorphous compound A. As used herein, the term "substantially free of amorphous compound A" means that the compound contains no significant amount of amorphous compound A. In certain embodiments, at least about 95% by weight of crystalline compound A is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound A is present.
[0037] It has been found that compound A can exist in at least two distinct polymorphic forms.
In certain embodiments, the present disclosure provides a polymorphic form of compound A referred to herein as Form A. In certain embodiments, the present disclosure provides a polymorphic form of compound A referred to herein as Form B. In certain embodiments, the present disclosure provides a mixture of Form A and Form B of compound A.
[0038] In some embodiments, compound A is amorphous. In some embodiments, compound A is amorphous, and is substantially free of crystalline compound A.
Form A of Compound A
[0039] In some embodiments, Form A of compound A has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 1 below.
Table 1 - XRPD Peak Positions for Form A of Compound A
Figure imgf000006_0001
Figure imgf000007_0001
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[0040] In some embodiments, Form A of compound A is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 17.2, about 19.2 and about 26.7 degrees 2-theta. Tn some embodiments, Form A of compound A is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 17.2, about 19.2 and about 26.7 degrees 2-theta. In some embodiments, Form A of compound A is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 17.2, about 19.2 and about 26.7 degrees 2-theta.
[0041] In certain embodiments, the X-ray powder diffraction pattern of Form A of compound A is substantially similar to the XRPD provided in FIG. 1. In certain embodiments, the Differential Scanning Calorimetry (DSC) of Form A of compound A is substantially similar to the DSC provided in FIG. 2.
[0042] Methods for preparing Form A of compound A are described infra.
Form B of Compound A
[0043] In some embodiments, Form B of compound A has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 2 below.
Table 2 - XRPD Peak Positions for Form B of Compound A
Figure imgf000008_0001
Figure imgf000009_0001
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[0044] In some embodiments, Form B of compound A is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 13.7, about 18.3 and about 19.8 degrees 2-theta. In some embodiments, Form B of compound A is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 13.7, about 18.3 and about 19.8 degrees 2-theta. In some embodiments, Form B of compound A is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 13.7, about 18.3 and about 19.8 degrees 2-theta.
[0045] In certain embodiments, the X-ray powder diffraction pattern of Form B of compound A is substantially similar to the XRPD provided in FIG. 3. In certain embodiments, the DSC of Form B of compound A is substantially similar to the DSC provided in FIG. 4.
[0046] Methods for preparing Form B of compound A are described infra. Mixture of Form A and Form B of Compound A
[0047] In some embodiments, the present disclosure provides a mixture of Form A and Form B of compound A, which has an X-ray powder diffraction pattern substantially similar to the XRPD provided in FIG. 5.
[0048] In some embodiments, a mixture of Form A and Form B of compound A has a TGA/DSC substantially similar to the TGA/DSC provided in FIG. 6.
[0049] Methods for preparing a mixture of Form A and Form B of compound A are described infra.
[0050] In some embodiments, the present disclosure provides compound A:
Figure imgf000010_0001
A wherein the compound is crystalline.
[0051] In some embodiments, the present disclosure provides compound A, wherein the compound is substantially free of amorphous compound A.
[0052] In some embodiments, the present disclosure provides compound A, wherein the compound is substantially free of impurities.
[0053] In some embodiments, the present disclosure provides compound A, wherein the compound has an XRPD substantially similar to that depicted in FIG. 1.
[0054] In some embodiments, the present disclosure provides compound A, wherein the compound has an XRPD substantially similar to that depicted in FIG. 3.
[0055] In some embodiments, the present disclosure provides compound A, wherein the compound has an XRPD substantially similar to that depicted in FIG. 5.
[0056] In some embodiments, the present disclosure provides a composition comprising compound A and a pharmaceutically acceptable carrier or excipient.
[0057] In some embodiments, the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound A or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound A or composition thereof.
[0058] In some embodiments, the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound A or composition thereof. In some embodiments, the TEAD-mediated disorder is a proliferative disease such as cancer.
Salt Forms o f Compound A
[0059] In some embodiments, an acid and compound A are ionically bonded to form one of compounds 1 through 6, described below. It is contemplated that compounds 1 through 6 can exist in a variety of physical forms. For example, compounds 1 through 6 can be in solution, suspension, or in solid form. In certain embodiments, compounds 1 through 6 are in solid form. When compounds 1 through 6 are in solid form, the compounds may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms of compounds 1 through 6 are described below.
Compound 1 (Maleate Salt of Compound A)
[0060] According to one embodiment, the present disclosure provides a maleate salt of compound A, represented by compound 1 :
Figure imgf000011_0001
[0061] It will be appreciated by one of ordinary skill in the art that the maleic acid and compound A are ionically bonded to form compound 1. It is contemplated that compound 1 can exist in a variety of physical forms. For example, compound 1 can be in solution, suspension, or in solid form. In certain embodiments, compound 1 is in solid form. When compound 1 is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below. [0062] In some embodiments, the present disclosure provides compound 1 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess maleic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 1. In certain embodiments, at least about 95% by weight of compound 1 is present. In still other embodiments of the disclosure, at least about 99% by weight of compound 1 is present.
[0063] According to one embodiment, compound 1 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition. According to another embodiment, compound 1 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. In other embodiments, compound 1 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
[0064] The structure depicted for compound 1 is also meant to include all tautomeric forms of compound 1. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure.
[0065] It has been found that compound 1 can exist in a variety of solid forms. Exemplary forms include polymorphs such as those described herein.
[0066] In certain embodiments, compound 1 is a crystalline solid. In other embodiments, compound 1 is a crystalline solid substantially free of amorphous compound 1. As used herein, the term "substantially free of amorphous compound 1" means that the compound contains no significant amount of amorphous compound 1. In certain embodiments, at least about 95% by weight of crystalline compound 1 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 1 is present.
[0067] It has been found that compound 1 can exist in at least two distinct polymorphic forms. In some embodiments, the present disclosure provides a polymorphic form of compound 1 referred to herein as Form A. Tn some embodiments, the present disclosure provides a polymorphic form of compound 1 referred to herein as Form B.
[0068] In some embodiments, compound 1 is amorphous. In some embodiments, compound 1 is amorphous, and is substantially free of crystalline compound 1.
Form A of Compound 1
[0069] In some embodiments, Form A of compound 1 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 3 below.
Table 3- XRPD Peak Positions for Form A of Compound 1
Figure imgf000013_0001
Figure imgf000014_0001
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[0070] In some embodiments, Form A of compound 1 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 12.0 and about 20.7 degrees 2-theta. In some embodiments, Form A of compound 1 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 12.0 and about 20.7 degrees 2-theta. In some embodiments, Form A of compound 1 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 7.8, about 12.0 and about 20.7 degrees 2-theta.
[0071] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 7. In certain embodiments, the DSC is substantially similar to the DSC provided in FIG. 8. In certain embodiments, the TGA is substantially similar to the TGA provided in FIG. 8.
[0072] Methods for preparing Form A of compound 1 are described infra.
Form B of Compound 1
[0073] In some embodiments, Form B of compound 1 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 4 below.
Table 4 - XRPD Peak Positions for Form B of Compound 1
Figure imgf000014_0002
Figure imgf000015_0002
1 In this and all subsequent tables, the position 20 is within ± 0.2.
[0074] In some embodiments, Form B of compound 1 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 18.9 and about 21.8 degrees 2-theta. In some embodiments, Form B of compound 1 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 18.9 and about 21.8 degrees 2-theta. In some embodiments, Form B of compound 1 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 18.9 and about 21.8 degrees 2-theta.
[0075] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 9. In certain embodiments, the DSC is substantially similar to the DSC provided in FIG. 10. In certain embodiments, the TGA is substantially similar to the TGA provided in FIG. 10.
[0076] Methods for preparing Form B of compound 1 are described infra.
[0077] In some embodiments, the present disclosure provides compound 1:
Figure imgf000015_0001
[0078] In some embodiments, the present disclosure provides compound 1, wherein the compound is crystalline.
[0079] In some embodiments, the present disclosure provides compound 1, wherein the compound is a crystalline solid substantially free of amorphous compound 1.
[0080] In some embodiments, the present disclosure provides compound 1, wherein the compound is substantially free of impurities.
[0081] In some embodiments, the present disclosure provides compound 1, wherein the compound has one or more peaks in its XRPD selected from those at 7.8, about 12.0 and about 20.7 degrees 2-theta. In some embodiments, the present disclosure provides compound 1, wherein the compound has at least two peaks in its XRPD selected from those at about 7.8, about 12.0 and about 20.7 degrees 2-theta. In some embodiments, the present disclosure provides compound 1, wherein the compound is of Form A.
[0082] In some embodiments, the present disclosure provides compound 1, wherein the compound has an XRPD substantially similar to that depicted in FIG. 7.
[0083] In some embodiments, the present disclosure provides compound 1, wherein the compound has one or more peaks in its XRPD selected from those at 13.3, about 18.9 and about 21.8 degrees 2-theta. In some embodiments, the present disclosure provides compound 1, wherein the compound has at least two peaks in its XRPD selected from those at about 13.3, about 18.9 and about 21.8 degrees 2-theta. In some embodiments, the present disclosure provides compound 1, wherein the compound is of Form B.
[0084] In some embodiments, the present disclosure provides compound 1, wherein the compound has an XRPD substantially similar to that depicted in FIG. 9.
[0085] In some embodiments, the present disclosure provides a composition comprising compound 1 and a pharmaceutically acceptable carrier or excipient.
[0086] In some embodiments, the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 1 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 1 or composition thereof.
[0087] In some embodiments, the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 1 or composition thereof. Tn some embodiments, the TEAD-mediated disorder is a proliferative disease such as cancer.
Compound 2 (Hemi-Maleate Salt of Compound A)
[0088] According to one embodiment, the present disclosure provides a maleate hemi-salt of compound A, represented by compound 2:
Figure imgf000017_0001
2.
[0089] It will be appreciated by one of ordinary skill in the art that the maleic acid and compound A are ionically bonded to form compound 2. It is contemplated that compound 2 can exist in a variety of physical forms. For example, compound 2 can be in solution, suspension, or in solid form. In certain embodiments, compound 2 is in solid form. When compound 2 is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
[0090] In some embodiments, the present disclosure provides compound 2 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess maleic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 2. In certain embodiments, at least about 95% by weight of compound 2 is present. In still other embodiments of the disclosure, at least about 99% by weight of compound 2 is present.
[0091] According to one embodiment, compound 2 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition. According to another embodiment, compound 2 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. In other embodiments, compound 2 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
[0092] The structure depicted for compound 2 is also meant to include all tautomeric forms of compound 2. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure.
[0093] It has been found that compound 2 can exist in at least one distinct polymorphic form. In some embodiments, the present disclosure provides a polymorphic form of Compound 2 referred to herein as Form A. In some embodiments, Form A of Compound 2 comprises compound A and maleic acid in a ratio of about 2: 1.
[0094] In certain embodiments, compound 2 is a crystalline solid. In other embodiments, compound 2 is a crystalline solid substantially free of amorphous compound 2. As used herein, the term "substantially free of amorphous compound 2" means that the compound contains no significant amount of amorphous compound 2. In certain embodiments, at least about 95% by weight of crystalline compound 2 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 2 is present.
[0095] It has been found that compound 2 can exist in at least one distinct polymorphic form. In some embodiments, the present disclosure provides a polymorphic form of Compound 2 referred to herein as Form A.
[0096] In some embodiments, compound 2 is amorphous. In some embodiments, compound 2 is amorphous, and is substantially free of crystalline compound 2.
Form A of Compound 2
[0097] In some embodiments, Form A of compound 2 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 5 below.
Table 5 - XRPD Peak Positions for Form A of Compound 2
Figure imgf000018_0001
Figure imgf000019_0001
1 In this and all subsequent tables, the position 20 is within ± 0.2.
[0098J In some embodiments, Form A of compound 2 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.3, about 11.3 and about 16.0 degrees 2-theta. In some embodiments, Form A of compound 2 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.4, about 12.3 and about 17.8 degrees 2-theta. In some embodiments, Form A of compound 2 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 7.4, about 12.3 and about 17.8 degrees 2-theta.
[0099] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 11. In certain embodiments, the DSC is substantially similar to the DSC provided in FIG. 12. In certain embodiments, the TGA is substantially similar to the TGA provided in FIG. 12.
[00100] Methods for preparing Form A of compound 2 are described infra.
[00101] In some embodiments, the present disclosure provides compound 2:
Figure imgf000020_0001
2.
[00102] In some embodiments, the present disclosure provides compound 2, wherein the compound is crystalline.
[00103] In some embodiments, the present disclosure provides compound 2, wherein the compound is a crystalline solid substantially free of amorphous compound 2.
[00104] In some embodiments, the present disclosure provides compound 2, wherein the compound is substantially free of impurities.
[00105] In some embodiments, the present disclosure provides compound 2, wherein the compound has one or more peaks in its XRPD selected from those at about 7.4, about 12.3 and about 17.8 degrees 2-theta. In some embodiments, the present disclosure provides compound 2, wherein the compound has at least two peaks in its XRPD selected from those at about 7.4, about 12.3 and about 17.8 degrees 2-theta. In some embodiments, the present disclosure provides compound 2, wherein the compound is of Form A. In some embodiments, Form A of Compound 2 comprises compound A and maleic acid in a ratio of about 2: 1.
[00106] In some embodiments, the present disclosure provides compound 2, wherein the compound has an XRPD substantially similar to that depicted in FIG. 11.
[00107] In some embodiments, the present disclosure provides a composition comprising compound 2 and a pharmaceutically acceptable carrier or excipient.
[00108] In some embodiments, the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 2 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 2 or composition thereof.
[00109] In some embodiments, the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 2 or composition thereof. Tn some embodiments, the TEAD-mediated disorder is a proliferative disease such as cancer.
Compound 3 (Mesylate Salt of Compound A)
[00110] According to one embodiment, the present disclosure provides a mesylate salt of compound A, represented by compound 3:
Figure imgf000021_0001
[00111] It will be appreciated by one of ordinary skill in the art that the methanesulfonic acid and compound A are ionically bonded to form compound 3. It is contemplated that compound 3 can exist in a variety of physical forms. For example, compound 3 can be in solution, suspension, or in solid form. In certain embodiments, compound 3 is in solid form. When compound 3 is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
[00112] In some embodiments, the present disclosure provides compound 3 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess methanesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 3. In certain embodiments, at least about 95% by weight of compound 3 is present. In still other embodiments of the disclosure, at least about 99% by weight of compound 3 is present.
[00113] According to one embodiment, compound 3 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition. According to another embodiment, compound 3 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. In other embodiments, compound 3 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
[00114] The structure depicted for compound 3 is also meant to include all tautomeric forms of compound 3. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure.
[00115] It has been found that compound 3 can exist in at least one distinct polymorphic form. In some embodiments, the present disclosure provides a polymorphic form of Compound 3 referred to herein as Form A.
[00116] In certain embodiments, compound 3 is a crystalline solid. In other embodiments, compound 3 is a crystalline solid substantially free of amorphous compound 3. As used herein, the term "substantially free of amorphous compound 3" means that the compound contains no significant amount of amorphous compound 3. In certain embodiments, at least about 95% by weight of crystalline compound 3 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 3 is present.
[00117] In some embodiments, compound 3 is amorphous. In some embodiments, compound 3 is amorphous, and is substantially free of crystalline compound 3.
Form A of Compound 3
[00118] In some embodiments, Form A of compound 3 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 6 below.
Table 6 - XRPD Peak Positions for Form A of Compound 3
Figure imgf000022_0001
Figure imgf000023_0002
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[00119] In some embodiments, Form A of compound 3 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta. In some embodiments, Form A of compound 3 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta.
[00120] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 13. In certain embodiments, the DSC is substantially similar to the DSC provided in FIG. 14. In certain embodiments, the TGA is substantially similar to the TGA provided in FIG. 14.
[00121] Methods for preparing Form A of compound 3 are described infra.
[00122] In some embodiments, the present disclosure provides compound 3:
Figure imgf000023_0001
3
[00123] In some embodiments, the present disclosure provides compound 3, wherein the compound is crystalline.
[00124] In some embodiments, the present disclosure provides compound 3, wherein the compound is a crystalline solid substantially free of amorphous compound 3.
[00125] In some embodiments, the present disclosure provides compound 3, wherein the compound is substantially free of impurities.
[00126] In some embodiments, the present disclosure provides compound 3, wherein the compound has one or more peaks in its XRPD selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta. In some embodiments, the present disclosure provides compound 3, wherein the compound has at least two peaks in its XRPD selected from those at about 13.3, about 14.7 and about 4.4 degrees 2-theta. In some embodiments, the present disclosure provides compound 3, wherein the compound is of Form A.
[00127] In some embodiments, the present disclosure provides compound 3, wherein the compound has an XRPD substantially similar to that depicted in FIG. 13.
[00128] In some embodiments, the present disclosure provides a composition comprising compound 3 and a pharmaceutically acceptable carrier or excipient.
[00129] In some embodiments, the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 3 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 3 or composition thereof.
[00130] In some embodiments, the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 3 or composition thereof. In some embodiments, the TEAD-mediated disorder is a proliferative disease such as cancer.
Compound 4 (Tosylate Salt of Compound A)
[00131] According to one embodiment, the present disclosure provides a tosylate salt of compound A, represented by compound 4:
Figure imgf000025_0001
[00132] It will be appreciated by one of ordinary skill in the art that the p-toluenesulfonic acid and compound A are ionically bonded to form compound 4. It is contemplated that compound 4 can exist in a variety of physical forms. For example, compound 4 can be in solution, suspension, or in solid form. In certain embodiments, compound 4 is in solid form. When compound 4 is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
[00133] In some embodiments, the present disclosure provides compound 4 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess / oluenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 4. In certain embodiments, at least about 95% by weight of compound 4 is present. In still other embodiments of the disclosure, at least about 99% by weight of compound 4 is present.
[00134] According to one embodiment, compound 4 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition. According to another embodiment, compound 4 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. Tn other embodiments, compound 4 contains no more than about 1 .0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
[00135] The structure depicted for compound 4 is also meant to include all tautomeric forms of compound 4. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure.
[001361 It has been found that compound 4 can exist in at least one distinct solid form. Exemplary forms include polymorphs such as those described herein.
[00137] It has been found that compound 4 can exist in at least one distinct polymorphic form. In some embodiments, the present disclosure provides a polymorphic form of Compound 4 referred to herein as Form A.
[00138] In certain embodiments, compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound contains no significant amount of amorphous compound 4. In certain embodiments, at least about 95% by weight of crystalline compound 4 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 4 is present.
[00139] In some embodiments, compound 4 is amorphous. In some embodiments, compound 4 is amorphous, and is substantially free of crystalline compound 4.
Form A of Compound 4
[00140] In some embodiments, Form A of compound 4 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 7 below.
Table 7 - XRPD Peak Positions for Form A of Compound 4
Figure imgf000026_0001
Figure imgf000027_0002
the position 2d is within ± 0.2.
[00141] In some embodiments, Form A of compound 4 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta. In some embodiments, Form A of compound 4 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta. In some embodiments, Form A of compound 4 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta.
[00142] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 15. In certain embodiments, the DSC is substantially similar to the DSC provided in FIG. 16. In certain embodiments, the TGA is substantially similar to the TGA provided in FIG. 16.
[00143] Methods for preparing Form A of compound 4 are described infra.
[00144] In some embodiments, the present disclosure provides compound 4:
Figure imgf000027_0001
4.
[00145] In some embodiments, the present disclosure provides compound 4, wherein the compound is crystalline. [00146] In some embodiments, the present disclosure provides compound 4, wherein the compound is a crystalline solid substantially free of amorphous compound 4.
[00147] In some embodiments, the present disclosure provides compound 4, wherein the compound is substantially free of impurities.
[00148] In some embodiments, the present disclosure provides compound 4, wherein the compound has one or more peaks in its XRPD selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta. In some embodiments, the present disclosure provides compound 4, wherein the compound has at least two peaks in its XRPD selected from those at about 9.4, about 5.2 and about 14.0 degrees 2-theta. In some embodiments, the present disclosure provides compound 4, wherein the compound is of Form A.
[00149] In some embodiments, the present disclosure provides compound 4, wherein the compound has an XRPD substantially similar to that depicted in FIG. 15. In certain embodiments, the DSC is substantially similar to the DSC provided in FIG. 16. In certain embodiments, the TGA is substantially similar to the TGA provided in FIG. 16.
[00150] In some embodiments, the present disclosure provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.
[00151] In some embodiments, the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 4 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 4 or composition thereof.
[00152] In some embodiments, the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 4 or composition thereof. In some embodiments, the TEAD-mediated disorder is a proliferative disease such as cancer.
Compound 5 (Tosylate Bis-Salt of Compound A)
[00153] According to one embodiment, the present disclosure provides a bis-tosylate salt of compound A, represented by compound 5:
Figure imgf000029_0001
[00154] It will be appreciated by one of ordinary skill in the art that the p-toluenesulfonic acid and compound A are ionically bonded to form compound 5. It is contemplated that compound 5 can exist in a variety of physical forms. For example, compound 5 can be in solution, suspension, or in solid form. In certain embodiments, compound 5 is in solid form. When compound 5 is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
[00155] In some embodiments, the present disclosure provides compound 5 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess p-toluenesulfonic acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 5. In certain embodiments, at least about 95% by weight of compound 5 is present. In still other embodiments of the disclosure, at least about 99% by weight of compound 5 is present.
[00156] According to one embodiment, compound 5 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, 99.8 weight percent where the percentages are based on the total weight of the composition. According to another embodiment, compound 5 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. Tn other embodiments, compound 5 contains no more than about 1 .0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
[00157] The structure depicted for compound 5 is also meant to include all tautomeric forms of compound 5. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure.
[001581 It has been found that compound 5 can exist in at least one distinct polymorphic form. In some embodiments, the present disclosure provides a polymorphic form of Compound 5 referred to herein as Form A.
[00159] In certain embodiments, compound 5 is a crystalline solid. In other embodiments, compound 5 is a crystalline solid substantially free of amorphous compound 5. As used herein, the term "substantially free of amorphous compound 5" means that the compound contains no significant amount of amorphous compound 5. In certain embodiments, at least about 95% by weight of crystalline compound 5 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 5 is present.
[00160] In some embodiments, compound 5 is amorphous. In some embodiments, compound 5 is amorphous, and is substantially free of crystalline compound 5.
Form A of Compound 5
[00161] In some embodiments, Form A of compound 5 has at least 1, 2, 3, 4 or 5 spectral peak(s) selected from the peaks listed in Table 8 below.
Table 8 - XRPD Peak Positions for Form A of Compound 5
Figure imgf000030_0001
Figure imgf000031_0001
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[001621 In some embodiments, Form A of compound 5 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 18.8 and about 19.3 degrees 2-theta. In some embodiments, Form A of compound 5 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 18.8 and about 19.3 degrees 2-theta. In some embodiments, Form A of compound 5 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 18.8 and about 19.3 degrees 2-theta.
[00163] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 17. In certain embodiments, the DSC is substantially similar to the DSC provided in FIG. 18. In certain embodiments, the TGA is substantially similar to the TGA provided in FIG. 18.
[00164] Methods for preparing Form A of compound 5 are described infra.
[00165] In some embodiments, the present disclosure provides compound 5:
Figure imgf000032_0001
[00166] In some embodiments, the present disclosure provides compound 5, wherein the compound is crystalline.
[00167] In some embodiments, the present disclosure provides compound 5, wherein the compound is a crystalline solid substantially free of amorphous compound 5.
[00168] In some embodiments, the present disclosure provides compound 5, wherein the compound is substantially free of impurities.
[00169] In some embodiments, the present disclosure provides compound 5, wherein the compound has one or more peaks in its XRPD selected from those at about 5.6, about 18.8 and about 19.3 degrees 2-theta. In some embodiments, the present disclosure provides compound 5, wherein the compound has at least two peaks in its XRPD selected from those at about 5.6, about
18.8 and about 19.3 degrees 2-theta. In some embodiments, the present disclosure provides compound 5, wherein the compound is of Form A.
[00170] In some embodiments, the present disclosure provides compound 5, wherein the compound has an XRPD substantially similar to that depicted in FIG. 17.
[00171] In some embodiments, the present disclosure provides a composition comprising compound 5 and a pharmaceutically acceptable carrier or excipient.
[00172] In some embodiments, the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 5 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 5 or composition thereof.
[00173] In some embodiments, the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 5 or composition thereof. Tn some embodiments, the TEAD-mediated disorder is a proliferative disease such as cancer.
Compound 6 (HCl Salts of Compound A)
[00174] According to one embodiment, the present disclosure provides an HCl salt of compound A, represented by compound 6:
Figure imgf000033_0001
6 wherein x is about 0.5, about 1, or about 2.
[00175] It will be appreciated by one of ordinary skill in the art that the hydrochloric acid and compound A are ionically bonded to form compound 6. In some embodiments, compound A and hydrochloric acid are in a ratio of about 1 : 1. In some embodiments, compound A and hydrochloric acid are in a ratio of about 2: 1. In some embodiments, compound A and hydrochloric acid are in a ratio of about 1:2. It is contemplated that compound 6 can exist in a variety of physical forms. For example, compound 6 can be in solution, suspension, or in solid form. In certain embodiments, compound 6 is in solid form. When compound 6 is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.
[00176] In some embodiments, the present disclosure provides compound 6 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amount of extraneous matter. Such extraneous matter may include excess hydrochloric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation of, and/or isolation of, compound 6. In certain embodiments, at least about 95% by weight of compound 6 is present. In still other embodiments of the disclosure, at least about 99% by weight of compound 6 is present.
[00177] According to one embodiment, compound 6 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent where the percentages are based on the total weight of the composition. According to another embodiment, compound 6 contains no more than about 3.0 area percent HPLC of total organic impurities and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram. In other embodiments, compound 6 contains no more than about 1.0% area percent HPLC of any single impurity; no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity, relative to the total area of the HPLC chromatogram.
[00178] The structure depicted for compound 6 is also meant to include all tautomeric forms of compound 6. Additionally, structures depicted here are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this disclosure.
[00179] It has been found that compound 6 can exist in at least one distinct polymorphic form. In some embodiments, the present disclosure provides a polymorphic form of Compound 6 referred to herein as Form A.
[00180] In certain embodiments, compound 6 is a crystalline solid. In other embodiments, compound 6 is a crystalline solid substantially free of amorphous compound 6. As used herein, the term "substantially free of amorphous compound 6" means that the compound contains no significant amount of amorphous compound 6. In certain embodiments, at least about 95% by weight of crystalline compound 6 is present. In still other embodiments of the disclosure, at least about 99% by weight of crystalline compound 6 is present.
[00181] In some embodiments, compound 6 is amorphous. In some embodiments, compound 6 is amorphous, and is substantially free of crystalline compound 6.
Form A of Compound 6
[00182] In some embodiments, Form A of compound 6 has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from the peaks listed in Table 9 below.
Table 9 - XRPD Peak Positions for Form A of Compound 6
Figure imgf000034_0001
Figure imgf000035_0002
1 In this and all subsequent tables, the position 20 is within ± 0.2.
[00183] In some embodiments, Form A of compound 6 is characterized in that it has one or more peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta. In some embodiments, Form A of compound 6 is characterized in that it has two or more peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta. In some embodiments, Form A of compound 6 is characterized in that it has all three peaks in its X-ray powder diffraction pattern selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta.
[00184] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 19. In certain embodiments, the DSC is substantially similar to the DSC provided in FIG. 20. In certain embodiments, the TGA is substantially similar to the TGA provided in FIG. 20.
[00185] Methods for preparing Form A of compound 6 are described infra.
[00186] In some embodiments, the present disclosure provides compound 6:
Figure imgf000035_0001
6 wherein x is about 0.5, about 1, or about 2.
[001871 In some embodiments, the present disclosure provides compound 6, wherein the compound is crystalline.
[00188] In some embodiments, the present disclosure provides compound 6, wherein the compound is a crystalline solid substantially free of amorphous compound 6.
[00189] In some embodiments, the present disclosure provides compound 6, wherein the compound is substantially free of impurities.
[00190] In some embodiments, the present disclosure provides compound 6, wherein the compound has one or more peaks in its XRPD selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta. Tn some embodiments, the present disclosure provides compound 6, wherein the compound has at least two peaks in its XRPD selected from those at about 4.6, about 13.9 and about 18.6 degrees 2-theta. In some embodiments, the present disclosure provides compound 6, wherein the compound is of Form A. In some embodiments, Form A of Compound 6 comprises compound A and hydrochloric acid in a ratio of about 1 :1. In some embodiments, Form A of Compound 6 comprises compound A and hydrochloric acid in a ratio of about 1 :2. In some embodiments, Form A of Compound 6 comprises compound A and hydrochloric acid in a ratio of about 2: 1.
[00191] In some embodiments, the present disclosure provides compound 6, wherein the compound has an XRPD substantially similar to that depicted in FIG. 19.
[00192] In some embodiments, the present disclosure provides a composition comprising compound 6 and a pharmaceutically acceptable carrier or excipient.
[00193] In some embodiments, the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient compound 6 or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient compound 6 or composition thereof.
[00194] In some embodiments, the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof compound 6 or composition thereof. Tn some embodiments, the TEAD-mediated disorder is aproliferative disease such as cancer.
[001951 In some embodiments, the present disclosure provides a compound selected from: compound A, Form A; compound A, Form B; compound 1, Form A; compound 1, Form B; compound 2, Form A; compound 3, Form A; compound 4, Form A; compound 5, Form A; and compound 6, Form A. In some embodiments, the present disclosure provides a composition comprising one of the above compound forms and a pharmaceutically acceptable carrier or excipient.
[00196] In some embodiments, the present disclosure provides a method of inhibiting TEAD in a patient comprising administering to the patient a compound of the present disclosure or composition thereof. In some embodiments, the present disclosure provides a method of treating one or more disorders associated with activity of TEAD comprising administering to the patient a compound of the present disclosure or composition thereof.
[00197] In some embodiments, the present disclosure provides a method for treating an TEAD- mediated disorder comprising the step of administering to a patient in need thereof a compound of the present disclosure or composition thereof. In some embodiments, the TEAD-mediated disorder is a proliferative disease such as cancer.
General Methods of Providing Compound A
[00198] Compound A is prepared according to the methods described in detail herein.
[00199] In some embodiments, the present disclosure provides a method for preparing compound A as shown in the scheme:
Figure imgf000037_0001
intermediate 4 Compound A
[00200] In some embodiments, the present disclosure provides a method for preparing
Intermediate 4 as shown in the scheme:
Figure imgf000038_0001
[00201] In some embodiments, the present disclosure provides a method for preparing
Intermediate 3 as shown in the scheme:
Figure imgf000038_0002
Intermediate 2 Intermediate 3
[00202] In some embodiments, the present disclosure provides a method for preparing
Intermediate 2 as shown in the scheme:
Figure imgf000038_0003
Intermediate 1 Intermediate 2
General Methods of Providing a Salt Compound
[00203] Compound A is prepared according to the methods described in detail herein. Salt compounds of general formula X, which formula encompasses, inter alia, salt compounds 1 through 6, and/or particular forms thereof, are prepared from compound A, according to the general Scheme below.
Figure imgf000039_0001
[00204] For instance, each of compounds 1 through 6, and forms thereof, are prepared from compound A by combining compound A with an appropriate acid to form a salt of that acid. Thus, another aspect of the present disclosure provides a method for preparing compounds 1 through 6, and forms thereof.
[00205] As described generally above, in some embodiments, the present disclosure provides a method for preparing a salt compound of the general formula X:
Figure imgf000039_0002
salt compound X comprising steps of: combining compound A:
Figure imgf000039_0003
with a suitable acid and optionally a suitable solvent under conditions suitable for forming a salt compound of general formula X. [00206] In some embodiments, a suitable acid is maleic acid. Tn some embodiments, the present disclosure provides a method of making a maleate salt of compound A. In certain embodiments, the maleate salt of compound A is compound 1. In certain embodiments, the maleate salt of compound A is Form A of compound 1. In certain embodiments, the maleate salt of compound A is Form B of compound 1. In certain embodiments, the maleate salt of compound A is hemimaleate salt compound 2. In certain embodiments, the hemi-maleate salt of compound A is Form A of compound 2.
[00207] In some embodiments, a suitable acid is methanesulfonic acid. In some embodiments, the present disclosure provides a method of making a mesylate salt of compound A. In certain embodiments, the mesylate salt of compound A is compound 3. In certain embodiments, the mesylate salt of compound A is Form A of compound 3.
[00208] In some embodiments, a suitable acid is p-toluenenesulfonic acid. In some embodiments, the present disclosure provides a method of making a tosylate salt of compound A. In certain embodiments, the tosylate salt of compound A is compound 4. In certain embodiments, the tosylate salt of compound A is Form A of compound 4. In certain embodiments, the tosylate salt of compound A is bis-tosylate salt compound 5. In certain embodiments, the bis-tosylate salt of compound A is Form A of compound 5.
[00209] In some embodiments, a suitable acid is hydrochloric acid. In some embodiments, the present disclosure provides a method of making an HC1 salt of compound A. In certain embodiments, the HO salt of compound A is compound 6. In certain embodiments, the HC1 salt of compound A is Form A of compound 6.
[00210] A suitable solvent may be any solvent system (e.g., one solvent or a mixture of solvents) in which compound A and/or an acid are soluble, or are at least partially soluble.
[00211] Examples of suitable solvents useful in the present disclosure include, but are not limited to protic solvents, aprotic solvents, polar aprotic solvent, or mixtures thereof. In certain embodiments, suitable solvents include an ether, an ester, an alcohol, a ketone, or a mixture thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.
[00212] In certain embodiments, a suitable solvent is methanol, ethanol, isopropanol, or acetone wherein the solvent is anhydrous or in combination with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. Tn some embodiments, a suitable solvent is ethanol. In some embodiments, a suitable solvent is anhydrous ethanol. In some embodiments, the suitable solvent is MTBE.
[00213] In some embodiments, a suitable solvent is ethyl acetate. In some embodiments, a suitable solvent is a mixture of methanol and methylene chloride. In some embodiments, a suitable solvent is a mixture of acetonitrile and water. In certain embodiments, a suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, a suitable solvent is diethylether. In certain embodiments, a suitable solvent is water. In certain embodiments, a suitable solvent is methyl ethyl ketone. In certain embodiments, a suitable solvent is toluene.
[00214] In some embodiments, the present disclosure provides a method for preparing a salt compound of the general formula X, comprising one or more steps of removing a solvent and adding a solvent In some embodiments, an added solvent is the same as the solvent removed. In some embodiments, an added solvent is different from the solvent removed. Means of solvent removal are known in the synthetic and chemical arts and include, but are not limited to, any of those described herein and in the Exemplification.
[00215] In some embodiments, a method for preparing a salt compound of the general formula X comprises one or more steps of heating or cooling a preparation.
[00216] In some embodiments, a method for preparing a salt compound of the general formula X comprises one or more steps of agitating or stirring a preparation.
[00217] In some embodiments, a method for preparing a salt compound of the general formula X comprises a step of adding a suitable acid to a solution or slurry of compound A.
[00218] In some embodiments, a method for preparing a salt compound of the general formula X comprises a step of heating.
[00219] In certain embodiments, a salt compound of formula X precipitates from the mixture. In another embodiment, a salt compound of formula X crystallizes from the mixture. In other embodiments, a salt compound of formula X crystallizes from solution following seeding of the solution (i.e., adding crystals of a salt compound of formula X to the solution).
[00220] A salt compound of formula X can precipitate out of the reaction mixture, or be generated by removal of part or all of the solvent through methods such as evaporation, distillation, fdtration (ex. nanofdtration, ultrafdtration), reverse osmosis, absorption and reaction, by adding an anti-solvent such as heptane, by cooling or by different combinations of these methods. [00221] As described generally above, a salt compound of formula X is optionally isolated. It will be appreciated that a salt compound of formula X may be isolated by any suitable physical means known to one of ordinary skill in the art. In certain embodiments, precipitated solid salt compound of formula X is separated from the supernatant by filtration. In other embodiments, precipitated solid salt compound of formula X is separated from the supernatant by decanting the supernatant.
[00222] In certain embodiments, a salt compound of formula X is separated from the supernatant by filtration.
[00223] In certain embodiments, an isolated salt compound of formula X is dried in air. In other embodiments, isolated salt compound of formula X is dried under reduced pressure, optionally at elevated temperature.
Uses, Formulation and Administration and Pharmaceutically acceptable compositions Pharmaceutically acceptable compositions
[00224] According to another embodiment, the disclosure provides a pharmaceutical composition comprising a compound of this disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this disclosure is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that is effective to measurably inhibit TEAD, or a variant or mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient.
[00225] The terms “patient” or “subject” as used herein, means an animal, preferably a mammal, and most preferably a human.
[00226] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[00227] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.
[00228] As used herein, the term "inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of TEAD, or a variant or mutant thereof.
[00229] Compositions of the present disclosure can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this disclosure can be aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
[00230] For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
[00231] Pharmaceutically acceptable compositions of this disclosure can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.
[00232] Alternatively, pharmaceutically acceptable compositions of this disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
[00233] Pharmaceutically acceptable compositions of this disclosure can also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[00234] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches can also be used.
[00235] For topical applications, provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
[00236] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.
[00237] Pharmaceutically acceptable compositions of this disclosure can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
[00238] Most preferably, pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.
[00239] The amount of compounds of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form varies depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
[00240] It should also be understood that a specific dosage and treatment regimen for any particular patient depends upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition also depends upon the particular compound in the composition.
Uses of Compounds and Pharmaceutically Acceptable Compositions The Hippo Signaling Network
[00241] The Hippo signaling network (also known as the Salvador/Warts/Hippo (SWH) pathway) is a master regulator of cell proliferation, death, and differentiation. In some embodiments, the main function of the Hippo signaling pathway is to regulate negatively the transcriptional co-activators Yes-associated protein (YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ; also known as WWTR1). The Hippo kinase cascade phosphorylates and inhibits YAP/TAZ by promoting its cytoplasmic retention and degradation, thereby inhibiting the growth promoting function regulated under the YAP/TAZ control. In an un- phosphorylated/de-phosphorylated state, YAP, also known as YAP1 or YAP65, together with TAZ, are transported into the nucleus where they interact with TEAD family of transcription factors toupregulate genes that promote proliferation and migration, and inhibit apoptosis. In some instances, unregulated upregulation of these genes involved in proliferation, migration, and antiapoptosis leads to development of cancer. In some instances, overexpression of YAP/TAZ is associated with cancer.
[00242] Additional core members of the Hippo signaling pathway comprise the serine/threonine kinases MST1/2 (homologues of Hippo/Hpo in Drosophila), Latsl/2 (homologues of Warts/Wts), and their adaptor proteins Savl (homologue of Salvador/Sav) and Mob (MOBKL1A and MOBKL1B; homologues of Mats), respectively. In general, MST1/2 kinase complexes with the scaffold protein Savl, which in turn phosphorylates and activates Latsl/2 kinase. Latsl/2 is also activated by the scaffold protein Mob. The activated Latsl/2 then phosphorylates and inactivates YAP or its paralog TAZ. The phosphorylation of YAP/TAZ leads to their nuclear export, retention within the cytoplasm, and degradation by the ubiquitin proteasome system.
[00243] In some instances, Latsl/2 phosphorylates YAP at the [HXRXXS] (SEQ ID NO: 21) consensus motifs. YAP comprises five [HXRXXS] (SEQ ID NO: 21) consensus motifs, wherein X denotes any amino acid residue. In some instances, Latsl/2 phosphorylates YAP at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates YAP at all five of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S127 amino acid position. The phosphorylation of YAP S127 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of YAP. Mutation of YAP at the S127 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation. [00244] Additional phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and on the corresponding site in TAZ primes both proteins for further phosphorylation events by CK I 8/s in the degradation motif, which then signals for interaction with the P-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.
[00245] In some instances, Latsl/2 phosphorylates TAZ at the [HXRXXS] (SEQ ID NO: 21) consensus motifs. TAZ comprises four [HXRXXS] (SEQ ID NO: 21) consensus motifs, wherein X denotes any amino acid residues. In some instances, Latsl/2 phosphorylates TAZ at one or more of the consensus motifs. In some instances, Latsl/2 phosphorylates TAZ at all four of the consensus motifs. In some instances, Latsl/2 phosphorylate at the S89 amino acid position. The phosphorylation of TAZ S89 promotes 14-3-3 protein binding and results in cytoplasmic sequestration of TAZ. Mutation of TAZ at the S89 position thereby disrupts its interaction with 14-3-3 and subsequently promotes nuclear translocation.
[00246] In some embodiments, phosphorylated YAP/TAZ accumulates in the cytoplasm, and undergoes SCFk| RC -mediated ubiquitination and subsequent proteasomal degradation. In some instances, the Skp, Cullin, F-box containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that comprises a F-box family member protein (e.g. Cdc4), Skpl, a bridging protein, and RBX1, which contains a small RING Finger domain which interacts with E2 -ubiquitin conjugating enzyme. In some cases, the F-box family comprises more than 40 members, in which exemplary members include F-box/WD repeat-containing protein 1A (FBXW1A, PTrCPl, Fbxwl, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-associated proteins 2 (SKP2). In some embodiments, the SCF complex (e.g. SCFpTrCP1) interacts with an El ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme to catalyze the transfer of ubiquitin to the YAP/TAZ substrate. Exemplary El ubiquitin-activating enzymes include those encoded by the following genes: UBA1, UBA2, UBA3, UBA5, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the following genes: UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE20, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, the ubiquitinated YAP/TAZ further undergoes the degradation process through the 26S proteasome. [00247] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulators. In some instances, the Hippo pathway is regulated by the G-protein and its coupled receptors, the Crumbs complex, regulators upstream of the MST kinases, and the adherens junction.
YAP/TAZ Interaction with TEAD
[00248] In some embodiments, un-phosphorylated and/or dephosphorylated YAP/TAZ accumulates in the nucleus. Within the nucleus, YAP/TAZ interacts with the TEAD family of transcription factors (e.g., human TEAD1 (UniProt KB ID P28347-1 (SEQ ID NO: 1)), human TEAD2 (UniProtKB ID Q15562 (SEQ ID NO: 2)), human TEAD3 (UniProtKB ID Q99594 (SEQ ID NO: 3)), and human TEAD4 (UniProtKB ID QI 5561 (SEQ ID NO: 4)) to activate genes involved in anti-apoptosis and proliferation, such as for example CTFG, Cyr61, and FGF1.
[00249] Proteomic and biochemical studies have shown that the TEAD (TEA Domain) transcription factors are palmitoylated at evolutionarily conserved cysteine residues. Three cysteine residues were found that are evolutionarily conserved and mutated to serine in human TEAD1 (C53S, C327S and C359S) to test whether the mutation affects TEAD1 palmitoylation. The C359S mutant showed the greatest loss of palmitoylation, and C327S and C53S also showed decreased palmitoylation. These results suggest that C359 plays a critical role in TEAD1 palmitoylation. Furthermore, combination mutation of all three cysteine residues, C53/327/359S (3CS), completely ablated TEAD1 palmitoylation, indicating that these residues are involved in TEAD1 palmitoylation. It has been found that TEADs undergo PAT -independent autopalmitoylation, under physiological concentrations of palmitoy 1-CoA. Furthermore, autopalmitoylation plays critical roles in regulating TEAD-YAP association and their physiological functions in vitro and in vivo. Chan, et al. Nature Chem. Biol. 12, pages 282-289 (2016); Noland, et al. Structure, 24, 1-8 (2016); Gibault et al. J. Med. Chem. 61, 5057-5072 (2018). Therefore, palmitoylation of TEADs play important roles in regulating Hippo pathway transcriptional complexes.
[00250] In some embodiments, the compounds disclosed herein modulate the interaction between YAP/TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP/TAZ and TEAD. [00251] In some embodiments, the compounds described herein reversibly inhibit a TEAD transcription factor. In some embodiments, the transcription factor is TEAD1. In some embodiments, the transcription factor is TEAD2. In some embodiments, the transcription factor is TEAD3. In some embodiments, the transcription factor is TEAD4. In some embodiments, the compounds described herein reversibly inhibit the activity of a TEAD transcription factor (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4).
[00252] In some embodiments, the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD2 and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the compounds disclosed herein bind to TEAD3 and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD4 and disrupt or inhibit the interaction between YAP and TEAD4.
[00253] In some embodiments, the compounds disclosed herein bind to TEAD1 and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C405, and disrupt or inhibit the interaction between YAP and TEAD 1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD I . In some embodiments, the compounds disclosed herein bind to TEAD I at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEADl. In some embodiments, the compounds disclosed herein bind to TEADl at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEADl. In some embodiments, the compounds disclosed herein bind to TEAD1 at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEADl at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEAD1.
[00254] In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEADl palmitoylation at C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359 and C327. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEAD1 palmitoylation at C359 and C53. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEAD1 palmitoylation at C53 and C327. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359 and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C53 and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C327 and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359, C327, and C53. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359, C327, and C405. In some embodiments, the compounds disclosed herein bind to TEAD l and prevent TEAD l palmitoylation at C359, C353, and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C327, C53, and C405. In some embodiments, the compounds disclosed herein bind to TEADl and prevent TEADl palmitoylation at C359, C327, C53, and C405.
[00255] In some embodiments, the compounds disclosed herein bind to TEAD, prevent TEAD palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD. In some embodiments, the compounds disclosed herein bind to TEADI and prevent TE ADI palmitoylation at C359, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C327, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C53 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C327 and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C53, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEAD1 and prevent TEAD1 palmitoylation at C359, C327, and C405, and disrupt or inhibit the interaction between YAP and TEAD1. In some embodiments, the compounds disclosed herein bind to TEADI and prevent TEADI palmitoylation at C359, C353, and C405, and disrupt or inhibit the interaction between YAP and TEADI. In some embodiments, the compounds disclosed herein bind to TEADI and prevent TEADI palmitoylation at C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEADI . In some embodiments, the compounds disclosed herein bind to TEADI and prevent TEADI palmitoylation at C359, C327, C53, and C405, and disrupt or inhibit the interaction between YAP and TEADI. [00256] In some embodiments, the compounds disclosed herein bind to TEAD2 at C380, and disrupt or inhibit the interaction between YAP and TEAD2.
[00257] In some embodiments, the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380.
[00258] In some embodiments, the compounds disclosed herein bind to TEAD2, prevent TEAD2 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD2. In some embodiments, the compounds disclosed herein bind to TEAD2 and prevent TEAD2 palmitoylation at C380, and disrupt or inhibit the interaction between YAP and TEAD2.
[00259] In some embodiments, the compounds disclosed herein bind to TEAD3 at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3.
[00260] In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368 and C371.
[00261] In some embodiments, the compounds disclosed herein bind to TEAD3, prevent TEAD3 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C368, and disrupt or inhibit the interaction between YAP and TEAD3. In some embodiments, the compounds disclosed herein bind to TEAD3 and prevent TEAD3 palmitoylation at C371 and C368, and disrupt or inhibit the interaction between YAP and TEAD3.
[00262] In some embodiments, the compounds disclosed herein bind to TEAD4 at C367, and disrupt or inhibit the interaction between YAP and TEAD4. [00263] In some embodiments, the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation. In some embodiments, the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367.
[00264] In some embodiments, the compounds disclosed herein bind to TEAD4, prevent TEAD4 palmitoylation, and disrupt or inhibit the interaction between YAP and TEAD4. In some embodiments, the compounds disclosed herein bind to TEAD4 and prevent TEAD4 palmitoylation at C367, and disrupt or inhibit the interaction between YAP and TEAD4.
YAP/TAZ regulation mediated by G-proteins/GPCRs
[00265] In some embodiments, the Hippo pathway is regulated by the G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding proteins) family of proteins. G proteins are molecular switches that transmit extracellular stimuli into the cell through GPCRs. In some instances, there are two classes of G proteins: monomeric small GTPases and heterotrimeric G protein complexes. In some instances, the latter class of complexes comprise of alpha (Ga), beta (Gp), and gamma (GY) subunits. In some cases, there are several classes of Ga subunits: Gq/na, Giz/ , Gi/Oa (G inhibitory, G other), and Gsa (G stimulatory).
[00266] In some instances, Gia (G inhibitory), Goa (G other), Gq/l la, and G12/13a coupled GPCRs activate YAP/TAZ and promote nuclear translocation. In other instances, Gsa (G stimulatory) coupled GPCRs suppress YAP/TAZ activity, leading to YAP/TAZ degradation.
[00267] In some cases, Gia (G inhibitory), Goa (G other), Gq/na, and Gn/ua coupled GPCRs activate YAP/TAZ through repression of Latsl/2 activities. In contrast, Gsa, in some embodiments, induces Latsl/2 activity, thereby promoting YAP/TAZ degradation.
Gq Family
[00268] Gqa (also known as Gq/n protein), participates in the inositol trisphosphate (IP3) signal transduction pathway and calcium (Ca2+) release from intracellular storage through the activation of phospholipase C (PLC). The activated PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacyl glycerol (DAG) and IP3. In some instances, IP3 then diffuses through the cytoplasm into the ER or the sarcoplasmic reticulum (SR) in the case of muscle cells, and then binds to inositol trisphosphate receptor (InsP3R), which is a Ca2+ channel. In some cases, the binding triggers the opening of the Ca2+ channel, and thereby increases the release of Ca2+ into the cytoplasm. [00269] In some embodiments, the GPCRs that interact with Gqa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT? and 5-HT3; alpha-1 adrenergic receptor; vasopressin type 1 receptors 1A and IB; angiotensin II receptor type 1; calcitonin receptor; histamine Hl receptor; metabotropic glutamate receptor, group I; muscarinic receptors Mi, M3, and M5; and trace amine-associated receptor 1.
[00270] In some instances, there are several types of Gqa: Gq, Gq/n, Gq/i4, and Gq/is. The Gq protein is encoded by GNAQ. Gq/n is encoded by GNA11. Gq/i4 is encoded by GNA14. Gq/is is encoded by GNA15.
[00271] In some instances, mutations or modifications of the Gqa genes have been associated with cancer. Indeed, studies have shown that mutations in Gqa promote uveal melanoma (UM) tumorigenesis. In some instances, about 80% of UM cases have been detected to contain a mutation in GNAQ and/or GNA11.
[00272] In some instances, mutations or modifications of the Gqa genes have been associated with congenital diseases. In some instances, mutations of Gqa have been observed in congenital diseases such as Port-Wine Stain and/or Sturge-Weber Syndrome. In some instances, about 92% of Port-Wine stain cases harbors a mutation in GNAQ. In some instances, about 88% of Sturge- Weber Syndrome harbors a mutation in GNAQ.
G12/13 Family
[00273] Gi2/i3a modulates actin cytoskeletal remodeling in cells and regulates cell processes through guanine nucleotide exchange factors (GEFs). GEFs participate in the activation of small GTPases which acts as molecular switches in a variety of intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g, Rho family such as Cdc42), which is involved in cell differentiation, proliferation, cytoskeletal organization, vesicle trafficking, and nuclear transport.
[00274] In some embodiments, the GPCRs that interact with Gi2/i3a include, but are not limited to, purinergic receptors (e.g, P2Yi, P2Y2, P2Y4, P2Ye); muscarinic acetylcholine receptors Ml and M3; receptors for thrombin [protease-activated receptor (PAR)-l, PAR-2]; thromboxane (TXA2); sphingosine 1 -phosphate (e.g., SIP2, SIP3, SIP4 and SIP5); lysophosphatidic acid (e.g., LPAi, LPA2, LPA3); angiotensin II (ATI); serotonin (5-HT2C and 5-HT4); somatostatin (ssts); endothelin (ETA and ETB); cholecystokinin (CCKi); Via vasopressin receptors; D5 dopamine receptors; fMLP formyl peptide receptors; GAL2 galanin receptors; EP3 prostanoid receptors; Ai adenosine receptors; cn adrenergic receptors; BB2 bombesin receptors; B2 bradykinin receptors; calcium-sensing receptors; KSHV-ORF74 chemokine receptors; NKi tachykinin receptors; and thyroid-stimulating hormone (TSH) receptors.
[00275] In some instances, G12/1301 is further subdivided into G12 and GB types which are encoded by GNA12 and GNA13, respectively.
Gi/o Family
[00276] Gi/od (G inhibitory, G other) (also known as Gi/G0 or Gi protein) suppresses the production of 3’, 5 ’-cyclic AMP (cAMP) from adenosine triphosphate (ATP) through an inhibition of adenylate cyclase activity, which converts ATP to cAMP.
[00277] In some embodiments, the GPCRs that interact with Gia include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HTi and 5-HTs; muscarinic acetylcholine receptors such as M2 and M4; adenosine receptors such as Ai and A3; adrenergic receptors such as d2A, d2B, and a2c; apelin receptors; calcium-sensing receptor; cannabinoid receptors CB1 and CB2; chemokine CXCR4 receptor; dopamines D2, D3, and D4; GABAB receptor; glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8); histamine receptors such as H3 andEU receptors; melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and melatonin receptor type 3 (MT3); niacin receptors such as NIACR1 and NIACR2; opioid receptors such as 8, K, p, and nociceptin receptors; prostaglandin receptors such as prostaglandin E receptor 1 (EPi), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP); somatostatin receptors ssti, sst2, ssts, sst4, and ssts; and trace amine-associated receptor 8.
[00278] In some instances, there are several types of Gia: Gial, Gia2, Gi0t3, Gia4, Goa, Gt, Ggust, and Gz. Gial is encoded by GNAII. Gia2 is encoded by GNAI2. Gia3 is encoded by GNAI3. Goa, the a0 subunit, is encoded by GNA01. Gt is encoded by GNAT1 and GNAT2. Ggust is encoded by GNAT3. Gz is encoded by GNAZ.
Gs Family
[00279] Gsa (also known as G stimulatory, Gs alpha subunit, or Gs protein) activates the cAMP- dependent pathway through the activation of adenylate cyclase, which convers adenosine triphosphate (ATP) to 3 ’,5 ’-cyclic AMP (cAMP) and pyrophosphate In some embodiments, the GPCRs that interact with Gsa include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HTe, and 5-HT?; adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R); adenosine receptor types A2a and Ait,; arginine vasopressin receptor 2 (AVPR2); 0-adrenergic receptors Pi, P2, and P3; calcitonin receptor; calcitonin gene-related peptide receptor; corticotropin-releasing hormone receptor; dopamine receptor DI -like family receptors such as Di and D5; follicle-stimulating hormone receptor (FSH- receptor); gastric inhibitory polypeptide receptor; glucagon receptor; histamine H2 receptor; luteinizing hormone/choriogonadotropin receptor, melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R; parathyroid hormone receptor 1; prostaglandin receptor types D2 and I2; secretin receptor; thyrotropin receptor; trace amine-associated receptor 1; and box jellyfish opsin.
[00280] In some instances, there are two types of Gsa: Gs and Goir. Gs is encoded by GNAS. Goif is encoded by GN AL.
Additional Regulators of the Hippo signaling network
[00281] In some embodiments, the additional regulator of the Hippo signaling pathway is the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some instances, the Crumbs complex comprises transmembrane CRB proteins which assemble multi-protein complexes that function in cell polarity. In some instances, CRB complexes recruit members of the Angiomotin (AMOT) family of adaptor proteins that interact with the Hippo pathway components. In some instances, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and inhibits its nuclear localization.
[00282] In some instances, the additional regulator of the Hippo signaling pathway comprises regulators of the MST kinase family. MST kinases monitor actin cytoskeletal integrity. In some instances, the regulators include TAO kinases and cell polarity kinase PAR-1.
[00283] In some instances, the additional regulator of the Hippo signaling pathway comprises molecules of the adherens junction. In some instances, E-Cadherin (E-cad) suppresses YAP nuclear localization and activity through regulating MST activity. In some embodiments, E-cad- associated protein a-catenin regulates YAP through sequestering YAP/14-3-3 complexes in the cytoplasm. In other instances, Ajuba protein family members interact with Latsl/2 kinase activity, thereby preventing inactivation of YAP/TAZ. [00284] In some embodiments, additional proteins that interact with YAP/TAZ either directly or indirectly include, but are not limited to, Merlin, protocadherin Fat 1, MASK1/2, HIPK2, PTPN14, RASSF, PP2A, Salt-inducible kinases (SIKs), Scribble (SCRIB), the Scribble associated proteins Discs large (Dig), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1/2.
[00285] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the dephosphorylation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP). In some embodiments, the compounds increase the ubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP) or decrease the deubiquitination of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcriptional coactivator (TAZ/YAP).
[00286] In some embodiments, the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by, or related to, the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein and/or its coupled GPCR. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a G-protein. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of the Gqa family proteins such as Gq, Gq/n, Gq/14, and Gq/15; the Gn/na family of proteins such as G12 and G13; or the Gia family of proteins such as Gial, G,a2, G,a3, Gta4, Goa, Gt, Ggust, and Gz. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/n. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/14. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gq/15. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G12. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of G13. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gial . In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia2. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gta3. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gia4. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Goa. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gt. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Ggust Tn some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Gz.
[002871 In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a core protein of the Hippo pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Savl. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Mob. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of YAP. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TAZ. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of TEAD.
[00288] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein associated with the ubiquitination and proteasomal degradation pathway. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a proteasomal degradation pathway protein (e.g, 26S proteasome).
[00289] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Ras superfamily of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a protein of the Rho family of proteins. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of Cdc42.
[00290] Cdc42 is a member of the Ras superfamily of small GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, in which the family members participate in diverse and critical cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some instances, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, an inhibitor of Cdc42 is a compound disclosed herein.
[00291] In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a deubiquitinating enzyme. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of a cysteine protease or a metalloprotease. In some embodiments, an inhibitor of the Hippo pathway is an inhibitor of an ubiquitin-specific protease. USP47 is a member of the ubiquitin-specific protease (USP/UBP) superfamily of cysteine proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47.
[00292] In some embodiments, the present disclosure provides a use of a compound, or a pharmaceutical salt or composition thereof, for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.
[002931 The activity of a compound utilized in this disclosure as an inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, can be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof. Detailed conditions for assaying a compound utilized in this disclosure as an inhibitor of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are set forth in the Examples below. See, for example, Examples 2 and 5.
[00294] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example, to prevent or delay their recurrence.
[00295] The provided compounds are inhibitors of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) and are therefore useful for treating one or more disorders associated with activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4). Thus, in certain aspects and embodiments, the present disclosure provides a method for treating a TEAD-mediated disorder comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof.
[00296] As used herein, the term “TEAD-mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, is known to play a role. Accordingly, another aspect or embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, are known to play a role. [00297] As used herein, the term “a therapeutically effective amount of’ refers to the amount of a TEAD inhibitor or a pharmaceutically acceptable salt thereof, which is effective to reduce or attenuate the biological activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) or a variant or mutant thereof, provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition in a biological sample or in a patient. In some embodiments, “a therapeutically effective amount of’ refers to the amount of a TEAD inhibitor or a pharmaceutically acceptable salt thereof that measurably decreases the binding or signaling activity of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4), or a variant or mutant thereof, or any TEAD-mediated activity. The term “therapeutically effective amount” can encompass, in some embodiments, an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibition of a TEAD transcription factor. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease.
[00298] In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof. In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof. In some aspects and embodiments, provided herein are methods of treating, reducing the severity of, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof of a disease or disorder in which inhibition or antagonizing of the Hippo pathway is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective compound of the present disclosure, or pharmaceutically acceptable composition thereof.
[002991 In some aspects and embodiments, the present disclosure provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder, comprising administering to a patient in need thereof, a TEAD inhibitor compound as described herein, or a pharmaceutical salt or composition thereof. In some embodiments, a cellular proliferative disorder is cancer. In some embodiments, the cancer is characterized by increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) activity.
[00300] As used herein, the terms "increased," “elevated,” or “enhanced,” are used interchangeably and encompass any measurable increase in a biological function and/or biological activity and/or a concentration. For example, an increase can be by at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4- fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20- fold, about 25-fold, about 50-fold, about 100-fold, or higher, relative to a control or baseline amount of a function, or activity, or concentration.
[00301] As used herein, the terms “increased expression” and/or “increased activity” of a substance, such as TEAD, in a sample or cancer or patient, refers to an increase in the amount of the substance, such as TEAD, of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 20-fold, about 25-fold, about 50- fold, about 100-fold, or higher, relative to the amount of the substance, such as TEAD, in a control sample or control samples, such as an individual or group of individuals who are not suffering from the disease or disorder (e.g., cancer) or an internal control, as determined by techniques known in the art. A subject can also be determined to have an “increased expression” or “increased activity” of TEAD if the expression and/or activity of TEAD is increased by one standard deviation, two standard deviations, three standard deviations, four standard deviations, five standard deviations, or more, relative to the mean (average) or median amount of TEAD in a control group of samples or a baseline group of samples or a retrospective analysis of patient samples. As practiced in the art, such control or baseline expression levels can be previously determined, or measured prior to the measurement in the sample or cancer or subject, or can be obtained from a database of such control samples.
[00302] As used herein, a “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology, Cambridge University Press: Cambridge, UK, 1990). A proliferative disease can be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes, such as the matrix metalloproteinases (e.g, collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e. /‘malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases.
Cancer
[00303] The cancer or proliferative disorder or tumor to be treated using the compounds and methods and uses described herein include, but are not limited to, a hematological cancer, a lymphoma, a myeloma, a leukemia, a neurological cancer, skin cancer, breast cancer, a prostate cancer, a colorectal cancer, lung cancer, head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a bone cancer, renal cancer, and a vascular cancer.
[00304] In some embodiments of the methods and uses described herein, a cancer is mediated by activation of transcriptional coactivator with PDZ binding motif/Yes-associated protein transcription coactivator (TAZ/YAP). In some embodiments of the methods and uses described herein, a cancer is mediated by modulation of the interaction of YAP/TAZ with TEAD (e.g, TEAD1, TEAD2, TEAD3, and/or TEAD4). In some embodiments of the methods and uses described herein, the cancer is characterized by or associated with increased TEAD (e.g., TEAD1, TEAD2, TEAD3, and/or TEAD4) expression and/or increased TEAD (e.g, TEAD1, TEAD2, TEAD3, and/or TEAD4) activity. Tn some embodiments of the methods and uses described herein, the cancer is a cancer in which YAP is localized in the nucleus of the cancer cells.
[003051 In some embodiments, a cancer is characterized by a mutant Ga-protein. In some embodiments, a mutant Ga-protein is selected from G12, G13, Gq, Gi l, Gi, Go, and Gs. In some embodiments, a mutant Ga-protein is G12. In some embodiments, a mutant Ga-protein is G13. In some embodiments, a mutant Ga-protein is Gq. In some embodiments, a mutant Ga-protein is Gl 1. In some embodiments, a mutant Ga-protein is Gi. In some embodiments, a mutant Ga-protein is Go. In some embodiments, a mutant Ga-protein is Gs.
[00306] In some embodiments of the methods and uses described herein, a cancer is treated by inhibiting or reducing or decreasing or arresting further growth or spread of the cancer or tumor. In some embodiments of the methods and uses described herein, a cancer is treated by inhibiting or reducing the size (e.g, volume or mass) of the cancer or tumor by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90% or at least 99% relative to the size of the cancer or tumor prior to treatment. In some embodiments of the methods and uses described herein, a cancer is treated by reducing the quantity of the cancers or tumors in the patient by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 90% or at least 99% relative to the quantity of the cancers or tumors prior to treatment.
[00307] In some embodiments of the methods and uses described herein, the cancer is lung cancer, thyroid cancer, ovarian cancer, colorectal cancer, prostate cancer, cancer of the pancreas, cancer of the esophagus, liver cancer, breast cancer, skin cancer, or mesothelioma. In some embodiments, the cancer is mesothelioma, such as malignant mesothelioma. In some embodiments, cancer includes, without limitation, leukemias (e.g, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g, Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).
[00308] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.
[00309] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e. , Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human. In some embodiments, the patient is a child or pediatric patient.
[00310] Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkins’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.
[00311] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/ stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma.
[00312] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
[00313] In some embodiments, a cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise an abnormal mass of tissue that typically does not include cysts or liquid areas. In some embodiments, the cancer is selected from renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; or medulloblastoma.
[00314] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
[00315] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
[00316] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). Tn some embodiments, the cancer is hepatocholangiocarcinoma. Tn some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis- 1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma.
[00317] In some embodiments, a cancer is a viral-associated cancer, including human immunodeficiency virus (HIV) associated solid tumors, human papillomavirus (HPV)-16 positive incurable solid tumors, and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV-I in leukemic cells (See https://clinicaltrials.gov/ct2/show/study/ NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinoma of the head and neck, and Merkel cell carcinoma. (See https://clinicaltrials.gov/ct2/show/study/NCT02488759; see also https://clinicaltrials.gov/ct2/show/study/NCT0240886; https://clinicaltrials.gov/ct2/show/ NCT02426892)
[00318] In some embodiments, a cancer is melanoma cancer. In some embodiments, a cancer is breast cancer. In some embodiments, a cancer is lung cancer. In some embodiments, a cancer is small cell lung cancer (SCLC). In some embodiments, a cancer is non-small cell lung cancer (NSCLC).
[00319] The compounds and compositions, according to the method of the present disclosure, can be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer. The exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like. Compounds of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure is decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The terms “patient” or “subject,” as used herein, means an animal, preferably a mammal, and most preferably a human. [00320] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the disclosure can be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
[00321] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00322] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[00323] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00324] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[00325] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
[00326] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
[00327] Solid compositions of a similar type can also be employed as fdlers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They can optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
[00328] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
[003291 Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Co-Administration with One or More Other Therapeutic Agent(s)
[00330] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, can also be present in the compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”
[00331] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
[00332] A compound of the current disclosure can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy. [00333] A compound of the current disclosure can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the disclosure and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current disclosure can besides, or in addition, be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible, as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
[00334] One or more other therapeutic agent(s) can be administered separately from a compound or composition of the disclosure, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents can be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent(s) and a compound or composition of the disclosure can be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent(s) and a compound or composition of the disclosure are administered as a multiple dosage regimen within greater than 24 hours apart.
[00335] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure can be administered with one or more other therapeutic agent(s) simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound of the current disclosure, one or more other therapeutic agent(s), and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
[00336] The amount of a compound of the disclosure and one or more other therapeutic agent(s) (in those compositions which comprise an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Preferably, a composition of the disclosure should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of a compound of the disclosure can be administered.
[00337] In those compositions which comprise one or more other therapeutic agent(s), the one or more other therapeutic agent(s) and a compound of the disclosure can act synergistically. Therefore, the amount of the one or more other therapeutic agent(s) in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 pg/kg body weight/day of the one or more other therapeutic agent(s) can be administered.
[00338] The amount of one or more other therapeutic agent(s) present in the compositions of this disclosure may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent(s) in the presently disclosed compositions ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent(s) is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is approved for dosing per the FDA label insert.
[00339] The compounds of this disclosure, or pharmaceutical compositions thereof, can also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this disclosure are another embodiment of the present disclosure.
Exemplary Other Therapeutic Agents
[00340] In some embodiments, one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected from olaparib (LYNPARZA®, AstraZeneca); rucaparib (RUBRACA®, Clovis Oncology); niraparib (ZEJULA®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).
[00341] In some embodiments, one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor is selected from vorinostat (ZOLINZA®, Merck); romidepsin (ISTODAX®, Celgene); panobinostat (FARYDAK®, Novartis); belinostat (BELEODAQ®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (EPIDAZA®, HBI-8000, Chipscreen Biosciences, China).
[00342] In some embodiments, one or more other therapeutic agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6 inhibitor is selected from palbociclib (IBRANCE®, Pfizer); ribociclib (KISQALI®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).
[00343] In some embodiments, one or more other therapeutic agent is a phosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, a PI3K inhibitor is selected from idelalisib (ZYDELIG®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).
[00344] In some embodiments, one or more other therapeutic agent is a platinum-based therapeutic, also referred to as platins. Platins cause cross-linking of DNA, such that they inhibit DNA repair and/or DNA synthesis, mostly in rapidly reproducing cells, such as cancer cells. In some embodiments, a platinum-based therapeutic is selected from cisplatin (PLATINOL®, Bristol-Myers Squibb); carboplatin (PARAPLATIN®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (ELOXITIN® Sanofi -Aventis); nedaplatin (AQUPLA®, Shionogi), picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).
[00345] In some embodiments, one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some embodiments, a taxane compound is selected from paclitaxel (TAXOL®, Bristol-Myers Squibb), docetaxel (TAXOTERE®, Sanofi-Aventis; DOCEFREZ®, Sun Pharmaceutical), albumin-bound paclitaxel (ABRAXANE®; Abraxis/Celgene), cabazitaxel (JEVTANA®, Sanofi -Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).
[00346] In some embodiments, one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.
[00347] In some embodiments, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, YONDELIS®, Janssen Oncology), mechlorethamine (alkylating agent, VALCHLOR®, Aktelion Pharmaceuticals); vincristine (ONCOVIN®, Eli Lilly; VINCASAR®, Teva Pharmaceuticals, MARQIBO®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4-carboxamide (MTIC) TEMODAR®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CEENU®, Bristol-Myers Squibb; GLEOSTINE®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, VIDAZA®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, SYNRIBO®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, ELSPAR®, Lundbeck; ERWINAZE®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, HALAVEN®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, JEVTANA®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, XELODA®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, TREANDA®, Cephalon/Teva); ixabepilone (semi-synthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, IXEMPRA®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, ARRANON®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, CLOLAR®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine- based nucleoside analog and thymidine phosphorylase inhibitor, LONSURF®, Taiho Oncology). [00348] In some embodiments, one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present disclosure include: bevacizumab (AVASTIN®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (CYRAMZA®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (ZALTRAP®; Regeneron/Sanofi). VEGFR inhibitors, such as regorafenib (STIVARGA®, Bayer); vandetanib (CAPRELSA®, AstraZeneca); axitinib (INLYTA®, Pfizer); and lenvatinib (LENVIMA®, Eisai); Raf inhibitors, such as sorafenib (NEXAVAR®, Bayer AG and Onyx); dabrafenib (TAFTNLAR®, Novartis); and vemurafenib (ZELBORAF®, Genentech/Roche); MEK inhibitors, such as cobimetanib (COTELLIC®, Exelexis/Genentech/Roche); trametinib (MEKINIST®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (GLEEVEC®, Novartis); nilotinib (TASIGNA®, Novartis); dasatinib (SPRYCEL®, BristolMyersSquibb); bosutinib (BOSULIF®, Pfizer); and ponatinib (INCLUSIG®, Ariad Pharmaceuticals); EIer2 and EGFR inhibitors, such as gefitinib (IRESSA®, AstraZeneca); erlotinib (TARCEEVA®, Genentech/Roche/Astellas); lapatinib (TYKERB®, Novartis); afatinib (GILOTRIF®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca); and brigatinib (ALUNBRIG®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (COMETRIQ®, Exelexis); and multikinase inhibitors, such as sunitinib (SUTENT®, Pfizer); pazopanib (VOTRIENT®, Novartis); ALK inhibitors, such as crizotinib (XALKORI®, Pfizer); ceritinib (ZYKADIA®, Novartis); and alectinib (ALECENZa®, Genentech/Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (IMBRUVICA®, Pharmacyclics/Janssen); and Flt3 receptor inhibitors, such as midostaurin (R YD APT®, Novartis).
[00349] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present disclosure include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (SUPECT®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (JAKAFI®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib ( Amgen/T akeda) .
[00350] In some embodiments, one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (AFINITOR®, Novartis); temsirolimus (TORISEL®, Pfizer); and sirolimus (RAPAMUNE®, Pfizer).
[00351] In some embodiments, one or more other therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present disclosure include bortezomib (VELCADE®, Takeda); carfilzomib (KYPROLIS®, Amgen); and ixazomib (NINLARO®, Takeda). [00352] In some embodiments, one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present disclosure include olaratumab (LARTRUVO®; Eli Lilly). Approved EGFR antagonists which may be used in the present disclosure include cetuximab (ERBITUX®, Eli Lilly); necitumumab (PORTRAZZA®, Eli Lilly), panitumumab (VECTIBIX®, Amgen); and osimertinib (targeting activated EGFR, TAGRISSO®, AstraZeneca).
[00353] In some embodiments, one or more other therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (AROMASIN®, Pfizer); anastazole (ARIMIDEX®, AstraZeneca) and letrozole (FEMARA®, Novartis).
[00354] In some embodiments, one or more other therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present disclosure include sonidegib (0D0MZ0®, Sun Pharmaceuticals); and vismodegib (ERIVEDGE®, Genentech), both for treatment of basal cell carcinoma.
[00355] In some embodiments, one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present disclosure include pemetrexed (ALIMTA®, Eli Lilly).
[00356] In some embodiments, one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present disclosure include mogamulizumab (POTELIGEO®, Kyowa Hakko Kirin, Japan).
[00357] In some embodiments, one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present disclosure include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).
[00358] In some embodiments, one or more other therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may be used in the present disclosure include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences). [00359] In some embodiments, one or more other therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present disclosure include CB-839 (Calithera Biosciences).
[00360] In some embodiments, one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present disclosure include rituximab (RITUXAN®, Genentech/Biogenldec); ofatumumab (anti-CD20, ARZERRA®, GlaxoSmithKline), obinutuzumab (anti-CD20, GAZYVA®, Genentech), ibritumomab (anti- CD20 and Yttrium-90, ZEVALIN®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, DARZALEX®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, UNITUXIN®, United Therapeutics); trastuzumab (anti-HER2, HERCEPTIN®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, KADCYEA®, Genentech); and pertuzumab (anti-HER2, PERJETA®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, ADCETRIS®, Seattle Genetics).
[00361] In some embodiments, one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present disclosure include irinotecan (ONIVYDE®, Merrimack Pharmaceuticals); topotecan (HYCAMTIN®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present disclosure include pixantrone (PIXUVRI®, CTI Biopharma).
[00362] In some embodiments, one or more other therapeutic agent is an inhibitor of anti- apoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present disclosure include venetoclax (VENCLEXTA®, AbbVie/Genentech); and blinatumomab (BLINCYTO®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present disclosure include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).
[00363] In some embodiments, one or more other therapeutic agent is an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present disclosure include enzalutamide (XTANDI®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, FIRMAGON®, Ferring Pharmaceuticals). [00364] In some embodiments, one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present disclosure include raloxifene (EVISTA®, Eli Lilly).
[00365] In some embodiments, one or more other therapeutic agent is an inhibitor of bone resorption. An approved therapeutic which inhibits bone resorption is Denosumab (XGEVA®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases. Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).
[00366] In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present disclosure include ALRN- 6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).
[00367] In some embodiments, one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGF13). Inhibitors of TGF-beta proteins being studied which may be used in the present disclosure include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) IntT J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PD- Ll/TGFB trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgGl antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGF|3“trap .” [00368] In some embodiments, one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti -gly coprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.
[00369] In some embodiments, one or more other therapeutic agents is an antiproliferative compound. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17- DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, TEMODAL CNF 1010, CNF2024, CNF 1010 from Conforma Therapeutics; temozolomide (TEMODAL®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZde244 from AstraZeneca, PD181461 from Pfizer and leucovorin.
[00370] The term “aromatase inhibitor” as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name AROMASIN™. Formestane is marketed under the trade name LENTARON™. Fadrozole is marketed under the trade name AFEMA™. Anastrozole is marketed under the trade name ARTMTDEX™ Letrozole is marketed under the trade names FEMARA™ or FEMAr™. Aminoglutethimide is marketed under the trade name ORIMETEN™. A combination of the disclosure comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.
[00371] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name NOLVADEX™. Raloxifene hydrochloride is marketed under the trade name EVISTA™. Fulvestrant can be administered under the trade name FASLODEX™. A combination of the disclosure comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.
[00372] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (CASODEX™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name ZOLADEX™.
[00373] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g., in the form as it is marketed, e.g., under the trademark CAMPTOSAR™. Topotecan is marketed under the trade name HYCAMPTIN™.
[00374] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as CAELYX™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name ETOPOPHOS™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name ACRIBLASTIN™ or ADRIAMYCIN™. Epirubicin is marketed under the trade name FARMORUBICINTM. Idarubicin is marketed, under the trade name ZAVEDOS™. Mitoxantrone is marketed under the trade name NOVANTRON™. [00375] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name TAXOL™ Docetaxel is marketed under the trade name TAXOTERE™. Vinblastine sulfate is marketed under the trade name VINBLASTIN R.P™. Vincristine sulfate is marketed under the trade name FARMISTIN™.
[00376] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name CYCLOSTIN™. Ifosfamide is marketed under the trade name HOLOXAN™
[00377] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).
[00378] The term "antineoplastic antimetabolite" includes, but is not limited to, 5 -fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name XELODA™. Gemcitabine is marketed under the trade name GEMZAR™.
[00379] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATIN™.
[00380] The term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB- 111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factorreceptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor T (TGF-TR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin- dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (GLEEVEC™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490, Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4- {[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFRi ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (HERCEPTIN™), cetuximab (ERBITUX™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, El.l, E2.4, E2.5, E6.2, E6.4, E2.l l, E6.3 or E7.6.3, and 7H- pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-IAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PB 1-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).
[00381] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3 -kinase family, including, but not limited to PI3Ka, PI3Ky, PI3K5, PI3K , PI3K-C2a, PI3K-C2 , PI3K- C2y, Vps34, pl lO-a, pl 10-p, pl lO-y, pl 10-8, p85-a, p85-P, p55-y, pl50, pl 01, and p87. Examples of PI3K inhibitors useful in this disclosure include but are not limited to ATU-027, SF-1126, DS- 7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.
[00382] The term “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see W02008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see W02004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ, of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.
[00383] The term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.
[00384] The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT- 062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.
[00385] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this disclosure can be found in W02008039218 and WO2011090760, the entirety of which are incorporated herein by reference.
[00386] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this disclosure can be found in W02003063794, W02005007623, and W02006078846, the entirety of which are incorporated herein by reference. [00387] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this disclosure can be found in W02004019973, W02004089925, W02007016176, US8138347, W02002088112, W02007084786,
W02007129161, W02006122806, W02005113554, and W02007044729 the entirety of which are incorporated herein by reference.
[00388] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this disclosure can be found in W02009114512, W02008109943, W02007053452, W02000142246, and W02007070514, the entirety of which are incorporated herein by reference.
[00389] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. , unrelated to protein or lipid kinase inhibition e.g. , thalidomide (THALOMID™) and TNP-470.
[00390] Examples of proteasome inhibitors useful for use in combination with compounds of the disclosure include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708. [00391] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.
[00392] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- y- or 8- tocopherol or a- y- or 8-tocotrienol.
[00393] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (CELEBREX™), rofecoxib (VIOXX™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.
[00394] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name DIDRONEL™. Clodronic acid is marketed under the trade name BONEFOS™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name AREDIA™. Alendronic acid is marketed under the trade name FOSAMAX™. Ibandronic acid is marketed under the trade name BONDRANAT™. Risedronic acid is marketed under the trade name ACTONEL™. Zoledronic acid is marketed under the trade name ZOMETA™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (RAPAMUNE®), everolimus (CERTICAN™), CCI-779 and ABT578.
[00395] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.
[00396] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "famesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (ZARNESTRA™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin. [00397] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.
[00398] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (VELCADE™) and MLN 341.
[00399] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g., hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.
[00400] The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-P-D-arabinofuransyl cytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.
[00401] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.
[00402] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.
[00403] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (HERCEPTIN™), Trastuzumab-DMl, erbitux, bevacizumab (AVASTIN™), rituximab (RITUXAN®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity. [00404] For the treatment of acute myeloid leukemia (AML), compounds of the current disclosure can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current disclosure can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
[00405] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2 -alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HD AC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-lH-indol-3-yl)-ethyl]- amino]methyl]phenyl]- 2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2- hydroxyethyl){2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1 , pp. 248-275 (1993). [00406] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5 -fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.
[00407] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; ANGIOSTATIN™; ENDOSTATIN™; anthranilic acid amides; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (AVASTIN™).
[00408] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as VISUDYNE™ and porfimer sodium.
[00409] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.
[00410] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.
[00411] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.
[00412] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g., Patents International (e.g., IMS World Publications).
Exemplary Immuno-Oncology agents
[00413] In some embodiments, one or more other therapeutic agent is an immuno-oncology agent. As used herein, the term “an immuno-oncology agent” refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject. In some embodiments, the administration of an immuno-oncology agent with a compound of the disclosure has a synergic effect in treating a cancer.
[004141 An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human.
[00415] In some embodiments, an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a co- inhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses. [00416] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/ Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI/TL I A, TRAMP/DR3, EDAR, EDAI, XEDAR, EDA2, TNFR1, Lymphotoxin a/TNFP, TNFR2, TNFot, LTPR, Lymphotoxin aip2, FAS, FASL, RELT, DR6, TROY, NGFR.
[00417] In some embodiments, an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL- 10, TGF-P, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.
[00418] In some embodiments, a combination of a compound of the disclosure and an immuno- oncology agent can stimulate T cell responses. In some embodiments, an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM- 4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, TCOS-L, 0X40, OX40L, GTTR, GITRL, CD70, CD27, CD40, DR3 and CD28H.
[004191 In some embodiments, an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonists of activating receptors on NK cells. In some embodiments, an immuno-oncology agent is an antagonist of KIR, such as lirilumab.
[00420] In some embodiments, an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).
[00421] In some embodiments, an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.
[00422] In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.
[00423] In some embodiments, an immuno-oncology agent is a PD-1 antagonist. In some embodiments, a PD-1 antagonist is administered by infusion. In some embodiments, an immuno- oncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In some embodiments, an immuno-oncology agent may be pidilizumab (CT- 011). In some embodiments, an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP -224. [00424] In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Tn some embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS- 936559 (W02007/005874), and MSB0010718C (WO2013/79174).
[00425] In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. In some embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, a LAG3 antibody is BMS-986016 (W010/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).
[00426] In some embodiments, an immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, a CD137 antibody is urelumab or PF-05082566 (WO12/32433).
[00427] In some embodiments, an immuno-oncology agent is a GITR agonist In some embodiments, a GITR agonist is an agonistic GITR antibody. In some embodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (W0006/105021, WG009/009116), or MK- 4166 (WO 11/028683).
[00428] In some embodiments, an immuno-oncology agent is an indoleamine (2,3)- dioxygenase (IDO) antagonist. In some embodiments, an IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (W009/73620, WO009/1156652, WO11/56652, WO12/142237).
[00429] In some embodiments, an immuno-oncology agent is an 0X40 agonist. In some embodiments, an 0X40 agonist is an agonistic 0X40 antibody. In some embodiments, an 0X40 antibody is MEDL6383 or MEDI-6469.
[00430] In some embodiments, an immuno-oncology agent is an OX40L antagonist. In some embodiments, an OX40L antagonist is an antagonistic 0X40 antibody. In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).
[00431] In some embodiments, an immuno-oncology agent is a CD40 agonist. In some embodiments, a CD40 agonist is an agonistic CD40 antibody. In some embodiments, an immuno- oncology agent is a CD40 antagonist. Tn some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab.
[004321 In some embodiments, an immuno-oncology agent is a CD27 agonist. In some embodiments, a CD27 agonist is an agonistic CD27 antibody. In some embodiments, a CD27 antibody is varlilumab.
[00433] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO 11/109400).
[00434] In some embodiments, an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.
[00435] In some embodiments, an immuno-oncology agent is an immunostimulatory agent. For example, antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumor- reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou e/c//. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti -angiogenic therapy.
[00436] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be used in the present disclosure include pomalidomide (POMALYST®, Celgene); lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEO Pharma).
[00437] In some embodiments, an immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex/ Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, an immuno-oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (REOLYSIN®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS -activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCTO 1166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GL- ONC1 (GLV-lh68/GLV-lhl53, Genelux GmbH), vaccinia viruses engineered to express betagalactosidase (beta-gal)/beta-glucoronidase or beta-gal/human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).
[004381 In some embodiments, an immuno-oncology agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5- fluorocytosine to the cytotoxic drug 5 -fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3-E2F-delta24-hTNFa-IRES- hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8+ T cell response. [00439] In some embodiments, an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR. The T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.
[00440] CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex.
[00441] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June et al , hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD 19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD 19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently in progress employing CAR-T in a wide range of indications. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=l].
[00442] In some embodiments, an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor y (RORyt). RORyt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Thl7) and CD8+ (Tcl7) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells. In some embodiments, an activator of RORyt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).
[00443] In some embodiments, an immunostimulatory agent is an agonist or activator of a tolllike receptor (TLR). Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 which may be used in the present disclosure include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).
[004441 Other immuno-oncology agents that can be used in the present disclosure include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol- Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (ZPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti -KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.
[00445] In some embodiments, an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORyt.
[00446] In some embodiments, an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453). In some embodiments, an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, an IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/ Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the soluble IL- 15 binding protein IL- 15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.
[00447] In some embodiments, an immuno-oncology agent is selected from those descripted in Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages 603-622, the content of which is incorporated herein by refenrece in its entirety. In some embodimetne, an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams el al. In some embodiments, an immuno-oncology agent is a small molecule targeting an immuno-oncoloby target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, an immuno-oncology agent is a small molecule agent selectd from those listed in Table 2 of Jerry L. Adams et al. [00448] In some embodiments, an immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the content of which is incorporated herein by refenrece in its entirety. In some embodiments, an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.
[00449] In some embodiments, an immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BITE® ) antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390, the conten of which is incorporated herein by reference in its entirety. In some embodiments, an immuno-oncology agent is a bispecific T cell engager (BITE®) antibody construct. In some embodimens, a bispecific T cell engager (BITE®) antibody construct is a CD19/CD3 bispecific antibody construct. In some embodimens, a bispecific T cell engager (BITE®) antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodimens, a bispecific T cell engager (BITE®) antibody construct activates T cells which result in induced bystander cell lysis. In some embodiments, the bystander cells are in solid tumors. In some embodiments, the bystander cells being lysed are in proximity to the BITE®-acticvated T cells. In some embodiment, the bystander cells comprise tumor-associated antigen (TAA) negatgive cancer cells. In some embodiment, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, an immuno- oncology agent is an antibody which blocks the PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncology agent is an ex vivo expanded tumor-infdtrating T cell. In some embodiments, an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs).
Exemplary Immune Checkpoint Inhibitors
[00450] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein. [00451] The term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient. One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.
[00452] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.
[00453] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti -tumor immune response.
[00454] In some embodiments, the checkpoint inhibitor is a biologic therapeutic or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In some embodiments, the interleukin is IL-7 or IL- 15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.
[00455] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors can include small molecule inhibitors or can include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7- H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, y5, and memory CD8+ (( 3) T cells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7- H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS- 936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7- H4, CD28, CD86 and TIM-3.
[00456] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-Ll antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (OPDIVO®), ipilimumab (YERVOY®), and pembrolizumab (KEYTRUDA®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, OPDIVO®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, KEYTRUDA®, Merck); ipilimumab (anti-CTLA-4 antibody, YERVOY®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, EMFINZI®, AstraZeneca); and atezolizumab (anti-PD-Ll antibody, TECENTRIQ®, Genentech).
[00457] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (KEYTRUDA®), and tremelimumab. [00458] In some embodiments, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT- 011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (BAVENCIO®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).
[00459] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the present disclosure include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti- TIM-3 antibody which is being studied in advanced malignancies (NCT02608268).
[00460] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that may be used in the present disclosure include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428) [00461] In some embodiments, a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be used in the present disclosure include BMS- 986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).
[00462] Checkpoint inhibitors that can be used in the present disclosure include 0X40 agonists. 0X40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MED 10562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol- Myers Squibb) an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475).
[00463] Checkpoint inhibitors that can be used in the present disclosure include CD137 (also called 4-1BB) agonists. CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody in metastatic or locally advanced malignancies (NCT03881488).
[00464] Checkpoint inhibitors that can be used in the present disclosure include CD27 agonists. CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038). [00465] Checkpoint inhibitors that can be used in the present disclosure include glucocorticoid- induced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgGl Fc domain, in advanced solid tumors (NCT02583165). [00466] Checkpoint inhibitors that can be used in the present disclosure include inducible T- cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists that are being studied in clinical trials include MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).
[00467] Checkpoint inhibitors that can be used in the present disclosure include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti -KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045). [00468] Checkpoint inhibitors that can be used in the present disclosure include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgGl, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 and NCT02663518); CC- 90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc ), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509).
[004691 Checkpoint inhibitors that can be used in the present disclosure include CD73 inhibitors. CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).
[00470] Checkpoint inhibitors that can be used in the present disclosure include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). Agonists of STING that are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU- S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).
[00471] Checkpoint inhibitors that can be used in the present disclosure include CSF1R inhibitors. CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-lR antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((lR,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2- carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).
[00472] Checkpoint inhibitors that can be used in the present disclosure include NKG2A receptor inhibitors. NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH220I, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).
[00473] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.
[00474] In order that the disclosure described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any manner. EXEMPLIFICATION
[004751 As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
General Procedures
X-ray Powder Diffraction (XRPD)
[00476] XRPD patterns were collected using a PANalytical XPert Pro or Empyrian diffractometer. The specimen was analyzed using Cu radiation produced using an Optix long fine- focus source. An elliptically graded multilayer mirror was used to focus the Cu Ka X-rays of the source through the specimen and onto the detector. The specimen was sandwiched between 3- micron thick films, analyzed in transmission geometry, and rotated parallel to the diffraction vector to optimize orientation statistics. A beam-stop and helium purge was used to minimize the background generated by air scattering. Soller slits were used for the incident and diffracted beams to minimize axial divergence. Diffraction patterns were collected using a scanning positionsensitive detector (X'Celerator) located 240 mm from the specimen. The data- acquisition parameters of each diffraction pattern are displayed above the image of each pattern in the data section. Prior to the analysis a silicon specimen (NIST standard reference material 640c) was analyzed to verify the position of the silicon 111 peak.
[00477] Alternatively, PXRD was carried out via Bruker D8 XRD. Approximately 2-50 mg of material (pending the availability of sample amount) was transferred to a zero background sample holder coated with a thin layer of petroleum jelly and leveled with a glass plate. Samples were characterized via reflectance geometry. The following table 10 describes experimental parameters.
Table 10.
Figure imgf000105_0001
Differential Scanning Calorimetry (DSC)
[00478] DSC was carried out via TA Instruments DSC Q2000 V24. l l Build 124. Approximately 2mg to 6mg of sample was weighed into Aluminum hermetically sealed pans. Samples were heated at a ramp rate of 10°C/min under a Nitrogen atmosphere. Initial and final temperature ranges varied by experiment; generally samples were ramped from 25°C to approximately 250°C. Specific initial and final temperatures for individual experiments are visible in DSC thermograms.
Thermogravimetric (TG) Analysis
[00479] TG analyses were performed using a TA Instruments thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel™ Each sample was placed in a platinum pan. The sample was hermetically sealed, the lid pierced, then inserted into the TG furnace. The furnace was heated under nitrogen. The data acquisition parameters are displayed in the image of each thermogram. The method code on the thermogram is an abbreviation for the start and end temperature as well as the heating rate; e.g., 00-350-10 means "from ambient to 350 °C, at l0 °C/min".
[00480] Alternatively, TGA was carried out via TA Instruments TGA Q50 V20.13 Build 39. Approximately 2-8mg of sample was placed onto a platinum pan. Samples were heated at a ramp rate of 10°C/min from 25°C to 35O°C under a Nitrogen atmosphere. Nuclear Magnetic Resonance (NMR) Spectroscopy
[00481] The solution 1H NMR spectra were acquired at ambient temperature with a Varian UNITYINOVA- 400 spectrometer. The samples were dissolved in DMSO-d6. The residual peak from incompletely deuterated DMSO is at approximately 2.50 ppm. The spectra were referenced to internal tetramethylsilane (TMS) at 0.0 ppm.
[00482] Alternatively, Proton (XH) NMR spectra were obtained on 400 MHz Bruker spectrometer. Chemical shifts are expressed in parts per million (ppm) downfield from tetramethylsilane and referenced to D SO-t/6 as an internal reference. Commercially available deuterated solvent ampoules were obtained from Cambridge Isotope Laboratories, Inc.
Primary Salt Screening
[00483] Salt screening experiments were conducted using eight (8) acid salt formers, with a variety of crystallization techniques (cooling, slurrying, evaporation, and vapor diffusion) being employed. The experimental details for each salt forming attempt are described in Table 11.
Table 11. Salt Screening Experiments
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0002
1 (X:Y) = Compound A:acid molar ratio
Example A - General Preparation of Compound A
Figure imgf000110_0001
[00484] The title compound was prepared according to the steps and intermediates described below.
Synthesis of compound 2. no
Figure imgf000111_0001
1 2
[00485] Two reactions were carried out in parallel. To a solution of compound 1 (900 g, 3.29 mmol) in THF (3.60 L) was added MeNFL (685 g, 6.62 mol, 30% purity,) dropwise at 0 °C and stirred at 25 °C for 1 hr. TLC (Petroleum ether : Ethyl acetate = 3 : 1, Rr = 0.3) showed the starting material was consumed completely. Combine two reactions for work up. The reaction mixture was quenched by HC1 (2000 mb, 1 M), extracted with EtOAc (500 mb). The combined organic layers were washed with brine (500 mb), dried over JSfeSCb, filtered and concentrated under reduced pressure to give compound 2 (1.8 kg, crude) as a gray solid.
Synthesis of compound 3.
Figure imgf000111_0002
2 3
[00486] Three reactions were carried out in parallel. To a solution of compound 2 (600 g, 2.24 mol) in DMSO (3.00 L) was added compound 2B (470 g, 2.69 mol, 382 mL) and DIEA (347 g, 2.69 mol, 468 mL). The mixture was stirred at 140 °C for 12 hrs. HPLC (ET39195-5-P1A1, product: RT = 3.489 min, starting material: RT = 2.439 min) showed the startig material was consumed completely. Combine three reactions for work up.
The reaction mixture was poured into water (5.00 L), extracted with EtOAc (3.00 L, 2.00 L). The combined organic layers were washed with water (300 mL), brine (300 mL), dried over NazSO-i, filtered and concentrated under reduced pressure. The crude product was triturated with isopropylether : n-heptane = 1:5 (12.0 L) at 25 °C for 30 min to give compound 3 (2.80 kg, crude) as a white solid. Synthesis of compound 4.
Figure imgf000112_0001
[00487] Six reactions were earned out in parallel. To a solution of compound 3 (347 g, 820 mmol) in dioxane (2.43 L,7V) was added KOAc (161 g, 1.64 mol), BPD (417 g, 1.64 mol). Then the suspension was degassed with N2 three times and then Pd(PPh3)2C12 (28.8 g, 41.0 mmol) was added. After addition, the suspension was degassed with N2 three times again and then heated to 75 °C stirred for 16 hrs under N2. LCMS (ET39195-13- P1B3, product: RT = 2.977 min, starting material: RT = 3.024 min) showed the starting material was consumed completely. The six reactions were combined for work up. The solvent was removed and the residue was treated with water (5.00 L), extracted with EtOAc (5.00 L, 3.00 L). The combined organic layers were washed with brine (2.00 L), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Then the residue was triturated with n-heptane : isopropyl ether = 1: 1 (10.0 L) for 1 hr at 0 - 10 °C to give 450 g of compound 4. Meanwhile, the mother liquor was purified by column chromatography (SiO2, n-heptane : Ethyl acetate = 50 : 1 to 0 : 1) to give 690 g of compound 4 as a white solid.
Synthesis of Compound A
Figure imgf000113_0001
[00488] To a solution of compound 4 (240 g, 510 mmol, 1 eq) in DMF (1.44 L), H2O (280 mL) was added 4-iodo-l-methyl-imidazole (127 g, 612 mmol, 1 .2 eq) K2CO3 (212 g, 1 .53 mol, 3 eq), Pd(dtbpf)C12 (16.6 g, 25.5 mmol, 0.05 eq at 20 °C under N2. After addition, the suspension was heated to 100 °C and stirred for 5 hrs at 100 °C. TLC (Petroleum ether: ethyl acetate = 1: 1, product: Rf = 0.5) showed that the starting material was consumed completely. Water (2.80 L) was added to the suspension at 20-30 °C. Then the mixture was extracted with EtOAc (3.00 L, 2.00 L). All of the organic phase was combined, which was washed with brine (2.00 L), and concentrated to give the crude product. The crude product was added to MeOH (500 mL) and stirred for 1 hr at 20 °C. Then the suspension was fdtered and collected the product as white solid. Then, the filter cake was dissolved by DCM (3.20 L) and stirred for 2 hrs at 40 °C.
Finally, the solution was concentrated to remove most of solvent and filtered to give Compound A (135 g, 318 mmol, 62.3% yield) as a white solid, which was characterized as predominantly Form B.
Example 1 - Preparation of Free Base Forms A and B of Compound A
Figure imgf000113_0002
Form A of Compound A [0001] Form A of compound A was prepared as described above.
[0002] Compound A (8.6 kg) was dissolved in acetone (141 kg) and circulated through a cartridge of SiliaThiol. Combined with acetone rinse (5 kg), the solution was distilled to 86 L (at jacket temperature NMT 55 °C), added ethanol (102 kg), distilled to 86 L (at jacket temperature NMT 55 °C), added ethanol (68 kg), distilled to 86 L, added ethanol (68 kg), distilled to 86 L(at jacket temperature NMT 55 °C), stirred at room temperature for at least 4 hrs and fdtered. The solid was rinsed with ethanol (34 L) and dried at not more than 45 C, yielding the final product (6.65 kg, Form A as determined by XRPD).
[0003] Table 1, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound A.
Table 1 - XRPD Peak Positions for Form A of Compound A
Figure imgf000114_0001
Figure imgf000115_0001
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[0004] FIG. 1 depicts an XRPD pattern of Form A of compound A.
[0005] FIG. 2 depicts a TGA/DTA trace of Form A of compound A.
Form B of Compound A
[0006] Form B of compound A was prepared as described above.
[0007] Compound A (2.8 kg) was dissolved in acetone (28 L), filtered through celite, rinsed with acetone (1-2 L), treated with SiliaThiol, filtered, and rinsed with acetone (2 L) at room temperature. The filtrate is added water (56 L) and stirred for 2 hrs at room temperature. The mixture was charged with additional water (56 L) and stirred (overnight) at room temperature and filtered. The solid was rinsed with water (15 L) and dried in oven at 45 °C, yielding the final product (2.4 kg, Form B as determined by XRPD).
[0008] Table 2, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form C of compound A.
Table 2 - XRPD Peak Positions for Form B of Compound A
Figure imgf000116_0001
Figure imgf000117_0002
1 In this and all subsequent tables, the position 20 is within ± 0.2.
[0009] FIG. 3 depicts an XRPD pattern of Form B of compound A.
[0010] FIG. 4 depicts a TGA/DSC trace of Form B of compound A.
Example 2 - Preparation of Forms A and B of Compound 1
Figure imgf000117_0001
Form A of Compound 1
[0011] Form A of compound 1 was prepared as described above.
[0012] Table 3, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 1.
Table 3 - XRPD Peak Positions for Form A of Compound 1
Figure imgf000117_0003
Figure imgf000118_0001
[0013] FIG. 7 depicts an XRPD pattern of Form A of compound 1.
[0014] FIG. 8 depicts a TGAZDSC trace of Form A of compound 1.
Form B of Compound 1
[0015] Form B of compound 1 was prepared as described above. [0016] Table 4, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form B of compound 1.
Table 4 - XRPD Peak Positions for Form B of Compound 1
Figure imgf000119_0002
[0017] FIG. 9 depicts an XRPD pattern of Form B of compound 1 with trace amount Form A. [0018] FIG. 10 depicts a TGA/DSC trace of Form B of compound 1 with trace amount Form
Example 3 - Preparation of Form A of Compound 2
Figure imgf000119_0001
Form A of Compound 2 [0019] Form A of compound 2 was prepared as described above.
[0020] Table 5, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 2.
Table 5 - XRPD Peak Positions for Form A of Compound 2
Figure imgf000120_0002
[0021] FIG. 11 depicts an XRPD pattern of Form A of compound 2.
[0022] FIG. 12 depicts a TGA/DSC trace of Form A of compound 2.
Example 4 - Preparation of Form A of Compound 3
Figure imgf000120_0001
Form A of Compound 3
[0023] Form A of compound 3 was prepared as described above. [0024] Table 6, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 3.
Table 6 - XRPD Peak Positions for Form A of Compound 3
Figure imgf000121_0002
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[0025] FIG. 13 depicts an XRPD pattern of Form A of compound 3.
[0026] FIG. 14 depicts a TGA/DSC trace of Form A of compound 3.
Example 5 - Preparation of Form A of Compound 4
Figure imgf000121_0001
Form A of Compound 4
[0027] Form A of compound 4 was prepared as described above.
[0028] Table 7, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 4.
Table 7 - XRPD Peak Positions for Form A of Compound 4
Figure imgf000122_0001
1 In this and all subsequent tables, the position 26 is within ± 0.2.
[0029] FIG. 15 depicts an XRPD pattern of Form A of compound 4.
[0030] FIG. 16 depicts a TGA/DSC trace of Form A of compound 4.
Example 6 - Preparation of Form A of Compound 5
Figure imgf000123_0001
Form A of Compound 5
[0031] Form A of compound 5 was prepared as described above.
[0032] Table 8, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 5.
Table 8 - XRPD Peak Positions for Form A of Compound 5
Figure imgf000123_0002
Figure imgf000124_0002
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[0033] FIG. 17 depicts an XRPD pattern of Form A of compound 5.
[0034] FIG. 18 depicts a TGA/DSC trace of Form A of compound 5.
Example 7 - Preparation of Form A of Compound 6
Figure imgf000124_0001
6 wherein X is about 0.5, about 1, or about 2.
Form A of Compound 6
[0035] Form A of compound 6 was prepared as described above.
[0036] Table 9, supra, is reproduced below and sets forth the X-ray diffraction peaks observed for Form A of compound 6.
Table 9 - XRPD Peak Positions for Form A of Compound 6
Figure imgf000124_0003
Figure imgf000125_0001
1 In this and all subsequent tables, the position 29 is within ± 0.2.
[0037] FIG. 19 depicts an XRPD pattern of Form A of compound 6.
[0038] FIG. 20 depicts a TGA/DSC trace of Form A of compound 6.
Example 9 - Solubility Studies
[0039] Solubility of compound A was determined in various solvents as described below in Table 10.
Table 10- Solubility
Figure imgf000125_0002

Claims

CLAIMS We claim:
1. A solid form of Compound A:
Figure imgf000126_0001
2. The compound according to claim 1, wherein the compound is crystalline.
3. The compound according to claim 1, wherein the compound is a crystalline solid substantially free of amorphous compound A.
4. The compound according to claim 1, wherein the compound is substantially free of impurities.
5. The compound according to claim 1, wherein the compound is of Form A.
6. The compound according to claim 5, having one or more peaks in its XRPD selected from those at about 17.2 , about 19.2 and about 26.7 degrees 2-theta.
7. The compound according to claim 5, having at least two peaks in its XRPD selected from those at about 17.2 , about 19.2 and about 26.7 degrees 2-theta.
8. The compound according to claim 5, having an XRPD substantially similar to that depicted in FIG. 1.
9. The compound according to claim 1, wherein the compound is of Form B.
10. The compound according to claim 9, having one or more peaks in its XRPD selected from those at about 13.7, about 18.3 and about 19.8 degrees 2-theta.
11. The compound according to claim 9, having at least two peaks in its XRPD selected from those at about 13.7, about 18.3 and about 19.8 degrees 2-theta.
12. The compound according to claim 9, having an XRPD substantially similar to that depicted in FIG. 3.
13. A compound selected from:
Compound A:
Figure imgf000127_0001
of Form A or Form B;
Compound 1:
Figure imgf000127_0002
of Form A or Form B;
Compound 2:
Figure imgf000128_0004
2 of Form A;
Compound 3 :
Figure imgf000128_0001
of Form A;
Compound 4:
Figure imgf000128_0002
of Form A;
Compound 5:
Figure imgf000128_0003
5 of Form A; or Compound 6:
Figure imgf000129_0001
6 of Form A, wherein x is about 0.5, about 1, or about 2.
14. A pharmaceutical composition comprising a compound according to any one of claims 1- 13, and a pharmaceutically acceptable carrier, excipient, or vehicle.
15. A method for treating cancer in a patient, comprising administering to the patient a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14.
16. The method of claim 15, wherein the cancer is associated with increased TEAD expression.
17. The method of claims 15 or 16, wherein the cancer is associated with increased TEAD activity.
18. A method for inhibiting the progress of cancer in a patient, comprising administering to the patient a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14.
19. The method of claim 18, wherein the cancer is associated with increased TEAD expression.
20. The method of claims 18 or 19, wherein the cancer is associated with increased TEAD activity.
21 . A method of treating a patient having a disease or disorder associated with increased TEAD expression comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14.
22. A method of treating a patient having a disease or disorder associated with increased TEAD activity comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14.
23. A method of treating a disease or disorder in which inhibition of TEAD activity is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14.
24. A method of treating a disease or disorder in which Hippo pathway inhibition is beneficial comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 14.
25. The method of any one of claims 21-24, wherein the disease or disorder is a cellular proliferative disorder.
26. The method of claim 25, wherein the cellular proliferative disorder is cancer.
27. The method of any one of claims 15-20 and 26, wherein the cancer is a cancer in which YAP is localized in the nucleus of cells of the cancer.
28. The method of any one of claims 16, 17, and 19-23, wherein the increased TEAD expression or increased TEAD activity is increased TEAD1 expression or increased TEAD1 activity
29. The method of any one of claims 16, 17, and 19-23, wherein the increased TEAD expression or increased TEAD activity is increased TEAD2 expression or increased TEAD2 activity.
30. The method of any one of claims 16, 17, and 19-23, wherein the increased TEAD expression or increased TEAD activity is increased TEAD3 expression or increased TEAD3 activity.
31. The method of any one of claims 16, 17, and 19-23, wherein the increased TEAD expression or increased TEAD activity is increased TEAD4 expression or increased TEAD4 activity
32. The method of any one of claims 16, 17, and 19-23, wherein the increased TEAD expression or increased TEAD activity is increased TEAD1 expression or increased TEAD1 activity; increased TEAD2 expression or increased TEAD2 activity; increased TEAD3 expression or increased TEAD3 activity; increased TEAD4 expression or increased TEAD4 activity; or any combination thereof.
33. A method for preparing a salt compound of the formula X:
Figure imgf000131_0001
comprising steps of: combining A:
Figure imgf000132_0001
with an acid and optionally a solvent under conditions for forming a salt compound of formula X.
34. The method of claim 33, wherein:
(a) the suitable acid is maleic acid thereby forming a maleate salt of compound A and optionally crystallizing the mesylate salt to form Form A or Form B;
(b) the suitable acid is maleic acid thereby forming a hemi-maleate salt of compound A and optionally crystallizing the mesylate salt to form Form A;
(c) the suitable acid is methanesulfonic acid thereby forming a mesylate salt of compound A and optionally crystallizing the mesylate salt to form Form A;
(d) the suitable acid is p-toluenesulfonic acid thereby forming a tosylatye salt of compound A an optionally crystallizing the tosylate salt to form Form A;
(e) the suitable acid is p-toluenesulfonic acid thereby forming a bis-tosylate salt of compound A and optionally crystallizing the tartrate salt to form Form A; or
(f) the suitable acid is hydrochloric acid thereby forming an HC1 salt of compound A and optionally crystallizing HC1 oxalate salt to form Form A.
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